Колокольчик коерулус на перекрестке воспаления и нейродегенерации в множестве склерозов.

Introduction

Multiple sclerosis (MS) is increasingly seen as a disorder affecting distributed central nervous system (CNS) networks rather than just a focal white-matter (WM) demyelinating disease. Cortical and deep grey matter (GM) lesions, diffuse neurite injury, synapse loss, and GM atrophy are strongly linked to disability, depression, fatigue, and cognitive impairment. In this broader view, neuromodulatory brainstem nuclei, especially the locus coeruleus (LC), have gained attention as potential contributors to MS-related network dysfunction. The LC provides most of the brain’s noradrenergic (NAergic) input and regulates arousal, attention, stress responses, and mood. Beyond classical neurotransmission, noradrenaline (NA) restrains glial inflammatory activation, supports neurotrophic signaling, and limits oxidative stress through β-adrenergic receptor pathways [ 1 – 3 ]. Loss of LC neurons and reduced central NA levels are well characterized in Alzheimer’s disease (AD) and Parkinson’s disease (PD) [ 4 , 5 ]; animal studies in these diseases show that experimental LC lesion worsens pathology, whereas restoring NA levels confers benefit [ 6 , 7 ]. Comparable LC abnormalities with reduced NA are increasingly documented in MS [ 2 , 8 ].

In MS and experimental autoimmune encephalomyelitis (EAE), pathology in the LC and decreased NA levels were observed alongside increased glial activation, and showed only a weak association with focal plaque burden [ 8 ]. Structural and functional imaging studies also show disruption of monoaminergic pathways and changes in network connectivity, linking the LC and other brainstem nuclei to fatigue, slowed cognition, and selective attention deficits [ 9 – 12 ]. Furthermore, the LC’s proximity to blood vessels and its high neuromelanin content have led to the hypothesis that it may serve as an entry point for environmental toxic metals capable of triggering or worsening MS and other CNS disorders [ 13 , 14 ]. The exact causes of LC damage and NA depletion in MS are not fully understood and are likely to be multifactorial. Plausible contributors include loss of trophic support from widespread LC projection fields, disruption of the blood-brain barrier (BBB) and neurovascular unit, which may increase LC exposure to circulating inflammatory mediators and toxins, and intrinsic vulnerability conferred by dense vascularization, high metabolic demand, and the metal-binding capacity of neuromelanin-containing neurons.

While the importance of the LC-NA system in AD and PD has been documented for over 50 years [ 4 , 5 ], its role in the progression of MS has been comparatively less studied. To better understand how the LC-NA system influences MS, we review four related topics: (i) the biology and anti-inflammatory functions of the LC-NA system; (ii) evidence for LC and broader monoaminergic network involvement in MS; (iii) mechanisms that may underlie LC vulnerability, including toxicants and barrier dysfunction; and (iv) preclinical and clinical studies targeting the LC-NA axis. Finally, we propose a systems-level model linking brainstem vulnerability to neuroinflammation, demyelination, neuropsychiatric symptoms, and therapeutic opportunity in MS.

Biology of the LC-NA System

Anatomy, projections, and projection topography

Several reviews summarize the history of LC anatomy, its projections, and its functions [ 2 , 15 – 20 ]. In brief, the LC is a compact pontine nucleus located next to the fourth ventricle that contains tyrosine hydroxylase (TH)-positive NAergic neurons projecting throughout the brain and spinal cord. The LC was first described in the late eighteenth century by Félix Vicq d’Azyr [ 21 ] and was later described in the early nineteenth century in the human brain by Johann Christian Reil [ 22 ]. The area was named locus coeruleus in 1812 by Joseph and Karl Wenzel [ 23 ], based on its blue appearance; at the beginning of the twentieth century, it was termed the “nucleus pigmentosus pontis” because of the presence of melanin granules [ 24 ]. Early studies that relied on counting pigmented cells reported between 9,500 and 16,900 cells per LC side [ 25 – 27 ]. Subsequent staining for TH and dopamine β-hydroxylase (DBH) revealed between 45,000 and 60,000 total LC neurons in healthy adult humans [ 28 , 29 ], with approximately 1,500 in adult mice [ 30 , 31 ] and 3,600 in adult rats [ 32 , 33 ].

LC projections innervate cortical association areas, thalamus, cerebellum, limbic structures, brainstem autonomic nuclei, and the dorsal horn of the spinal cord. LC neurons also exhibit chemical heterogeneity. Quantitative analyses and three-dimensional reconstruction studies indicate that the LC is topographically organized, with partially segregated neuronal populations projecting to cortical, cerebellar, autonomic, and spinal targets [ 26 , 28 ]. Furthermore, in addition to classical NAergic transmission, LC neurons co-release neuropeptides, notably galanin, and potentially other modulators such as neuropeptide Y, enkephalins, and somatostatin within specific cellular subpopulations or circuit contexts [ 34 , 35 ]. These co-transmitters can influence stress responsiveness, inflammatory tone, and neuronal survival over timescales that differ from that of NA itself [ 36 ].

Although the LC is often treated as a homogeneous nucleus, genetic, molecular, anatomical, and electrophysiological studies show that it is organized into partially segregated modules [ 37 , 38 ]. Distinct, largely non-overlapping LC neurons preferentially innervate specific targets and possess distinct intrinsic properties, allowing targeted rather than purely global neuromodulation [ 37 , 38 ]. Projection-specific manipulations dissociate functions previously attributed to the LC as a whole; for example, spinal-projecting LC neurons mediate descending analgesia, whereas prefrontal-projecting neurons mediate aversion and anxiety-like behavior [ 37 ]. Specific neuronal subpopulations in the LC have been identified by a variety of techniques. These include viral tracing [ 39 ], electrophysiology, optogenetics and in situ hybridization [ 40 ], single-cell [ 35 , 41 ] and single-nuclear [ 42 ] RNA sequencing, as well as functional connectivity studies using fMRI in humans [ 43 ]. These methods have shown heterogeneity in LC neuropeptide and receptor expression, electrical waveform responses, age-related decreases in rostral LC connectivity [ 44 ], and selective responses to alpha2-adrenergic receptor activation [ 43 ]. Recent molecular analyses using single-cell (sc) or single-nucleus RNA sequencing (snRNAseq) provide evidence for LC neuronal subpopulations in both human [ 42 ] and mouse [ 35 , 41 ]. These findings have not only defined specific neuronal subtypes, but have also revealed heterogeneity of co-expressed neurotransmitters and their receptors within the same neurons, for example co-expression of cholinergic markers [ 42 ], and lack of co-expression of NPY but co-expression of galanin [ 35 ] in NAergic populations. Importantly, studies suggest that LC heterogeneity can influence neuronal vulnerability. As examples, tau accumulation in AD brains is greater in areas of the dorsal LC that preferentially project to AD-vulnerable regions such as HC and neocortex [ 45 ], and LC damage occurring in PD patients assessed by MRI shows a heterogeneous pattern of damage [ 46 ]. Altogether, the modularity within the LC may be directly relevant to MS since selective injury to specific LC subpopulations or projection modules could produce dissociable deficits in attention, mood, autonomic control, pain modulation, and anti-inflammatory regulation, helping to explain the clinical heterogeneity of LC-related symptoms.

Anti-inflammatory, neuroprotective, and myelinogenic properties of NA

A large body of literature demonstrates that activation of β-adrenergic receptors by NA increases intracellular cyclic adenosine monophosphate (cAMP), leading to protein kinase A (PKA)-mediated phosphorylation and activation of cAMP response element-binding protein (CREB), which initiates gene expression changes that suppress pro-inflammatory transcriptional programs [ 1 , 3 , 47 ]. Both in vitro and in vivo studies demonstrate that NA suppresses microglial and astrocytic production of pro-inflammatory cytokines, reduces inducible nitric oxide synthase expression, and protects neurons from excitotoxic injury. This has established the concept of the LC-NA system as an intrinsic anti-inflammatory circuit in the brain, in which endogenous NAergic tone acts as a central brake on neuroinflammatory responses; disruption of LC output is therefore be expected to remove this restraint and facilitate exaggerated glial activation and oxidative stress. NAergic activation of the cAMP/PKA/CREB pathway also engages neurotrophic signaling, promoting expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which support neuronal survival and limit amyloid and excitotoxic injury [ 48 , 49 ]. In addition, NA regulates astrocytic glutamate buffering that can reduce excitotoxic vulnerability in LC projection regions [ 50 , 51 ].

NA also has direct actions upon oligodendrocytes (OLGs) and OPCs. Early studies showed that NA stimulates phosphatidyl inositol hydrolysis in OLGs via activation of alpha1-adrenergic receptors (α1-ARs) [ 52 ]; that NA and directly beta-adrenergic receptor (β-AR) stimulation using isoproterenol reduced OPC proliferation but stimulated lineage progression [ 53 ]. More recent direct optogenetic studies demonstrate that LC-derived NA, acting primarily through α1 and β-ARs, drives arousal-locked calcium transients in cortical OPCs and directly stimulates their proliferation [ 54 , 55 ] implicating NA as a direct modulator of OPC calcium dynamics in vivo, with implications for remyelination capacity in demyelinating disease [ 54 , 56 , 57 ]. In contrast, it was reported that direct incubation of OLGs with NA induced toxicity [ 58 , 59 ] involving free radical production; however, that was reduced when co-cultured with astrocytes. Overall, these findings point to effects of NA on OPC proliferation; however, whether NA subsequently biases surviving OPCs toward terminal differentiation and myelination is less certain. Given the multiple consequences of reduced LC-NA output, spanning immune, glial, metabolic, vascular, and synaptic domains, the loss of β-AR restraint on glial cell activation, coupled with resultant declines in cAMP/PKA/CREB-dependent anti-inflammatory and neurotrophic transcription emerges as a likely driver of MS progression, as it simultaneously unleashes neuroinflammation and curtails OLG supportive signaling [ 60 – 62 ].

Locus coeruleus damage and monoaminergic network disconnection in MS

Preclinical biochemical evidence of LC-NA dysfunction

Substantial biochemical evidence indicates that the LC-NA system dysfunction develops dynamically during the course of EAE. Early studies reported that NA levels in cerebrospinal fluid and white matter were elevated before clinical signs appeared, but were reduced at later disease stages; NA levels were also lower in the brainstem and spinal cord of EAE rats compared to controls [ 63 – 65 ]. These early compensatory changes appear to be overtaken by progressive LC injury and impairment of the NA synthetic machinery, including TH and dopamine β-hydroxylase. We and others have similarly shown reduced NA levels in the spinal cord and frontal cortex of EAE mice, associated with atrophy and astrocyte activation of TH-positive LC neurons; these alterations occurred in the context of variable local demyelination and inflammatory infiltrates but did not scale directly with plaque burden, suggesting that LC dysfunction is not entirely explained by traditional lesion pathology [ 8 ].

In EAE, interventions targeting the LC modify the disease course. Treatment with vindeburnol, a vincamine derivative that enhances TH expression, reduces astrocyte activation, and supports LC neuron survival, improved clinical scores, reduced cerebellar demyelination, and increased spinal cord NA when administered after disease onset [ 7 ]. The NA-augmenting agent catalpol increased LC NA output, elevated spinal cord NA levels, and ameliorated EAE severity [ 66 ]. Combined treatment with the synthetic NA precursor L-DOPS and the reuptake inhibitor atomoxetine produced a substantially greater increase in central NA levels and a more pronounced reduction in disease severity than either agent alone, underscoring the importance of achieving sufficient central NAergic augmentation rather than simply blocking reuptake [ 6 ]. More recently, chemogenetic activation of LC NAergic neurons reduced demyelination and glial activation in the spinal cord and prefrontal cortex, with the greatest benefit when activation was initiated early in the disease course [ 67 ]. Taken together, these studies support the LC as an active regulator of CNS inflammation and tissue integrity, in which NAergic failure exacerbates demyelinating pathology, whereas restoration of LC function confers neuroprotection.

These preclinical findings can be integrated into a working model of LC-centered vulnerability in demyelinating disease (Fig. 1 ). Primary OLG stress, myelin breakdown, and glial activation may converge with LC neuronal stress and reduced TH-associated NAergic tone. Impaired LC-NA signaling in turn amplifies inflammatory signaling, oxidative stress, and deficient remyelination support across distributed projection territories, contributing to broader network instability and neuropsychiatric dysfunction.

Fig. 1 Proposed working model of the locus coeruleus (LC)-centered mechanistic cascade and relevance to Multiple Sclerosis. A Major LC projection territories. Sagittal schematic of the mouse brain showing the locus coeruleus (LC), which lies in the pons, and its principal projection targets, including the cortex (Ctx), hippocampus (HC), thalamus (Tha), hypothalamus (Hyp), and cerebellum (CB); corpus callosum (CC) and striatum. The inset shows double immunofluorescence of the LC region for tyrosine hydroxylase (TH, red), which labels noradrenergic neurons, and glial fibrillary acidic protein (GFAP, green), which labels astrocytes. B Cellular cascade of LC dysfunction in demyelinating pathology. A scheme to summarize experimentally observed and hypothesized interactions contributing to LC dysfunction in demyelinating pathology; it is provided as a working model for hypothesis generation. Early demyelination-associated changes (oligodendrocyte stress, myelin breakdown, and glial activation) are followed by secondary effects across LC projection regions (reduced trophic support, increased oxidative stress, and impaired glutamate homeostasis) and by downstream consequences of reduced LC-NA signaling (microglial priming, astrogliosis, and inflammatory amplification). These processes converge on proposed LC-centered changes, comprising LC neuronal stress and glial activation with reduced tyrosine hydroxylase (TH) expression and noradrenaline (NA) availability. The accompanying reduction in beta-adrenergic receptor (β-AR) and cAMP/CREB signaling releases the anti-inflammatory brake, and reduces trophic support normally provided by NA, which, together with elevated cytokines, promotes further oligodendrocyte stress, impaired oligodendrocyte precursor cell (OPC) support, reduced remyelination, and increased myelin breakdown, forming a self-amplifying loop. The convergent outcomes of the cascade are network instability, cognitive and affective dysfunction, and impaired repair capacity. Abbreviations : CREB, cAMP responsive element binding protein; NA, noradrenaline; OPC, oligodendrocyte progenitor cell; TH, tyrosine hydroxylase

Clinical and biochemical evidence of LC-NA dysfunction

Impaired LC-NA function is expected to blunt downstream cAMP/PKA/CREB signaling and the CREB-dependent transcription that supports neurotrophin expression, repair programs, and anti-inflammatory restraint, implicating that LC injury in MS has consequences beyond monoamine deficiency alone. Clinical studies support LC-NA dysregulation, although no single biochemical marker yet serves as a definitive surrogate of LC injury. Early cerebrospinal fluid studies found altered NA and metabolite levels; methoxy-hydroxyphenylglycol concentrations were inversely related to disease duration and relapse burden [ 68 , 69 ]. A multimodal strategy combining catecholamine metabolites, neuromelanin-sensitive LC imaging, spectroscopy, and tract-based structural or functional measures may therefore offer a more informative readout of LC integrity.

More recently, biochemical and molecular analyses have identified markers altered by LC stress and injury. In mice exposed to acute stress to increase LC release of NA, RNA-seq analysis identified a reproducible set of genes in the hippocampus (HC) altered by LC activation, many related to pathways involved in astrocyte energy metabolism [ 70 ]. Similarly, RNA-seq identified a large number of genes altered in the LC, but not the nucleus accumbens, following a prolonged stress model of PTSD; many of these were related to morphological changes, growth factors, brain development, and memory [ 71 ]. Whether any of these alterations cause associated systemic changes in gene expression and thus provide a biomarker for LC stress remains to be determined.

Monoaminergic tracts, connectivity, and fatigue

In addition to LC cell body damage, monoaminergic projection pathways are also affected in MS. Fixel-based analysis has shown reduced fiber density and cross-section within dopaminergic mesolimbic pathways, NAergic LC-to-prefrontal tracts, and serotonergic raphe-to-cerebellar projections in people with MS compared to healthy controls [ 9 ]. Axonal injury within mesocorticolimbic and LC-to-prefrontal tracts was associated with the severity of cognitive fatigue, supporting the notion that disruption of monoaminergic tracts contributes to central fatigue [ 10 ]. In a complementary resting-state fMRI study, reduced functional connectivity was observed between the VTA and default-mode network hubs, between the LC and right prefrontal cortex, and between raphe nuclei and the cerebellum in people with MS [ 9 ]. This pattern aligns with the known roles of these circuits in executive control, motivation, and affect, and matches the cognitive and mood symptoms commonly experienced in MS.

It has been reported that people with MS without self-reported cognitive fatigue show increased axial and radial diffusivity in fibers connecting the right posterior hypothalamus and the right LC, while those with fatigue do not exhibit this change and do not differ in lesion load or global atrophy. This pattern has been interpreted as a possible compensatory adaptation helping to maintain arousal by preventing excessive downregulation of wakefulness-related networks [ 12 ]. Reduced N-acetylaspartate/creatine (NAA/Cr) ratios in the right pontine LC region also predict selective auditory attention deficits in early RRMS, indicating that LC integrity has measurable functional consequences even when EDSS scores are low [ 11 ].

Infratentorial lesions and mood

Neuropsychiatric symptoms are common in MS, but their anatomical foundations are still not well understood. In a recent infratentorial lesion-mapping study, depression and anxiety were examined in relation to lesions in the raphe nuclei, the LC, and cerebellar lobule VIIA [ 72 ]. Depressive symptoms were significantly linked to lesions in both the raphe nuclei and the LC, while anxiety showed a possible trend-level association with LC lesions that did not reach standard statistical significance. These findings provide anatomical evidence that structural damage to brainstem monoaminergic nuclei increases vulnerability to mood disorders in MS, especially depression. Together, the evidence from neuropathology, molecular biology, toxicology, and structural and functional neuroimaging supports a multimodal model of LC-NA involvement in MS (Table 1 ).

Table 1 Multimodal evidence supporting involvement of the locus coeruleus-noradrenergic axis in multiple sclerosis Domain Specific Mechanism or Observation Key Findings & Anatomical Targets Clinical Relevance Ref Neuropathology Examination of MS autopsy tissue and EAE brains for LC pathology. Morphological alterations of TH + LC neurons, including hypertrophy and shrinkage. LC neuronal damage and gliosis occur independently of local white-matter plaque burden. Increased astrocytosis around LC neurons. Suggests LC injury as an independent contributor to MS neuropathology, not fully captured by plaque-based staging. [ 8 ] Molecular Biology NA activates β-ARs to suppress glial inflammatory activation. β-AR activation stimulates cAMP/CREB signaling. Suppression of pro-inflammatory cytokine production. Enhanced expression of neurotrophic factors. Identifies a druggable anti-inflammatory and neurotrophic pathway relevant to glial activation and repair in MS. [ 1 – 3 , 47 , 48 , 55 ] Toxicology LC neurons selectively accumulate heavy metals (‘heavy metal sink’ hypothesis). Selective accumulation of mercury, aluminum, and silver in LC neurons. Metals may increase LC neuronal vulnerability and potentially contribute to BBB dysfunction. Raises the possibility of environmental metal exposure as a modifiable risk factor for LC-related pathology; causal evidence in MS remains lacking. [ 13 , 14 , 73 , 74 ] Neuroimaging (Structural) Tractography and DTI assessment of monoaminergic projection integrity. Reduced fiber density in the LC-prefrontal tracts correlates with cognitive fatigue. Reduced integrity in raphe-cerebellar serotonergic tracts. Increased diffusivity within hypothalamic-LC pathways (proposed compensatory adaptation). Cognitive fatigue: candidate imaging marker for monoaminergic network disconnection. [ 10 , 12 ] Neuroimaging (Functional/Metabolic) rs-fMRI and spectroscopy assessment of network dynamics and metabolic health. Reduced functional connectivity between the brainstem and default mode/executive control networks. Reduced NAA/Cr ratios within the pons/LC region correlate with attentional deficits. Depressive and anxiety symptoms are associated with lesions involving the LC and raphe nuclei. Attentional deficits, depression, and anxiety. [ 9 , 11 , 72 ] Neurodegeneration (cross-disease context) Direct quantification of LC neuronal loss specific to MS post-mortem tissue remains limited. Cross-disease evidence from Alzheimer’s disease, Parkinson’s disease, Down syndrome, and multiple system atrophy indicates that LC neuronal vulnerability is a recurring feature of neurodegeneration (see main text, Sect. " LC vulnerability across neurodegenerative diseases " Supports LC failure as a candidate marker of neurodegenerative burden, particularly relevant to progressive MS. [ 5 , 25 , 75 – 77 ] Legend: Evidence categories summarize neuropathological, molecular, toxicological, structural imaging, functional/metabolic imaging, and cross-disease observations relevant to the LC-NA axis in MS. References are numbered according to the manuscript reference list BBB blood-brain barrier, CREB cAMP response element-binding protein, EAE experimental autoimmune encephalomyelitis, LC locus coeruleus, MS multiple sclerosis, NA noradrenaline, NAA/Cr N-acetylaspartate/creatine, rs-fMRI resting-state functional MRI, TH tyrosine hydroxylase

Causes and contributors to LC damage

Loss of trophic support

A plausible contributor to LC vulnerability in MS is loss of trophic support from projection fields. LC neurons maintain extensive axonal arbors and are therefore highly dependent on intact target interactions and retrograde or trans-synaptic trophic signaling (Fig. 1 ). In MS, widespread cortical, hippocampal, thalamic, and cerebellar pathology could secondarily destabilize LC neurons by diminishing trophic reciprocity across distributed projection networks. This possibility remains underexplored, but it provides a biologically coherent explanation for LC injury that cannot be reduced to local pontine lesions alone. In parallel, impaired cAMP/CREB-dependent transcription may reduce BDNF-linked trophic maintenance, further compromising neuronal repair and myelin support [ 1 , 48 ].

BBB loss and neurovascular unit integrity

A second contributor to LC damage is impaired BBB and neurovascular unit integrity. The LC-NA system participates in regulating the neurovascular unit and can influence BBB permeability, endothelial signaling, glial responses, and local blood flow [ 78 ]. More broadly, BBB integrity depends on tightly regulated astrocyte-endothelial interactions and neuronal support [ 79 ]. In MS, barrier dysfunction may increase LC exposure to circulating inflammatory mediators and toxic molecules; conversely, reduced LC output may weaken one of the endogenous systems that normally help stabilize the inflammatory tone of the neurovascular environment. This reciprocal relationship makes LC dysfunction both a potential consequence and an amplifier of BBB pathology. Since adrenergic pathways support BBB integrity, reduced NAergic signaling from a damaged LC could increase vascular permeability and thereby increase exposure of LC neurons and adjacent regions to circulating toxicants, including heavy metals proposed to accumulate in vulnerable brainstem nuclei [ 73 , 80 ]. Extracellular vesicles (EVs) represent an additional mechanism of peripheral-central communication. Circulating EVs may interact with endothelial cells and modulate BBB function, and altered EV cargo, including miRNA and protein content modified by systemic toxicant exposure, may reflect or contribute to neuroinflammatory signaling within the CNS [ 81 ]. Such mechanisms may represent an additional route by which environmental exposures contribute to glial activation, myelin injury, and disruption of neuroimmune regulation, processes that are normally modulated by the LC-NA system.

Toxic metal accumulation in LC neurons

The LC has high metabolic activity, dense vascular contacts, and neuromelanin-containing neurons with metal-binding capacity, making it a plausible target for circulating toxicants. Together with other associative findings, this has led to the hypothesis that environmental toxic metals are selectively absorbed by LC neurons, particularly during stress-related increases in firing and blood flow, and that metal-induced injury reduces central NA levels and increases vulnerability to neurodegenerative, demyelinating, and psychiatric disorders [ 13 ]. This possibility is supported by post-mortem studies that provide direct evidence of metal accumulation in LC neurons. One of the first reports came from histochemical staining using silver autometallography (AMG) which stains sulphide and selenide derivatives of mercury, silver, and bismuth. In brain sections from a man continuously exposed to mercury for 5 months, AMG revealed mercury in cortico-motor neurons, LC neurons, as well as undefined glial cells [ 82 ]. A subsequent study using sections from the same subject combined AMG with immunohistochemistry confirmed selective mercury deposition in cortical astrocytes, grey matter OLGs, cortico-motoneurons, and a subset of LC neurons [ 83 ]. The mercury deposits in cortico-motor neurons prompted comparison of the LC between patients with motor neuron disease (MND) and controls [ 84 ], and showed that the LC of 88% of MND patients had at least one neuron with heavy metal staining compared to 42% of controls. Of interest was the presence of heavy metal staining in the LC of the one MS patient within the control group, but not in the LC of 3 PD patients. A subsequent larger case-control study of 21 patients with MS and 109 controls using AMG and laser ablation-based elemental bio-imaging detected inorganic mercury, silver, or bismuth in LC neurons in both groups; however, in a subset of MS brains these metals also appeared in widespread blood vessels, OLGs, astrocytes, and neurons; and combinations of iron, silver, lead, aluminum, mercury, nickel, and bismuth were more frequently detected in the LC of MS cases than in controls [ 14 ]. Synchrotron X-ray fluorescence microscopy further revealed marked cell-to-cell variation in concentrations of mercury, selenium, iron, copper, and lead within individual LC neurons in brains of 7 women patients with MS, whereas neighboring anterior pons neurons outside the LC contained no mercury and lower copper levels [ 74 ]. Experimental studies further demonstrate that heavy metals can directly damage LC neurons: cellular iron concentrations directly affect NA transporter expression in the LC, with protein levels correlated with regional iron concentrations [ 85 ]; iron infusion into the rat LC induces lipid peroxidation, NA depletion, TH-positive neuron loss, and induction of apoptosis [ 86 ]. The observed uneven elemental burden suggests a possible explanation for heterogeneous LC neuronal loss which could contribute to clinical heterogeneity. At a broader conceptual level, the toxic metal hypothesis proposes that metal-mediated LC damage weakens the BBB in projection territories, allowing circulating toxicants to enter astrocytes and transfer to OLGs and neurons, thereby promoting demyelination and neurodegeneration across MS, amyotrophic lateral sclerosis, PD, and AD [ 73 ]. However, experimental evidence directly supporting these hypotheses is still lacking.

Implications for MS pathogenesis

The implications for MS pathogenesis can be assessed by distinguishing three levels of evidence. Established findings include the direct demonstration by AMG, laser ablation elemental bioimaging, and synchrotron X-ray fluorescence that redox-active metals accumulate in a subset of LC neurons and vary from cell to cell [ 74 , 87 ]. Associative observations include the more frequent detection of metal combinations in the LC of MS cases than controls in small post-mortem series [ 14 ]. Hypothetical mechanisms include the proposal that this accumulation causally drives LC injury, NA depletion, and downstream demyelination; this causal step has not been demonstrated and should be regarded as provisional pending prospective, exposure-controlled studies. Iron has a particularly high affinity for neuromelanin and is detected in the LC in Alzheimer’s disease, aging, Parkinson’s disease, and Huntington’s disease [ 88 , 89 ]. Mercury has also been reported in the LC of Parkinson’s disease patients [ 90 ], whereas is was not detected in the LC of autistic patients [ 91 ]. Mercury and related metals can induce oxidative stress, mitochondrial dysfunction, DNA damage, and immune dysregulation in CNS cells, processes that are widely implicated in the pathophysiology of MS [ 73 , 86 , 88 , 89 ]. Although causal evidence remains lacking, the toxic metal hypothesis provides a mechanistic framework linking environmental metal exposure, selective LC vulnerability, and downstream demyelination. Reduced NAergic output from a damaged LC could weaken glial anti-inflammatory restraint and barrier stability and may also impair OLG maturation programs that support remyelination. Although epidemiological evidence linking metal exposures to MS risk remains limited, the hypothesis has practical implications, since reductions in environmental metal pollution and occupational exposure could help lessen the burden of LC-linked neurological disorders.

LC vulnerability across neurodegenerative diseases

LC degeneration is not unique to MS, supporting the idea that this nucleus has inherent and possibly shared biological vulnerabilities. Parallel evidence from AD, PD, Down syndrome, and multiple system atrophy indicates that LC vulnerability is a recurring feature of neurodegenerative disorders, often preceding or amplifying cortical and subcortical pathology. Quantitative histological studies in both humans and rodents showed that LC neuron numbers remain relatively stable during healthy aging [ 27 , 30 , 33 ]. Significant loss of LC neurons projecting to the cerebral cortex was established as a core feature of senile dementia decades ago [ 25 ]. Advanced in vivo neuromelanin imaging has directly linked LC structural damage to cognitive dysfunction and altered brain metabolism in multiple system atrophy [ 75 ]. This cross-disease convergence reinforces the view that LC failure can magnify neuroinflammation, trophic insufficiency, and network dysfunction even when the primary initiating pathology differs [ 5 , 76 , 77 ]. However, the triggers of this vulnerability differ across disorders. In AD the LC accumulates hyperphosphorylated (pre-tangle) tau decades before cortical pathology and shows severe neuronal loss that correlates with plaque and tangle burden and disease duration, with reductions in central NA. In PD and MSA, alpha-synuclein pathology and loss of melanized neurons affect the LC alongside the SN, and LC neuromelanin loss tracks cognitive impairment and altered brain metabolism [ 46 , 75 ]. In progressive supranuclear palsy, tau aggregation and NAergic cell loss in the LC relate to clinical severity, and Down syndrome shows early LC tau pathology consistent with its Alzheimer-type trajectory [ 5 ]. These shared elements across diverse disorders suggest intrinsic features leading to LC vulnerability: long, highly arborised, metabolically demanding axons; pacemaker activity with a high oxidative load; neuromelanin with metal-binding capacity; and dense vascular contact. The disease-specific elements are the proteinopathies or primary insults that engage these vulnerabilities, namely tau, alpha-synuclein, or, in MS, autoimmune inflammation. Framing MS within this spectrum places LC failure as a convergent amplifier of neuroinflammation and trophic insufficiency rather than a disease-specific lesion, so that loss of NAergic anti-inflammatory restraint may be a common and broadly targetable downstream consequence.

Sex differences in LC vulnerability

The LC is a sexually dimorphic nucleus, which may be relevant to the female predominance of MS. Preclinical work shows structural and molecular sex differences in LC neurons, including differences in cell number, larger and more complex dendritic arbors in females, greater intrinsic excitability, and sex-biased gene expression ([ 92 , 93 ]). Female LC neurons are more sensitive to the stress peptide corticotropin-releasing factor and show estrogen-dependent enhancement of NA synthesis, features linked to the higher female prevalence of stress-related and affective disorders [ 94 – 96 ]. In vivo neuromelanin-sensitive MRI likewise reports higher LC signal in women than in men [ 97 ]. Sex-dependent differences have also been reported that are dependent upon LC projection areas [ 98 ], and led to the proposal that changes in estrogen levels could render the LC more susceptible to damage, which could contribute to increased prevalence of AD in women [ 99 ]. Whether these differences modify LC susceptibility to inflammatory or metal-related injury in MS is unknown, but they argue for treating sex as a biological variable in LC-focused MS studies.

LC, NA, and neuropsychiatric symptoms in MS

Fatigue, mood, and anxiety symptoms

Fatigue in MS is a heterogeneous and multidimensional symptom that likely reflects interactions between primary disease mechanisms and secondary clinical contributors. Evidence supports associations with immune activation, including pro-inflammatory cytokine signaling such as TNF-α and related inflammatory mediators [ 100 , 101 ], sleep disturbance [ 102 ], depressive symptoms [ 103 ], autonomic dysregulation [ 104 ], and neuroendocrine/HPA-axis imbalance [ 105 ]. Fatigue may also be worsened by medication effects or treatment-related adverse effects [ 106 ]. At the neural systems level, MS fatigue has been linked to structural and functional disruption of distributed cortico-thalamo-striatal, cortico-limbic, and monoaminergic networks, rather than to a single anatomical lesion or pathway [ 107 ]. Within this framework, LC–NA dysfunction should be viewed as one mechanistically plausible contributor, not as the sole cause of MS fatigue. Its relevance lies in the fact that the LC–NA system can influence arousal, attention, cognitive effort, autonomic regulation, and neuroimmune signaling, which is likely to vary across individuals.

The circuit- and cellular-level abnormalities described above provide a plausible framework for understanding fatigue and affective symptoms in MS. As detailed in Sect. " Monoaminergic tracts, connectivity, and fatigue ", fixel-based imaging and tractography studies have identified injury within NAergic LC–prefrontal and hypothalamic–brainstem pathways, with greater tract disruption associated with more severe cognitive fatigue. These findings support a network-level substrate for fatigability rather than a purely lesion-count-based explanation [ 9 , 10 , 12 ]. Mood symptoms may overlap mechanistically with fatigue rather than representing an entirely separate domain. As described in Sect. " Infratentorial lesions and mood ", infratentorial lesion-mapping studies have linked depressive symptoms to structural damage involving the LC and raphe nuclei [ 72 ], implicating disruption of NAergic and serotonergic systems. In parallel, clinical evidence that serotonin–noradrenaline (NA) reuptake inhibitors, such as duloxetine, can improve depressive symptoms in MS cohorts supports the therapeutic relevance of monoaminergic pathways, although this does not establish LC dysfunction as the sole mechanism [ 108 ]. Together, these data support a shared monoaminergic and network-level framework through which fatigue, mood disturbance, and anxiety-related symptoms may emerge in MS.

Cognitive dysfunction and monoaminergic modulation

Cognitive impairment affects many patients with MS and commonly involves slowed processing speed, executive dysfunction, episodic memory problems, and impaired learning. A recent network meta-analysis suggested low-certainty benefits of stimulant, glutamatergic, and NAergic agents on selected cognitive tests, with L-amphetamine showing possible improvement in memory function, but the evidence remained fragmented, and head-to-head comparisons were limited [ 109 ]. Atomoxetine, a selective NA reuptake inhibitor, has shown preliminary domain-specific cognitive benefits in clinical studies; these are discussed in detail in Sect. " NA reuptake inhibitors, SNRIs, and combination approaches " [ 110 ].

β₂-agonists, NA reuptake inhibitors, and LC-targeted therapies

Preclinical evidence: LC in the EAE model

As reviewed in Sect. " Preclinical biochemical evidence of LC-NA dysfunction ", experimental NA depletion worsens inflammation and tissue injury in EAE, while NA-augmenting strategies, including vindeburnol, catalpol, combined L-DOPS/atomoxetine, and chemogenetic LC activation, reduce disease severity, demyelination, and glial activation. This causal evidence provides the experimental basis for LC-NA-directed clinical strategies in MS.

β 2 -adrenergic agonists in clinical studies

β 2 -adrenergic agonists such as albuterol (salbutamol) increase intracellular cAMP and reduce interleukin-12 (IL-12) production in monocytes and dendritic cells, shifting T helper 1 cell responses away from pro-inflammatory phenotypes [ 111 – 113 ]. In early open-label work in secondary progressive MS, short-term oral salbutamol was associated with reduced IL-12 production by monocytes and dendritic cells, with suppression persisting for approximately one week after drug discontinuation [ 113 ]. In a key randomized controlled trial (ClinicalTrials.gov: NCT00039988 ), patients with RRMS receiving glatiramer acetate plus albuterol showed improved Multiple Sclerosis Functional Composite scores at six and twelve months, a delayed time to first relapse, and immunological changes consistent with reduced production of IL-13 and interferon-gamma (IFN-γ) [ 111 ]. On this basis, a narrative review concluded that salbutamol may represent a promising add-on immunomodulatory therapy in MS, while emphasizing the need for larger definitive trials [ 112 ]. Population-based pharmaco-epidemiological studies provide additional support. In a nationwide Taiwanese case-control study, β2-adrenergic agonist use was linked to a dose-dependent decrease in MS risk, with adjusted odds ratios below one across different exposure levels [ 114 ]. In a separate registry-based study, individuals later diagnosed with MS had fewer prescriptions for ipratropium or salmeterol than matched controls, and modeling indicated that use of these medications was associated with a lower chance of an eventual MS diagnosis [ 115 ]. However, the therapeutic effects of β₂-adrenergic agonists are not uniform across clinical outcomes. In a pilot randomized placebo-controlled trial in RRMS, oral salbutamol did not show superiority over placebo on fatigue outcomes, and no clinical benefit on disability measures was detected [ 116 ]. These neutral findings highlight that domain-specific outcomes, dosing schedules, CNS penetration, and patient heterogeneity could influence response.

NA reuptake inhibitors, SNRIs, and combination approaches

In patients with MS, atomoxetine has shown encouraging but preliminary effects on cognition. In a small randomized placebo-controlled trial, three months of atomoxetine treatment were associated with improvements in processing speed and performance on verbal learning and visual memory tests from the MACFIMS battery [ 110 ], whereas improvements in attention and cognitive speed were reported without corresponding gains in memory measures, indicating domain-specific and time-limited effects [ 117 ]. Clinical work with duloxetine in MS has shown benefit for depressive symptoms and fatigue [ 108 ], and a separate pilot study suggested a benefit for overactive bladder symptoms [ 118 ]. Venlafaxine, a serotonin-NA reuptake inhibitor (SNRI), has been shown in EAE to ameliorate disease severity through suppression of pro-inflammatory cytokines, including IL-12 p40, TNF-alpha, and IFN-gamma in encephalitogenic T cells, splenocytes, and macrophages, while simultaneously increasing BDNF expression in inflamed CNS tissue [ 119 ]. This convergent neuroimmune and neurotrophic profile suggests that SNRIs may exert benefits on both mood-related and immunological pathways.

Combination approaches have also been explored. In a randomized placebo-controlled trial of the Cari Loder regimen, all participants received weekly intramuscular vitamin B12, and the addition of oral lofepramine and L-phenylalanine produced a small but statistically significant additional improvement in disability and symptom scores, with changes becoming evident within a few weeks [ 120 ]. Activation of NAergic systems in the LC and lateral tegmentum was proposed as a possible mechanism, although this has not been directly tested [ 120 , 121 ]. A summary of preclinical and clinical interventions targeting the LC-NA axis is provided in Table 2 .

Table 2 Preclinical and clinical interventions targeting the locus coeruleus-noradrenergic axis in multiple sclerosis Intervention / Agent Study Type Proposed Mechanism of Action Key Outcomes / Findings Primary Therapeutic Target Ref β2-Adrenergic Agonists Salbutamol (Albuterol) Clinical (randomized controlled trial) Increases cAMP signaling; suppresses Th1 immune responses via reduced IL-12 production. Improved MS Functional Composite scores at 6 and 12 months but not sustained at 24 months; delayed time to first relapse; changes in the primary immunologic endpoints (IL-13 and IFN-gamma). Immunomodulatory [ 111 – 113 ] Salbutamol (Albuterol) Clinical (pilot randomized controlled trial) Immunomodulation and potential monoaminergic stimulation. Negative result: no significant advantage over placebo for fatigue severity (FSS) or neurological impact (NFI-MS) at 90 days. Immunomodulatory [ 116 ] Fenoterol Clinical (case-control study) β2-adrenergic agonism; increases cAMP signaling. Associated with a dose-dependent reduction in MS risk (adjusted odds ratios below 1). Immunomodulatory [ 114 ] Salmeterol / Ipratropium Clinical (case-control study) β2-adrenergic agonism (salmeterol). Associated with a reduced likelihood of subsequent MS diagnosis. Immunomodulatory [ 115 ] Reuptake Inhibitors (NRIs & SNRIs) Atomoxetine Clinical (randomized controlled trial; corroborated by network meta-analysis) Selective noradrenaline reuptake inhibitor; modulates frontoparietal networks. Significant improvements in processing speed and memory (CVLT, BVMT-R, SDMT) over 3 months. Neuromodulatory / cognitive [ 109 , 110 ] Atomoxetine Clinical (conference abstract) Selective noradrenaline reuptake inhibitor. Short-term improvement in processing speed and verbal learning; no durable effect on memory. A distinct cohort from the RCT above. Neuromodulatory / cognitive [ 117 ] Duloxetine Clinical (open-label study) Serotonin-noradrenaline reuptake inhibitor; dual action on mood and descending pain/autonomic pathways. Significant reduction in depression (BDI) and fatigue (MFIS); improved overactive bladder symptoms and quality of life. Neuromodulatory / symptomatic [ 108 , 118 ] Venlafaxine Preclinical (EAE model) Serotonin-noradrenaline reuptake inhibitor; suppresses pro-inflammatory cytokines (IL-12 p40, TNF-alpha, IFN-gamma). Ameliorated EAE course; increased CNS BDNF expression. Neuroprotective/immunomodulatory [ 119 ] Precursors & LC-Targeted Agents Atomoxetine + L-DOPS Preclinical (EAE model) A combination of a noradrenaline reuptake inhibitor and a synthetic noradrenaline precursor. Improved clinical scores and dampened astrogliosis; superior to either agent alone; no effect on peripheral Th1/Th17 cytokine production. Neuroprotective/astroglial modulation [ 6 ] Vindeburnol Preclinical (EAE model) Vincamine derivative; enhances tyrosine hydroxylase expression and LC neuron survival. Improved clinical scores; reduced cerebellar demyelination; normalized spinal cord NA levels when given after onset. Neuroprotective [ 7 ] Catalpol Preclinical (EAE model) Increases LC noradrenaline output. Raised spinal cord NA levels; ameliorated EAE severity. Neuroprotective [ 66 ] Lofepramine + L-Phenylalanine + B12 Clinical (randomized controlled trial) Tricyclic antidepressant plus amino acid precursor and cofactor; hypothesized to activate LC and lateral tegmental systems. Improved symptoms across MS subtypes with rapid onset of effect. Neuromodulatory / symptomatic [ 120 , 121 ] L-Amphetamine Clinical (network meta-analysis) CNS stimulant; enhances monoaminergic neurotransmission. Signals suggesting potential improvement in memory domains; evidence is fragmented. Neuromodulatory / cognitive [ 109 ] Legend: Preclinical and clinical interventions are grouped by pharmacological or mechanistic category. The table summarizes reported mechanisms and outcomes but does not imply proven efficacy across all MS phenotypes. References are numbered according to the manuscript reference list BDNF brain-derived neurotrophic factor, cAMP cyclic adenosine monophosphate, CNS central nervous system, EAE experimental autoimmune encephalomyelitis, IFN-gamma interferon-gamma, IL-12 interleukin-12, LC locus coeruleus, L-DOPS L-threo-3,4-dihydroxyphenylserine, MS multiple sclerosis, NA noradrenaline, NFI-MS Neurological Fatigue Index for MS, SNRI serotonin-noradrenaline reuptake inhibitor, T NF-alpha tumor necrosis factor-alpha

Limitations of the current therapeutic evidence

Despite the mechanistic appeal of LC-NA-targeted interventions, the clinical evidence base in MS remains limited by small sample sizes, short treatment durations, heterogeneous outcome measures, and minimal stratification by markers of LC or monoaminergic dysfunction. As illustrated by the neutral salbutamol fatigue trial (Sect. " β2-adrenergic agonists in clinical studies ") and the domain-limited atomoxetine findings, reported benefits have generally been modest and domain-specific, and caution against direct translation of preclinical findings into routine practice. Moreover, very few studies have incorporated LC imaging, quantitative assessment of monoaminergic tract integrity, or characterization of environmental exposures into their inclusion criteria or stratification strategies. As a result, patient subgroups who might be particularly responsive, such as those with demonstrable LC injury, high cognitive fatigue burden, or prominent depressive symptoms, may have been diluted within unselected trial cohorts.

Systems model: the LC as a hub integrating toxicants, neuroinflammation, and symptoms

Taken together, the LC can be viewed as a systems-level hub in MS (Fig. 2 ), characterized by the following:

Upstream vulnerability. Environmental exposures, especially toxic metals, may accumulate selectively in LC neurons, where variable elemental burden and morphological signs of stress have been observed in autopsy material and MS brains [ 13 , 14 , 83 , 122 ]. Genetic susceptibility and chronic disruption of NA synthesis may further increase vulnerability. Loss of intrinsic anti-inflammatory control. Reduced LC output weakens a major endogenous mechanism that normally restrains microglial and astrocytic activation, cytokine production, and oxidative stress through β-adrenergic signaling. Under such conditions, immune triggers are more likely to elicit exaggerated or poorly resolved glial activation and microglial priming [ 1 – 3 ]. Network-level consequences. Damage to the LC and related monoaminergic tracts is associated with altered connectivity and with fatigue, attentional deficits, and depressive symptoms in MS, supporting a role for monoaminergic network disconnection in symptom expression [ 9 – 12 , 72 ]. Interaction with demyelination and neurodegeneration. Impaired LC signaling may permit more aggressive or poorly resolved inflammatory injury, whereas restoration of NAergic tone improves demyelination, glial activation, and neuroprotective signaling in EAE [ 6 , 7 , 66 , 67 , 119 , 123 ]. Availability of standardized g-ratio analysis tools could further quantify myelin integrity and connect LC-targeted biology to OLG repair outcomes in preclinical work [ 123 ]. Therapeutic leverage within a hub-based framework. LC-NA-directed therapies may be most useful as biomarker-guided, add-on strategies aimed at selected symptom domains or patient subgroups, particularly those with demonstrable LC injury, high cognitive fatigue burden, or prominent depressive symptoms. Rather than replacing immunomodulatory therapies, LC-centered modulation may function as a complementary strategy that restores intrinsic regulatory balance and mitigates symptom burden

The myelin and axonal injury module in Fig. 2 is supported by evidence from human MS tissue, experimental demyelination models, MRI–pathology correlation studies, and serum biomarker cohorts. However, the specific directional links between LC–NA dysfunction and these downstream myelin/axon injury pathways remain partly hypothetical and require direct experimental validation.

Fig. 2 Multi-level model of locus coeruleus–noradrenergic axis dysfunction in multiple sclerosis. Schematic representation of a proposed multi-level framework linking upstream drivers of locus coeruleus–noradrenergic (LC–NA) dysfunction to downstream cellular and tissue-level injury, network-level dysregulation, clinical consequences, and possible therapeutic approaches in multiple sclerosis (MS). Multiple drivers (box 1) converge to induce LC dysfunction (box 2) culminating in reduced NA output, leading to dysregulation in LC target regions (box 3). These changes, which include glial cell activation, reduced trophic support, oxidative stress and loss of BBB integrity can contribute to oligodendrocyte and axonal injury, myelin loss, and alterations in nodal and paranodal organization (box 4). In addition, these changes could impair limited attempts at remyelination. We propose that the consequences of these combined perturbations interact with ongoing network pathologies (box 5) exacerbating behavioral syndromes including fatigue, memory impairment, ataxia, and other autonomic functions. To address this, we propose interventions to modulate the LC-NA axis (box 6) thereby increasing NA production or availability, reducing NA breakdown, activating b2-AR signaling, or potentially rescuing damaged LC neurons; which together are expected to result in beneficial outcomes (box 7) that limit further damage or potentially restore target area homeostasis. The interactions we illustrate in this schematic are derived from partially supported mechanisms, or proposed mechanistic links based on the correlative findings discussed. The model focuses on LC dysfunction, however it exists within the context of broader monoaminergic pathology. Abbreviations: BBB, blood–brain barrier; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; ER, endoplasmic reticulum; LC, locus coeruleus; MBP, myelin basic protein; MS, multiple sclerosis; NA, noradrenaline; OPC, oligodendrocyte precursor cell; PLP, proteolipid protein

The LC within a broader monoaminergic and network context

The LC does not act in isolation, but functions as a hub within a broader monoaminergic network that is disrupted in MS, and must be considered within this context when considering therapeutic leverage. While best characterized for NA synthesis and release, the LC is also a major source of dopamine (DA), the immediate precursor of NA. LC-derived DA is released in the HC [ 124 , 125 ] and thalamus [ 126 ], where it is involved in memory and stress responses. In some cases NA and DA are co-released from the same neurons [ 127 ]. In contrast, LC neurons do not express 5-hydroxy-tryptamine (serotonin); instead the LC receives serotonergic afferents originating in the dorsal raphe nucleus [ 128 ]. Similarly, while LC NAergic damage is well established, damage to both DAergic and serotonergic neurons occurs in neurodegenerative diseases including AD and PD. In MS, serotonergic raphe and DAergic mesolimbic systems are also affected, and fixel-based imaging shows reduced fiber density across raphe-to-cerebellar and ventral tegmental projections alongside LC-to-prefrontal tracts, with overlapping contributions to fatigue, affect, and cognition [ 10 ]. Reduced serotonin and DA availability are also implicated in MS fatigue and mood disturbance [ 107 ]. The clinical picture, therefore, reflects distributed monoaminergic and network-level pathology, with LC-NA dysfunction as one component. We emphasize the LC since it is the principal source of CNS NA [ 129 ], exerts distinctive anti-inflammatory and trophic influences on glia and OLGs [ 1 , 2 ], and is selectively vulnerable to toxin accumulation and stress [ 14 , 87 , 130 ].

LC dysfunction across MS phenotypes

MS phenotypes differ in their dominant biology. Relapsing-remitting MS is characterized by focal, blood-brain barrier-permeable inflammatory white matter lesions, whereas progressive MS is dominated by compartmentalized meningeal and parenchymal inflammation behind a relatively intact barrier, with diffuse grey matter demyelination, neuroaxonal loss, and microglial activation that track disability and cognitive decline more closely than focal plaque burden [ 131 , 132 ]. The LC is well placed to contribute to this progressive, neurodegenerative phase: its widespread cortical and deep grey matter projections [ 129 ], its role in restraining glial activation [ 51 ], and its support of neurotrophic and OLG repair programs [ 67 ] are all most relevant to the diffuse pathology that defines progression. Consistent with this, experimental NA depletion worsens [ 6 , 8 ], and NA augmentation reduces demyelination and glial activation independently of acute relapse activity [ 6 , 67 ]. We therefore propose the testable hypothesis that LC-NA dysfunction is more closely linked to smoldering inflammation and neurodegenerative progression in MS than to acute relapse activity. In this framework, LC pathology may contribute to chronic network inefficiency, fatigue, impaired arousal regulation, and progressive tissue vulnerability. Accordingly, LC-directed strategies may be most relevant as adjunctive neuroprotective or neuromodulatory approaches in progressive MS or in relapsing patients with progression independent of relapse activity. However, direct comparative data on LC pathology across relapsing-remitting and progressive MS remain limited, and stratified neuropathological, neuromelanin-sensitive MRI, tractography, and longitudinal clinical-imaging studies are needed to test this prediction.

Future directions

Several limitations temper the current conclusions. Much of the neuropathological and toxic metal evidence comes from small post-mortem series biased toward progressive or late-stage disease; similar studies in early-stage MS, including radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) could help to determine if toxic exposures play a role in early disease evolution. Longitudinal in vivo LC imaging has not yet been systematically implemented in MS, and toxic metal studies remain observational, limiting causal inference. Most interventional studies of β₂-AR agonists and NAergic modulators have been small, short, and methodologically heterogeneous; standardization across studies will be essential to draw stronger conclusions. For patient stratification, the most realistic near-term readouts are neuromelanin-sensitive MRI of the LC, diffusion-based measures of LC-to-prefrontal and hypothalamic-LC tract integrity, and magnetic resonance spectroscopy (NAA/Cr) in the pontine LC region, complemented, where feasible, by quantitation of catecholamine metabolites. Neuromelanin-sensitive MRI is the most well developed, has been validated histologically [ 133 ] and shows good reproducibility and disease sensitivity in PD [ 134 ], AD [ 135 ], and MSA [ 136 ]. This has been facilitated by automated LC segmentation pipelines [ 137 ]. although routine clinical application is still limited by technical limitations (i.e. differences in scanners, protocol standardization) and overall usage that could influence LC signal measurements. Despite this, it application to MS remains untested, as have studies of neuromelanin in MS. Neuromelanin-MRI therefore presents a promising but not yet validated MS biomarker. Other candidate LC-related biomarkers associated with clinical manifestations, and potential therapeutic strategies for future biomarker-enriched studies are summarized in Table 3 .

Table 3 LC-related biomarkers, clinical correlates, and candidate therapeutic strategies in multiple sclerosis Biomarker / Strategy Modality Validation Status in MS Associated Clinical Manifestations Candidate Therapeutic Strategy References Neuromelanin-sensitive MRI (NM-MRI) Structural MRI Validated histologically and has good reproducibility in PD, AD, and MSA. Its use in MS is lacking LC structural integrity: a candidate surrogate for LC neuronal loss. Patient stratification for LC-targeted trials. [ 133 – 137 ] Diffusion tractography (LC-prefrontal and hypothalamic-LC tracts) Diffusion MRI fixel-based analysis Demonstrated in MS cohorts. Not yet standardized for routine clinical use. Cognitive fatigue; attentional deficits. Stratification by tract-level LC network integrity. [ 9 , 10 , 12 ] Magnetic resonance spectroscopy (NAA/Cr, pontine LC region) MR spectroscopy Demonstrated in early relapsing-remitting MS in small cohorts to date. Selective attention deficits, even at low EDSS. Early identification of LC-related cognitive risk. [ 11 ] CSF/plasma catecholamine metabolites (e.g., MHPG) Biochemical assay Preliminary and associative. Not validated as a standalone biomarker. Disease duration and relapse burden. Adjunct biomarker for monitoring LC-NA tone alongside imaging. [ 68 , 69 ] β2-Adrenergic agonists (e.g., salbutamol) Pharmacological Immunomodulatory Mixed clinical trial evidence; positive on relapse-related composite outcomes, neutral on fatigue. Relapse activity; immune activation. Add-on immunomodulatory therapy. [ 111 , 116 ] NA reuptake inhibitors / SNRIs (e.g., atomoxetine, duloxetine) Pharmacological Neuromodulatory Preliminary, domain-specific clinical benefit in small trials. Cognitive dysfunction, fatigue, and depression. Add-on cognitive- or mood-targeted therapy. [ 108 , 110 ] Legend: Candidate biomarkers and therapeutic strategies are intended for hypothesis-generating, biomarker-enriched studies. Validation status refers specifically to MS unless otherwise stated. References are numbered according to the manuscript reference list AD Alzheimer's disease, Cr creatine, LC locus coeruleus, MHPG 3-methoxy-4-hydroxyphenylglycol, MS multiple sclerosis, MSA multiple system atrophy, NA noradrenaline, NAA N-acetylaspartate, NM-MRI neuromelanin-sensitive MRI, PD Parkinson's disease, SNRI serotonin-noradrenaline reuptake inhibitor Whether current disease-modifying therapies indirectly engage LC-related pathways is also untested. While there are promising results from small trials using NA-reuptake inhibitors or dual SNRIs [ 108 , 120 , 121 ], it is not known whether those treatments had any direct effect on NAergic neurons. Similarly, although several FDA-approved drugs enhance NA output from the LC or reduce NA breakdown (droxidopa, atomoxetine, modafinil, albuterol) there is no data supporting protective effects on LC neurons. Vindeburnol, thought to increase LC TH expression, and which is effective in EAE [ 7 ], was never approved for clinical use. Future work could therefore prioritize biomarker-enriched clinical trials that stratify participants by LC imaging, monoaminergic tract integrity, and neuropsychiatric phenotype. Incorporating environmental exposure data and genetic susceptibility factors, including those affecting detoxification capacity and mitochondrial resilience, will be important for testing toxicant-related hypotheses. Mechanistically informed combination strategies, such as pairing NA-augmenting agents with disease-modifying therapies, remyelination approaches, or cognitive rehabilitation, can be carried out in pre-clinical models (EAE, cuprizone) models. Finally, cross-disease comparisons between MS, AD, PD, and psychiatric disorders may help distinguish shared versus disease-specific contributions of the LC to pathology. Overall, we suggest that any LC-directed interventions should be viewed as potential adjunctive symptomatic or neuroprotective approaches rather than established disease-modifying therapies, that would complement, rather than replace, treatments targeting peripheral and central immune mechanisms in MS.

Conflicting findings and unresolved questions

Several lines of evidence complicate a simple LC-centered account. Early in EAE, NA levels can rise before falling, suggesting a dynamic, possibly compensatory response rather than uniform depletion [ 8 ]. LC damage correlates only weakly with focal plaque burden, which supports the hub argument but also leaves the relationship between LC injury and conventional lesion measures unresolved [ 8 ]. Clinical trials are not uniformly positive: oral salbutamol failed to improve fatigue in a placebo-controlled pilot [ 116 ], and the cognitive benefits of NAergic agents are small, domain-specific, and sometimes dissociated from memory outcomes [ 110 ]. The toxic metal data derive from small, late-stage post-mortem series and cannot establish causation or temporal order [ 14 , 87 ]. Neuromelanin MRI is not yet validated in MS. Finally, because serotonergic and dopaminergic systems are co-affected, attributing specific symptoms to the LC alone risks overinterpretation [ 138 ]. We therefore present the LC-NA framework as a hypothesis-generating synthesis that is consistent with, but not proven by, current data, and that requires prospective, stratified, and adequately powered testing.

Conclusions

The LC is more than an incidental casualty of MS. Its unique biological properties place it at the intersection of neuroinflammatory regulation, environmental vulnerability, and network-level symptom expression. Disruption of proper LC-NA output has the potential to remove a critical endogenous brake on glial cell activation, resulting in disruption of monoaminergic circuits supporting attention, mood, and arousal, and compromising necessary OLG repair programs. The convergence of neuropathological, toxicological, imaging, and experimental evidence reviewed here is consistent with LC-NA dysfunction as an active and potentially modifiable contributor to MS progression rather than a secondary epiphenomenon. At the same time, the LC represents one influential node within a broader monoaminergic and network-level pathology, and we advance it as a hub in that qualified sense rather than as a single master regulator. We suggest that a biomarker-guided strategy combining NAergic interventions with indicators of glial activity, myelin integrity, and environmental exposure could help identify patient subgroups most likely to benefit, moving beyond the unselected trial designs that have limited progress to date. Appreciating the LC as a systems-level hub opens a coherent and underexplored therapeutic avenue that complements existing disease-modifying strategies in MS.

Abbreviations

Alzheimer disease

β-adrenergic receptor

blood-brain barrier

Brain-derived neurotrophic factor

Cyclic adenosine monophosphate

Clinically isolated syndrome

Corpus callosum

Central nervous system

Creatine

Catechol-O-methyltransferase

CAMP response element-binding protein

Corticotropin-releasing factor

Dopamine

Dopaminergic

Dopamine β-hydroxylase

Default-mode network

Disease-modifying therapy

deoxyribonucleic acid

L-threo-dihydroxyphenylserine (droxidopa)

Experimental autoimmune encephalomyelitis

Expanded Disability Status Scale

Extracellular vesicle

Glial fibrillary acidic protein

Grey matter

Hypothalamic-pituitary-adrenal

Hippocampus

Interferon gamma

Interleukin-12

Locus coeruleus

Minimal Assessment of Cognitive Function in MS

Monoamine oxidase

3-methoxy-4-hydroxyphenylglycol

MicroRNA

Motor neuron disease

Magnetic resonance imaging

Multiple sclerosis

Multiple system atrophy

Noradrenaline

N-acetylaspartate

Noradrenergic

Noradrenaline reuptake inhibitor

Norepinephrine transporter

Nuclear factor kappa B

Nerve growth factor

Neuromelanin-sensitive magnetic resonance imaging

Nuclear factor erythroid 2-related factor 2

Oligodendrocyte

Oligodendrocyte precursor cell

Parkinson’s disease

Protein kinase A

Progressive multiple sclerosis

Primary progressive multiple sclerosis

Progressive supranuclear palsy

Post-traumatic stress disorder

Radiologically isolated syndrome

RNA sequencing

Relapsing-remitting multiple sclerosis

Substantia nigra

Serotonin-noradrenaline reuptake inhibitor

Secondary progressive multiple sclerosis

Tyrosine hydroxylase

Thalamus

Tumor necrosis factor

Terminal deoxynucleotidyl transferase dUTP nick-end labeling

Tentral tegmental area

White matter

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors' contributions

IA and DLF developed the initial concepts for this review. IA, RA, and DLF performed relevant literature searches. IA and RA designed figures and tables. IA wrote the initial draft, DLF revised and edited, RA was a major contributor to writing the manuscript. All authors approved the final version.

Funding

This work was funded in part by the Department of Veterans Affairs grants I01RX003955 and IK6BX004852 (DLF).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

References

1. Braun D Madrigal JL Feinstein DL Noradrenergic regulation of glial activation: molecular mechanisms and therapeutic implications Curr Neuropharmacol 2014 12 4 342 52 10.2174/1570159X12666140828220938 25342942 PMC4207074 Braun D, Madrigal JL, Feinstein DL. Noradrenergic regulation of glial activation: molecular mechanisms and therapeutic implications. Curr Neuropharmacol. 2014;12(4):342–52. 25342942 10.2174/1570159X12666140828220938 PMC4207074

2. Feinstein DL Kalinin S Braun D Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system J Neurochem 2016 139 Suppl 2 154 78 10.1111/jnc.13447 26968403 Feinstein DL, Kalinin S, Braun D. Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system. J Neurochem. 2016;139(Suppl 2):154–78. 26968403 10.1111/jnc.13447

3. Galea E Heneka MT Dello Russo C Feinstein DL Intrinsic regulation of brain inflammatory responses Cell Mol Neurobiol 2003 23 4–5 625 35 10.1023/A:1025084415833 14514020 PMC11530196 Galea E, Heneka MT, Dello Russo C, Feinstein DL. Intrinsic regulation of brain inflammatory responses. Cell Mol Neurobiol. 2003;23(4–5):625–35. 14514020 10.1023/A:1025084415833 PMC11530196

4. Bondareff W Mountjoy CQ Roth M Selective loss of neurones of origin of adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia Lancet (London England) 1981 1 8223 783 4 10.1016/S0140-6736(81)92657-X 6110985 Bondareff W, Mountjoy CQ, Roth M. Selective loss of neurones of origin of adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia. Lancet (London England). 1981;1(8223):783–4. 6110985 10.1016/s0140-6736(81)92657-x

5. Fructuoso M Vermeiren Y Boluda S Stimmer L Crans RAJ Xicota L Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer’s disease, Down syndrome, and Parkinson’s disease Alzheimer’s Dement J Alzheimer’s Assoc 2025 21 6 e70262 10.1002/alz.70262 PMC12159339 40501099 Fructuoso M, Vermeiren Y, Boluda S, Stimmer L, Crans RAJ, Xicota L, et al. Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer’s disease, Down syndrome, and Parkinson’s disease. Alzheimer’s Dement J Alzheimer’s Assoc. 2025;21(6):e70262. 10.1002/alz.70262 PMC12159339 40501099

6. Simonini MV Polak PE Sharp A McGuire S Galea E Feinstein DL Increasing CNS noradrenaline reduces EAE severity J Neuroimmune Pharmacol 2010 5 2 252 9 10.1007/s11481-009-9182-2 19957206 Simonini MV, Polak PE, Sharp A, McGuire S, Galea E, Feinstein DL. Increasing CNS noradrenaline reduces EAE severity. J Neuroimmune Pharmacol. 2010;5(2):252–9. 19957206 10.1007/s11481-009-9182-2

7. Polak PE Kalinin S Braun D Sharp A Lin SX Feinstein DL The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: effects on the Locus coeruleus J Neurochem 2012 121 2 206 16 10.1111/j.1471-4159.2012.07673.x 22288774 Polak PE, Kalinin S, Braun D, Sharp A, Lin SX, Feinstein DL. The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: effects on the Locus coeruleus. J Neurochem. 2012;121(2):206–16. 22288774 10.1111/j.1471-4159.2012.07673.x

8. Polak PE Kalinin S Feinstein DL Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis Brain 2011 134 Pt 3 665 77 10.1093/brain/awq362 21297130 PMC3105488 Polak PE, Kalinin S, Feinstein DL. Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain. 2011;134(Pt 3):665–77. 21297130 10.1093/brain/awq362 PMC3105488

9. Carandini T Mancini M Bogdan I Rae CL Barritt AW Clerico M In vivo evidence of functional disconnection between brainstem monoaminergic nuclei and brain networks in multiple sclerosis Multiple Scler Relat disorders 2021 56 103224 10.1016/j.msard.2021.103224 34461571 Carandini T, Mancini M, Bogdan I, Rae CL, Barritt AW, Clerico M, et al. In vivo evidence of functional disconnection between brainstem monoaminergic nuclei and brain networks in multiple sclerosis. Multiple Scler Relat disorders. 2021;56:103224. 10.1016/j.msard.2021.103224 34461571

10. Carandini T Mancini M Bogdan I Rae CL Barritt AW Sethi A Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis NeuroImage Clin 2021 30 102587 10.1016/j.nicl.2021.102587 33610097 PMC7903010 Carandini T, Mancini M, Bogdan I, Rae CL, Barritt AW, Sethi A, et al. Disruption of brainstem monoaminergic fibre tracts in multiple sclerosis as a putative mechanism for cognitive fatigue: a fixel-based analysis. NeuroImage Clin. 2021;30:102587. 33610097 10.1016/j.nicl.2021.102587 PMC7903010

11. Gadea M Martinez-Bisbal MC Marti-Bonmati L Espert R Casanova B Coret F Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis Brain 2004 127 Pt 1 89 98 10.1093/brain/awh002 14506072 Gadea M, Martinez-Bisbal MC, Marti-Bonmati L, Espert R, Casanova B, Coret F, et al. Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis. Brain. 2004;127(Pt 1):89–98. 14506072 10.1093/brain/awh002

12. Hanken K Manousi A Klein J Kastrup A Eling P Hildebrandt H On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network Eur J Neurol 2016 23 1 101 9 10.1111/ene.12815 26278274 Hanken K, Manousi A, Klein J, Kastrup A, Eling P, Hildebrandt H. On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network. Eur J Neurol. 2016;23(1):101–9. 26278274 10.1111/ene.12815

13. Pamphlett R Uptake of environmental toxicants by the locus ceruleus: a potential trigger for neurodegenerative, demyelinating and psychiatric disorders Med Hypotheses 2014 82 1 97 104 10.1016/j.mehy.2013.11.016 24315447 Pamphlett R. Uptake of environmental toxicants by the locus ceruleus: a potential trigger for neurodegenerative, demyelinating and psychiatric disorders. Med Hypotheses. 2014;82(1):97–104. 24315447 10.1016/j.mehy.2013.11.016

14. Pamphlett R Buckland ME Bishop DP Potentially toxic elements in the brains of people with multiple sclerosis Sci Rep 2023 13 1 655 10.1038/s41598-022-27169-9 36635465 PMC9837144 Pamphlett R, Buckland ME, Bishop DP. Potentially toxic elements in the brains of people with multiple sclerosis. Sci Rep. 2023;13(1):655. 36635465 10.1038/s41598-022-27169-9 PMC9837144

15. Aston-Jones G Waterhouse B Locus coeruleus: From global projection system to adaptive regulation of behavior Brain Res 2016 1645 75 8 10.1016/j.brainres.2016.03.001 26969408 PMC4969192 Aston-Jones G, Waterhouse B. Locus coeruleus: From global projection system to adaptive regulation of behavior. Brain Res. 2016;1645:75–8. 26969408 10.1016/j.brainres.2016.03.001 PMC4969192

16. Foote SL Berridge CW New developments and future directions in understanding locus coeruleus - Norepinephrine (LC-NE) function Brain Res 2019 1709 81 4 10.1016/j.brainres.2018.09.033 30267649 PMC6421084 Foote SL, Berridge CW. New developments and future directions in understanding locus coeruleus - Norepinephrine (LC-NE) function. Brain Res. 2019;1709:81–4. 30267649 10.1016/j.brainres.2018.09.033 PMC6421084

17. Maeda T The locus coeruleus: history J Chem Neuroanat 2000 18 1–2 57 64 10.1016/S0891-0618(99)00051-4 10708919 Maeda T. The locus coeruleus: history. J Chem Neuroanat. 2000;18(1–2):57–64. 10708919 10.1016/s0891-0618(99)00051-4

18. Nikolenko VN Borminskaya ID Nikitina AT Golyshkina MS Rizaeva NA Oganesyan MV Locus Coeruleus-Norepinephrine System: Spheres of Influence and Contribution to the Development of Neurodegenerative Diseases Front bioscience (Landmark edition) 2024 29 3 118 10.31083/j.fbl2903118 38538284 Nikolenko VN, Borminskaya ID, Nikitina AT, Golyshkina MS, Rizaeva NA, Oganesyan MV. Locus Coeruleus-Norepinephrine System: Spheres of Influence and Contribution to the Development of Neurodegenerative Diseases. Front bioscience (Landmark edition). 2024;29(3):118. 10.31083/j.fbl2903118 38538284

19. Reyes BAS The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders Eur J Neurosci 2025 61 7 e70111 10.1111/ejn.70111 40219735 PMC11992612 Reyes BAS. The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders. Eur J Neurosci. 2025;61(7):e70111. 40219735 10.1111/ejn.70111 PMC11992612

20. Schwarz LA Luo L Organization of the Locus Coeruleus-Norepinephrine System Curr biology: CB 2015 25 21 R1051 6 10.1016/j.cub.2015.09.039 26528750 Schwarz LA, Luo L. Organization of the Locus Coeruleus-Norepinephrine System. Curr biology: CB. 2015;25(21):R1051–6. 26528750 10.1016/j.cub.2015.09.039

21. Tubbs RS Loukas M Shoja MM Mortazavi MM Cohen-Gadol AA Félix Vicq d’Azyr (1746–1794): early founder of neuroanatomy and royal French physician Childs Nerv Syst 2011 27 7 1031 4 10.1007/s00381-011-1424-y 21445631 Tubbs RS, Loukas M, Shoja MM, Mortazavi MM, Cohen-Gadol AA. Félix Vicq d’Azyr (1746–1794): early founder of neuroanatomy and royal French physician. Childs Nerv Syst. 2011;27(7):1031–4. 21445631 10.1007/s00381-011-1424-y

22. Reil JC. Untersuchungen u¨ber den Bau des grossen Gehirns im Menschen. Arch Physiol 1809;9:136–524.

23. Wenzel J, Wenzel C. De Penitiori Structura Cerebri Hominis et Brutorum. Tubingen. 1812.

24. Jacobsohn L. On the nuclei of the human brainstem. Proceedings of the Royal Prussian Academy of Sciences. 1909.

25. Bondareff W Mountjoy CQ Roth M Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia Neurology 1982 32 2 164 8 10.1212/WNL.32.2.164 7198741 Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology. 1982;32(2):164–8. 7198741 10.1212/wnl.32.2.164

26. German DC Walker BS Manaye K Smith WK Woodward DJ North AJ The human locus coeruleus: computer reconstruction of cellular distribution J neuroscience: official J Soc Neurosci 1988 8 5 1776 88 10.1523/JNEUROSCI.08-05-01776.1988 PMC6569207 3367220 German DC, Walker BS, Manaye K, Smith WK, Woodward DJ, North AJ. The human locus coeruleus: computer reconstruction of cellular distribution. J neuroscience: official J Soc Neurosci. 1988;8(5):1776–88. 10.1523/JNEUROSCI.08-05-01776.1988 PMC6569207 3367220

27. Vijayashankar N Brody H A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging J Neuropathol Exp Neurol 1979 38 5 490 7 10.1097/00005072-197909000-00004 469568 Vijayashankar N, Brody H. A quantitative study of the pigmented neurons in the nuclei locus coeruleus and subcoeruleus in man as related to aging. J Neuropathol Exp Neurol. 1979;38(5):490–7. 469568 10.1097/00005072-197909000-00004

28. Baker KG Tork I Hornung JP Halasz P The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study Exp Brain Res 1989 77 2 257 70 10.1007/BF00274983 2571514 Baker KG, Tork I, Hornung JP, Halasz P. The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study. Exp Brain Res. 1989;77(2):257–70. 2571514 10.1007/BF00274983

29. Chan-Palay V Asan E Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression J Comp Neurol 1989 287 3 357 72 10.1002/cne.902870307 2570793 Chan-Palay V, Asan E. Quantitation of catecholamine neurons in the locus coeruleus in human brains of normal young and older adults and in depression. J Comp Neurol. 1989;287(3):357–72. 2570793 10.1002/cne.902870307

30. Sturrock RR Rao KA A quantitative histological study of neuronal loss from the locus coeruleus of ageing mice Neuropathol Appl Neurobiol 1985 11 1 55 60 10.1111/j.1365-2990.1985.tb00004.x 4000403 Sturrock RR, Rao KA. A quantitative histological study of neuronal loss from the locus coeruleus of ageing mice. Neuropathol Appl Neurobiol. 1985;11(1):55–60. 4000403 10.1111/j.1365-2990.1985.tb00004.x

31. Foote SL Bloom FE Aston-Jones G Nucleus locus ceruleus: new evidence of anatomical and physiological specificity Physiol Rev 1983 63 3 844 914 10.1152/physrev.1983.63.3.844 6308694 Foote SL, Bloom FE, Aston-Jones G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev. 1983;63(3):844–914. 6308694 10.1152/physrev.1983.63.3.844

32. Swanson LW The locus coeruleus: a cytoarchitectonic, Golgi and immunohistochemical study in the albino rat Brain Res 1976 110 1 39 56 10.1016/0006-8993(76)90207-9 776360 Swanson LW. The locus coeruleus: a cytoarchitectonic, Golgi and immunohistochemical study in the albino rat. Brain Res. 1976;110(1):39–56. 776360 10.1016/0006-8993(76)90207-9

33. Goldman G Coleman PD Neuron numbers in locus coeruleus do not change with age in Fisher 344 rat Neurobiol Aging 1981 2 1 33 6 10.1016/0197-4580(81)90056-7 7266740 Goldman G, Coleman PD. Neuron numbers in locus coeruleus do not change with age in Fisher 344 rat. Neurobiol Aging. 1981;2(1):33–6. 7266740 10.1016/0197-4580(81)90056-7

34. Weinshenker D Holmes PV Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin Brain Res 2016 1641 Pt B 320 37 10.1016/j.brainres.2015.11.025 26607256 PMC4874918 Weinshenker D, Holmes PV. Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin. Brain Res. 2016;1641(Pt B):320–37. 26607256 10.1016/j.brainres.2015.11.025 PMC4874918

35. Caramia M Romanov RA Sideromenos S Hevesi Z Zhao M Krasniakova M Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus Proc Natl Acad Sci U S A 2023 120 31 e2222095120 10.1073/pnas.2222095120 37487094 PMC10401028 Caramia M, Romanov RA, Sideromenos S, Hevesi Z, Zhao M, Krasniakova M, et al. Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus. Proc Natl Acad Sci U S A. 2023;120(31):e2222095120. 37487094 10.1073/pnas.2222095120 PMC10401028

36. Ross JA Van Bockstaele EJ The Locus Coeruleus- Norepinephrine System in Stress and Arousal: Unraveling Historical, Current, and Future Perspectives Front Psychiatry 2020 11 601519 10.3389/fpsyt.2020.601519 33584368 PMC7873441 Ross JA, Van Bockstaele EJ. The Locus Coeruleus- Norepinephrine System in Stress and Arousal: Unraveling Historical, Current, and Future Perspectives. Front Psychiatry. 2020;11:601519. 33584368 10.3389/fpsyt.2020.601519 PMC7873441

37. Hirschberg S, Li Y, Randall A, Kremer EJ, Pickering AE. Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. eLife. 2017;6:e29808. 10.7554/eLife.29808 PMC5653237 29027903

38. McKinney A, Hu M, Hoskins A, Mohammadyar A, Naeem N, Jing J et al. Cellular composition and circuit organization of the locus coeruleus of adult mice. eLife. 2023;12. 10.7554/eLife.80100 PMC9934863 36734517

39. Luskin AT Li L Fu X Martin MM Barcomb K Girven KS Heterogeneous pericoerulear neurons tune arousal and exploratory behaviours Nature 2025 643 8071 437 47 10.1038/s41586-025-08952-w 40335695 PMC12240712 Luskin AT, Li L, Fu X, Martin MM, Barcomb K, Girven KS, et al. Heterogeneous pericoerulear neurons tune arousal and exploratory behaviours. Nature. 2025;643(8071):437–47. 40335695 10.1038/s41586-025-08952-w PMC12240712

40. Silva Tortorelli L Garad M Megemont M Haga-Yamanaka S Goel A Yang H Variations of neuronal properties in the region of locus coeruleus of mice Brain Res 2024 1845 149289 10.1016/j.brainres.2024.149289 39442646 PMC12094211 Silva Tortorelli L, Garad M, Megemont M, Haga-Yamanaka S, Goel A, Yang H. Variations of neuronal properties in the region of locus coeruleus of mice. Brain Res. 2024;1845:149289. 39442646 10.1016/j.brainres.2024.149289 PMC12094211

41. Nardone S De Luca R Zito A Klymko N Nicoloutsopoulos D Amsalem O A spatially-resolved transcriptional atlas of the murine dorsal pons at single-cell resolution Nat Commun 2024 15 1 1966 10.1038/s41467-024-45907-7 38438345 PMC10912765 Nardone S, De Luca R, Zito A, Klymko N, Nicoloutsopoulos D, Amsalem O, et al. A spatially-resolved transcriptional atlas of the murine dorsal pons at single-cell resolution. Nat Commun. 2024;15(1):1966. 38438345 10.1038/s41467-024-45907-7 PMC10912765

42. Weber LM, Divecha HR, Tran MN, Kwon SH, Spangler A, Montgomery KD et al. The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics. eLife. 2024;12:RP84628. 10.7554/eLife.84628 PMC10945708 38266073

43. Wagner-Altendorf TA Fischer B Roeper J Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons Eur J Neurosci 2019 50 11 3772 85 10.1111/ejn.14553 31430399 Wagner-Altendorf TA, Fischer B, Roeper J. Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons. Eur J Neurosci. 2019;50(11):3772–85. 31430399 10.1111/ejn.14553

44. Veréb D, Mijalkov M, Canal-Garcia A, Chang YW, Gomez-Ruiz E, Gerboles BZ et al. Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions. eLife. 2023;12:RP87188. 10.7554/eLife.87188 PMC10471162 37650882

45. Gilvesy A Husen E Magloczky Z Mihaly O Hortobágyi T Kanatani S Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging Acta Neuropathol 2022 144 4 651 76 10.1007/s00401-022-02477-6 36040521 PMC9468059 Gilvesy A, Husen E, Magloczky Z, Mihaly O, Hortobágyi T, Kanatani S, et al. Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging. Acta Neuropathol. 2022;144(4):651–76. 36040521 10.1007/s00401-022-02477-6 PMC9468059

46. Madelung CF Meder D Fuglsang SA Marques MM Boer VO Madsen KH Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson’s Disease Mov Disord 2022 37 3 479 89 10.1002/mds.28945 35114035 PMC9303353 Madelung CF, Meder D, Fuglsang SA, Marques MM, Boer VO, Madsen KH, et al. Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson’s Disease. Mov Disord. 2022;37(3):479–89. 35114035 10.1002/mds.28945 PMC9303353

47. Lorton D Bellinger DL Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells Int J Mol Sci 2015 16 3 5635 65 10.3390/ijms16035635 25768345 PMC4394497 Lorton D, Bellinger DL. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015;16(3):5635–65. 25768345 10.3390/ijms16035635 PMC4394497

48. Counts SE, Mufson EJ. Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity. J Neurochem. 2010;113(3):649–60. 10.1111/j.1471-4159.2010.06622.x PMC2913691 20132474

49. O’Neill E Harkin A Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson’s disease Neural regeneration Res 2018 13 8 1332 7 10.4103/1673-5374.235219 PMC6108217 30106035 O’Neill E, Harkin A. Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson’s disease. Neural regeneration Res. 2018;13(8):1332–7. 10.4103/1673-5374.235219 PMC6108217 30106035

50. Iannitelli AF, Kelberman MA, Lustberg DJ, Korukonda A, McCann KE, Mulvey B et al. The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease. eNeuro. 2023;10(1):ENEURO.0483-22.2022. 10.1523/ENEURO.0483-22.2022 PMC9829100 36635251

51. Madrigal JL Feinstein DL Dello RC Norepinephrine protects cortical neurons against microglial-induced cell death J Neurosci Res 2005 81 3 390 6 10.1002/jnr.20481 15948176 Madrigal JL, Feinstein DL, Dello RC. Norepinephrine protects cortical neurons against microglial-induced cell death. J Neurosci Res. 2005;81(3):390–6. 15948176 10.1002/jnr.20481

52. Cohen RI Almazan G Norepinephrine-stimulated PI hydrolysis in oligodendrocytes is mediated by alpha 1A-adrenoceptors NeuroReport 1993 4 9 1115 8 8106008 Cohen RI, Almazan G. Norepinephrine-stimulated PI hydrolysis in oligodendrocytes is mediated by alpha 1A-adrenoceptors. NeuroReport. 1993;4(9):1115–8. 8106008

53. Ghiani CA Eisen AM Yuan X DePinho RA McBain CJ Gallo V Neurotransmitter receptor activation triggers p27(Kip1)and p21(CIP1) accumulation and G1 cell cycle arrest in oligodendrocyte progenitors Development 1999 126 5 1077 90 10.1242/dev.126.5.1077 9927607 Ghiani CA, Eisen AM, Yuan X, DePinho RA, McBain CJ, Gallo V. Neurotransmitter receptor activation triggers p27(Kip1)and p21(CIP1) accumulation and G1 cell cycle arrest in oligodendrocyte progenitors. Development. 1999;126(5):1077–90. 9927607 10.1242/dev.126.5.1077

54. Lu TY Hanumaihgari P Hsu ET Agarwal A Kawaguchi R Calabresi PA Norepinephrine modulates calcium dynamics in cortical oligodendrocyte precursor cells promoting proliferation during arousal in mice Nat Neurosci 2023 26 10 1739 50 10.1038/s41593-023-01426-0 37697112 PMC10630072 Lu TY, Hanumaihgari P, Hsu ET, Agarwal A, Kawaguchi R, Calabresi PA, et al. Norepinephrine modulates calcium dynamics in cortical oligodendrocyte precursor cells promoting proliferation during arousal in mice. Nat Neurosci. 2023;26(10):1739–50. 37697112 10.1038/s41593-023-01426-0 PMC10630072

55. Fiore F Alhalaseh K Dereddi RR Bodaleo Torres F Coban I Harb A Norepinephrine regulates calcium signals and fate of oligodendrocyte precursor cells in the mouse cerebral cortex Nat Commun 2023 14 1 8122 10.1038/s41467-023-43920-w 38065932 PMC10709653 Fiore F, Alhalaseh K, Dereddi RR, Bodaleo Torres F, Coban I, Harb A, et al. Norepinephrine regulates calcium signals and fate of oligodendrocyte precursor cells in the mouse cerebral cortex. Nat Commun. 2023;14(1):8122. 38065932 10.1038/s41467-023-43920-w PMC10709653

56. Taherian N Vaezi G Neamati A Hojjati V Ghorbani-Taherdehi F Sahebkar A The dose-dependent neuroprotective effect of norepinephrine in improving memory retrieval in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis Brain Res Bull 2024 209 110907 10.1016/j.brainresbull.2024.110907 38395110 Taherian N, Vaezi G, Neamati A, Hojjati V, Ghorbani-Taherdehi F, Sahebkar A, et al. The dose-dependent neuroprotective effect of norepinephrine in improving memory retrieval in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis. Brain Res Bull. 2024;209:110907. 38395110 10.1016/j.brainresbull.2024.110907

57. Paukert M Agarwal A Cha J Doze VA Kang JU Bergles DE Norepinephrine controls astroglial responsiveness to local circuit activity Neuron 2014 82 6 1263 70 10.1016/j.neuron.2014.04.038 24945771 PMC4080721 Paukert M, Agarwal A, Cha J, Doze VA, Kang JU, Bergles DE. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron. 2014;82(6):1263–70. 24945771 10.1016/j.neuron.2014.04.038 PMC4080721

58. Noble PG Antel JP Yong VW Astrocytes and catalase prevent the toxicity of catecholamines to oligodendrocytes Brain Res 1994 633 1–2 83 90 10.1016/0006-8993(94)91525-3 8137175 Noble PG, Antel JP, Yong VW. Astrocytes and catalase prevent the toxicity of catecholamines to oligodendrocytes. Brain Res. 1994;633(1–2):83–90. 8137175 10.1016/0006-8993(94)91525-3

59. Khorchid A Fragoso G Shore G Almazan G Catecholamine-induced oligodendrocyte cell death in culture is developmentally regulated and involves free radical generation and differential activation of caspase-3 Glia 2002 40 3 283 99 10.1002/glia.10123 12420309 Khorchid A, Fragoso G, Shore G, Almazan G. Catecholamine-induced oligodendrocyte cell death in culture is developmentally regulated and involves free radical generation and differential activation of caspase-3. Glia. 2002;40(3):283–99. 12420309 10.1002/glia.10123

60. Yang JH Lee EO Kim SE Suh YH Chong YH Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-beta peptide via action at beta-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages Exp Neurol 2012 236 2 199 206 10.1016/j.expneurol.2012.05.008 22609331 Yang JH, Lee EO, Kim SE, Suh YH, Chong YH. Norepinephrine differentially modulates the innate inflammatory response provoked by amyloid-beta peptide via action at beta-adrenoceptors and activation of cAMP/PKA pathway in human THP-1 macrophages. Exp Neurol. 2012;236(2):199–206. 22609331 10.1016/j.expneurol.2012.05.008

61. Ishii Y, Yamaizumi A, Kawakami A, Islam A, Choudhury ME, Takahashi H et al. Anti-inflammatory effects of noradrenaline on LPS-treated microglial cells: Suppression of NFkappaB nuclear translocation and subsequent STAT1 phosphorylation. Neurochem Int. 2015;90:56–66. 10.1016/j.neuint.2015.07.010 26190182

62. Sun Z Hou D Liu S Fu W Wang J Liang Z Norepinephrine inhibits the cytotoxicity of NK92–MI cells via the beta2–adrenoceptor/cAMP/PKA/p–CREB signaling pathway Mol Med Rep 2018 17 6 8530 5 29658580 10.3892/mmr.2018.8872 Sun Z, Hou D, Liu S, Fu W, Wang J, Liang Z. Norepinephrine inhibits the cytotoxicity of NK92–MI cells via the beta2–adrenoceptor/cAMP/PKA/p–CREB signaling pathway. Mol Med Rep. 2018;17(6):8530–5. 29658580 10.3892/mmr.2018.8872

63. Khoruzhaia TA Saakov BA [Change in monoamine content and monoamine oxidase activity in brain structures during experimental allergic encephalomyelitis] Biull Eksp Biol Med 1975 79 6 80 2 1222257 Khoruzhaia TA, Saakov BA. [Change in monoamine content and monoamine oxidase activity in brain structures during experimental allergic encephalomyelitis]. Biull Eksp Biol Med. 1975;79(6):80–2. 1222257

64. Krenger W Honegger CG Feurer C Cammisuli S Changes of neurotransmitter systems in chronic relapsing experimental allergic encephalomyelitis in rat brain and spinal cord J Neurochem 1986 47 4 1247 54 10.1111/j.1471-4159.1986.tb00747.x 2427658 Krenger W, Honegger CG, Feurer C, Cammisuli S. Changes of neurotransmitter systems in chronic relapsing experimental allergic encephalomyelitis in rat brain and spinal cord. J Neurochem. 1986;47(4):1247–54. 2427658 10.1111/j.1471-4159.1986.tb00747.x

65. White SR Bhatnagar RK Bardo MT Norepinephrine depletion in the spinal cord gray matter of rats with experimental allergic encephalomyelitis J Neurochem 1983 40 6 1771 3 10.1111/j.1471-4159.1983.tb08156.x 6602207 White SR, Bhatnagar RK, Bardo MT. Norepinephrine depletion in the spinal cord gray matter of rats with experimental allergic encephalomyelitis. J Neurochem. 1983;40(6):1771–3. 6602207 10.1111/j.1471-4159.1983.tb08156.x

66. Li Q Yang T Guo AC Fan YP Role of catalpol in ameliorating the pathogenesis of experimental autoimmune encephalomyelitis by increasing the level of noradrenaline in the locus coeruleus Mol Med Rep 2018 17 3 4163 72 29328415 10.3892/mmr.2018.8378 PMC5802186 Li Q, Yang T, Guo AC, Fan YP. Role of catalpol in ameliorating the pathogenesis of experimental autoimmune encephalomyelitis by increasing the level of noradrenaline in the locus coeruleus. Mol Med Rep. 2018;17(3):4163–72. 29328415 10.3892/mmr.2018.8378 PMC5802186

67. Torrillas-de la Cal A Torres-Sanchez S Bravo L Llorca-Torralba M Garcia-Partida JA Arroba AI Chemogenetic activation of locus coeruleus neurons ameliorates the severity of multiple sclerosis J Neuroinflamm 2023 20 1 198 10.1186/s12974-023-02865-z PMC10474779 37658434 Torrillas-de la Cal A, Torres-Sanchez S, Bravo L, Llorca-Torralba M, Garcia-Partida JA, Arroba AI, et al. Chemogenetic activation of locus coeruleus neurons ameliorates the severity of multiple sclerosis. J Neuroinflamm. 2023;20(1):198. 10.1186/s12974-023-02865-z PMC10474779 37658434

68. Barkhatova VP Zavalishin IA Askarova LS Shavratskii VK Demina EG Changes in neurotransmitters in multiple sclerosis Neurosci Behav Physiol 1998 28 4 341 4 10.1007/BF02464784 9762701 Barkhatova VP, Zavalishin IA, Askarova LS, Shavratskii VK, Demina EG. Changes in neurotransmitters in multiple sclerosis. Neurosci Behav Physiol. 1998;28(4):341–4. 9762701 10.1007/BF02464784

69. Markianos M Koutsis G Evangelopoulos ME Mandellos D Karahalios G Sfagos C Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis J Neurochem 2009 108 1 158 64 10.1111/j.1471-4159.2008.05750.x 19014375 Markianos M, Koutsis G, Evangelopoulos ME, Mandellos D, Karahalios G, Sfagos C. Relationship of CSF neurotransmitter metabolite levels to disease severity and disability in multiple sclerosis. J Neurochem. 2009;108(1):158–64. 19014375 10.1111/j.1471-4159.2008.05750.x

70. Privitera M, von Ziegler LM, Floriou-Servou A, Duss SN, Zhang R, Waag R et al. Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression. eLife. 2024;12:RP88559. 10.7554/eLife.88559 PMC10937036 38477670

71. Nahvi RJ Tanelian A Nwokafor C Godino A Parise E Estill M Transcriptome profiles associated with resilience and susceptibility to single prolonged stress in the locus coeruleus and nucleus accumbens in male sprague-dawley rats Behav Brain Res 2023 439 114162 10.1016/j.bbr.2022.114162 36257560 PMC9812303 Nahvi RJ, Tanelian A, Nwokafor C, Godino A, Parise E, Estill M, et al. Transcriptome profiles associated with resilience and susceptibility to single prolonged stress in the locus coeruleus and nucleus accumbens in male sprague-dawley rats. Behav Brain Res. 2023;439:114162. 36257560 10.1016/j.bbr.2022.114162 PMC9812303

72. Giofrè F Lugaresi A Baccari F Lui E Roberts S Malpas C The topography of infratentorial lesions in depression and anxiety in multiple sclerosis J Neurol 2025 272 6 420 10.1007/s00415-025-13167-0 40418350 PMC12106590 Giofrè F, Lugaresi A, Baccari F, Lui E, Roberts S, Malpas C, et al. The topography of infratentorial lesions in depression and anxiety in multiple sclerosis. J Neurol. 2025;272(6):420. 40418350 10.1007/s00415-025-13167-0 PMC12106590

73. Pamphlett R Bishop DP The toxic metal hypothesis for neurological disorders Front Neurol 2023 14 1173779 10.3389/fneur.2023.1173779 37426441 PMC10328356 Pamphlett R, Bishop DP. The toxic metal hypothesis for neurological disorders. Front Neurol. 2023;14:1173779. 37426441 10.3389/fneur.2023.1173779 PMC10328356

74. Pamphlett R Mak R Lee J Buckland ME Harding AJ Kum Jew S Concentrations of toxic metals and essential trace elements vary among individual neurons in the human locus ceruleus PLoS ONE 2020 15 5 e0233300 10.1371/journal.pone.0233300 32428015 PMC7237016 Pamphlett R, Mak R, Lee J, Buckland ME, Harding AJ, Kum Jew S, et al. Concentrations of toxic metals and essential trace elements vary among individual neurons in the human locus ceruleus. PLoS ONE. 2020;15(5):e0233300. 32428015 10.1371/journal.pone.0233300 PMC7237016

75. Pasquini J Sigurdsson HP Firbank M Best L Foster V Galley D Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy J Neurol 2025 272 3 195 10.1007/s00415-025-12932-5 39932591 PMC11814031 Pasquini J, Sigurdsson HP, Firbank M, Best L, Foster V, Galley D, et al. Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy. J Neurol. 2025;272(3):195. 39932591 10.1007/s00415-025-12932-5 PMC11814031

76. Chen Y, Chen T, Hou R. Locus coeruleus in the pathogenesis of Alzheimer’s disease: A systematic review. Volume 8. Alzheimer’s & dementia; 2022. p. e12257. (New York, N Y). 1. 10.1002/trc2.12257 PMC8900465 35282658

77. Holland N Robbins TW Rowe JB The role of noradrenaline in cognition and cognitive disorders Brain 2021 144 8 2243 56 10.1093/brain/awab111 33725122 PMC8418349 Holland N, Robbins TW, Rowe JB. The role of noradrenaline in cognition and cognitive disorders. Brain. 2021;144(8):2243–56. 33725122 10.1093/brain/awab111 PMC8418349

78. Pan Z Jia Z Jiang T Cai Q Di Z Gan L Modulation of the Neurovascular Unit by the Locus Coeruleus-Norepinephrine System: From Physiological Mechanisms to Therapeutic Applications Faseb j 2025 39 20 e71127 10.1096/fj.202502069R 41078309 PMC12516802 Pan Z, Jia Z, Jiang T, Cai Q, Di Z, Gan L, et al. Modulation of the Neurovascular Unit by the Locus Coeruleus-Norepinephrine System: From Physiological Mechanisms to Therapeutic Applications. Faseb j. 2025;39(20):e71127. 41078309 10.1096/fj.202502069R PMC12516802

79. Abbott NJ Rönnbäck L Hansson E Astrocyte-endothelial interactions at the blood-brain barrier Nat Rev Neurosci 2006 7 1 41 53 10.1038/nrn1824 16371949 Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. 16371949 10.1038/nrn1824

80. Kaplan L Chow BW Gu C Neuronal regulation of the blood-brain barrier and neurovascular coupling Nat Rev Neurosci 2020 21 8 416 32 10.1038/s41583-020-0322-2 32636528 PMC8934575 Kaplan L, Chow BW, Gu C. Neuronal regulation of the blood-brain barrier and neurovascular coupling. Nat Rev Neurosci. 2020;21(8):416–32. 32636528 10.1038/s41583-020-0322-2 PMC8934575

81. Ahmad I Muchiri RN van Breemen RB Rubinstein I Lindeblad M Feinstein DL Effects of Long-Acting Anticoagulant Rodenticides on Rabbit Plasma Extracellular Vesicles ACS omega 2025 10 16 16410 8 10.1021/acsomega.4c10887 40321562 PMC12044563 Ahmad I, Muchiri RN, van Breemen RB, Rubinstein I, Lindeblad M, Feinstein DL. Effects of Long-Acting Anticoagulant Rodenticides on Rabbit Plasma Extracellular Vesicles. ACS omega. 2025;10(16):16410–8. 40321562 10.1021/acsomega.4c10887 PMC12044563

82. Pamphlett R Waley P Motor neuron uptake of low dose inorganic mercury J Neurol Sci 1996 135 1 63 7 10.1016/0022-510X(95)00258-4 8926498 Pamphlett R, Waley P. Motor neuron uptake of low dose inorganic mercury. J Neurol Sci. 1996;135(1):63–7. 8926498 10.1016/0022-510x(95)00258-4

83. Pamphlett R Kum Jew S Inorganic mercury in human astrocytes, oligodendrocytes, corticomotoneurons and the locus ceruleus: implications for multiple sclerosis, neurodegenerative disorders and gliomas Biometals: Int J role metal ions biology Biochem Med 2018 31 5 807 19 10.1007/s10534-018-0124-4 PMC6133182 29959651 Pamphlett R, Kum Jew S. Inorganic mercury in human astrocytes, oligodendrocytes, corticomotoneurons and the locus ceruleus: implications for multiple sclerosis, neurodegenerative disorders and gliomas. Biometals: Int J role metal ions biology Biochem Med. 2018;31(5):807–19. 10.1007/s10534-018-0124-4 PMC6133182 29959651

84. Pamphlett R Kum Jew S Heavy metals in locus ceruleus and motor neurons in motor neuron disease Acta Neuropathol Commun 2013 1 81 10.1186/2051-5960-1-81 24330485 PMC3878779 Pamphlett R, Kum Jew S. Heavy metals in locus ceruleus and motor neurons in motor neuron disease. Acta Neuropathol Commun. 2013;1:81. 24330485 10.1186/2051-5960-1-81 PMC3878779

85. Beard JL Wiesinger JA Jones BC Cellular iron concentrations directly affect the expression levels of norepinephrine transporter in PC12 cells and rat brain tissue Brain Res 2006 1092 1 47 58 10.1016/j.brainres.2006.03.071 16650837 Beard JL, Wiesinger JA, Jones BC. Cellular iron concentrations directly affect the expression levels of norepinephrine transporter in PC12 cells and rat brain tissue. Brain Res. 2006;1092(1):47–58. 16650837 10.1016/j.brainres.2006.03.071

86. Chen KB Lin AM Chiu TH Oxidative injury to the locus coeruleus of rat brain: neuroprotection by melatonin J Pineal Res 2003 35 2 109 17 10.1034/j.1600-079X.2003.00063.x 12887654 Chen KB, Lin AM, Chiu TH. Oxidative injury to the locus coeruleus of rat brain: neuroprotection by melatonin. J Pineal Res. 2003;35(2):109–17. 12887654 10.1034/j.1600-079x.2003.00063.x

87. Pamphlett R Bishop DP Kum Jew S Doble PA Age-related accumulation of toxic metals in the human locus ceruleus PLoS ONE 2018 13 9 e0203627 10.1371/journal.pone.0203627 30231068 PMC6145836 Pamphlett R, Bishop DP, Kum Jew S, Doble PA. Age-related accumulation of toxic metals in the human locus ceruleus. PLoS ONE. 2018;13(9):e0203627. 30231068 10.1371/journal.pone.0203627 PMC6145836

88. Zecca L Stroppolo A Gatti A Tampellini D Toscani M Gallorini M The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging Proc Natl Acad Sci U S A 2004 101 26 9843 8 10.1073/pnas.0403495101 15210960 PMC470762 Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci U S A. 2004;101(26):9843–8. 15210960 10.1073/pnas.0403495101 PMC470762

89. Zecca L Casella L Albertini A Bellei C Zucca FA Engelen M Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease J Neurochem 2008 106 4 1866 75 10.1111/j.1471-4159.2008.05541.x 18624918 Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, et al. Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem. 2008;106(4):1866–75. 18624918 10.1111/j.1471-4159.2008.05541.x

90. Pamphlett R Bishop DP Mercury is present in neurons and oligodendrocytes in regions of the brain affected by Parkinson’s disease and co-localises with Lewy bodies PLoS ONE 2022 17 1 e0262464 10.1371/journal.pone.0262464 35015796 PMC8752015 Pamphlett R, Bishop DP. Mercury is present in neurons and oligodendrocytes in regions of the brain affected by Parkinson’s disease and co-localises with Lewy bodies. PLoS ONE. 2022;17(1):e0262464. 35015796 10.1371/journal.pone.0262464 PMC8752015

91. Pamphlett R Kum Jew S Locus ceruleus neurons in people with autism contain no histochemically-detectable mercury Biometals: Int J role metal ions biology Biochem Med 2016 29 1 171 5 10.1007/s10534-015-9898-9 PMC4735248 26613607 Pamphlett R, Kum Jew S. Locus ceruleus neurons in people with autism contain no histochemically-detectable mercury. Biometals: Int J role metal ions biology Biochem Med. 2016;29(1):171–5. 10.1007/s10534-015-9898-9 PMC4735248 26613607

92. Mulvey B Bhatti DL Gyawali S Lake AM Kriaucionis S Ford CP Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus Cell Rep 2018 23 8 2225 35 10.1016/j.celrep.2018.04.054 29791834 PMC6070358 Mulvey B, Bhatti DL, Gyawali S, Lake AM, Kriaucionis S, Ford CP, et al. Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus. Cell Rep. 2018;23(8):2225–35. 29791834 10.1016/j.celrep.2018.04.054 PMC6070358

93. Mariscal P Bravo L Llorca-Torralba M Razquin J Miguelez C Suarez-Pereira I Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice Biol Sex Differ 2023 14 1 64 10.1186/s13293-023-00550-7 37770907 PMC10540344 Mariscal P, Bravo L, Llorca-Torralba M, Razquin J, Miguelez C, Suarez-Pereira I, et al. Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice. Biol Sex Differ. 2023;14(1):64. 37770907 10.1186/s13293-023-00550-7 PMC10540344

94. Bangasser DA Curtis A Reyes BA Bethea TT Parastatidis I Ischiropoulos H Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology Mol Psychiatry 2010 15 9 877 10.1038/mp.2010.89 20548297 PMC2935505 Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H, et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry. 2010;15(9):877. 20548297 10.1038/mp.2010.66 PMC2935505

95. Bangasser DA Eck SR Telenson AM Salvatore M Sex differences in stress regulation of arousal and cognition Physiol Behav 2018 187 42 50 10.1016/j.physbeh.2017.09.025 28974457 PMC6402500 Bangasser DA, Eck SR, Telenson AM, Salvatore M. Sex differences in stress regulation of arousal and cognition. Physiol Behav. 2018;187:42–50. 28974457 10.1016/j.physbeh.2017.09.025 PMC6402500

96. Serova L Rivkin M Nakashima A Sabban EL Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus Neuroendocrinology 2002 75 3 193 200 10.1159/000048237 11914591 Serova L, Rivkin M, Nakashima A, Sabban EL. Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus. Neuroendocrinology. 2002;75(3):193–200. 11914591 10.1159/000048237

97. Riley E, Cicero N, Swallow K, De Rosa E, Anderson A. Locus coeruleus neuromelanin accumulation and dissipation across the lifespan. bioRxiv. 2023.

98. Sulkes Cuevas JN Watanabe M Uematsu A Johansen JP Whole-brain afferent input mapping to functionally distinct brainstem noradrenaline cell types Neurosci Res 2023 194 44 57 10.1016/j.neures.2023.04.004 37062443 Sulkes Cuevas JN, Watanabe M, Uematsu A, Johansen JP. Whole-brain afferent input mapping to functionally distinct brainstem noradrenaline cell types. Neurosci Res. 2023;194:44–57. 37062443 10.1016/j.neures.2023.04.004

99. Luckey AM Robertson IH Lawlor B Mohan A Vanneste S Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer’s Disease in Females J Alzheimer’s disease: JAD 2021 83 2 505 22 10.3233/JAD-210404 34334399 Luckey AM, Robertson IH, Lawlor B, Mohan A, Vanneste S. Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer’s Disease in Females. J Alzheimer’s disease: JAD. 2021;83(2):505–22. 34334399 10.3233/JAD-210404

100. Heesen C Nawrath L Reich C Bauer N Schulz KH Gold SM Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 2006 77 1 34 9 10.1136/jnnp.2005.065805 16361589 PMC2117393 Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry. 2006;77(1):34–9. 16361589 10.1136/jnnp.2005.065805 PMC2117393

101. Flachenecker P Bihler I Weber F Gottschalk M Toyka KV Rieckmann P Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Multiple sclerosis (Houndmills, Basingstoke England) 2004 10 2 165 9 10.1191/1352458504ms991oa 15124762 Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Multiple sclerosis (Houndmills, Basingstoke. England). 2004;10(2):165–9. 10.1191/1352458504ms991oa 15124762

102. Braley TJ Segal BM Chervin RD Obstructive sleep apnea and fatigue in patients with multiple sclerosis J Clin Sleep Med 2014 10 2 155 62 10.5664/jcsm.3442 24532998 PMC3899317 Braley TJ, Segal BM, Chervin RD. Obstructive sleep apnea and fatigue in patients with multiple sclerosis. J Clin Sleep Med. 2014;10(2):155–62. 24532998 10.5664/jcsm.3442 PMC3899317

103. Pucak ML Carroll KA Kerr DA Kaplin AI Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression Dialogues Clin Neurosci 2007 9 2 125 39 10.31887/DCNS.2007.9.2/mpucak 17726912 PMC3181849 Pucak ML, Carroll KA, Kerr DA, Kaplin AI. Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression. Dialogues Clin Neurosci. 2007;9(2):125–39. 17726912 10.31887/DCNS.2007.9.2/mpucak PMC3181849

104. Merkelbach S Haensch CA Hemmer B Koehler J Konig NH Ziemssen T Multiple sclerosis and the autonomic nervous system J Neurol 2006 253 Suppl 1 I21 5 10.1007/s00415-006-1105-z 16477481 Merkelbach S, Haensch CA, Hemmer B, Koehler J, Konig NH, Ziemssen T. Multiple sclerosis and the autonomic nervous system. J Neurol. 2006;253(Suppl 1):I21–5. 16477481 10.1007/s00415-006-1105-z

105. Deckx N Lee WP Berneman ZN Cools N Neuroendocrine immunoregulation in multiple sclerosis Clin Dev Immunol 2013 2013 705232 10.1155/2013/705232 24382974 PMC3870621 Deckx N, Lee WP, Berneman ZN, Cools N. Neuroendocrine immunoregulation in multiple sclerosis. Clin Dev Immunol. 2013;2013:705232. 24382974 10.1155/2013/705232 PMC3870621

106. Gasim M Bernstein CN Graff LA Patten SB El-Gabalawy R Sareen J Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review Multiple Scler Relat disorders 2018 26 124 56 10.1016/j.msard.2018.09.008 30248593 Gasim M, Bernstein CN, Graff LA, Patten SB, El-Gabalawy R, Sareen J, et al. Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review. Multiple Scler Relat disorders. 2018;26:124–56. 10.1016/j.msard.2018.09.008 30248593

107. Carotenuto A Valsasina P Preziosa P Mistri D Filippi M Rocca MA Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression J Neurol Neurosurg Psychiatry 2023 94 2 94 101 10.1136/jnnp-2022-330109 36229193 Carotenuto A, Valsasina P, Preziosa P, Mistri D, Filippi M, Rocca MA. Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression. J Neurol Neurosurg Psychiatry. 2023;94(2):94–101. 36229193 10.1136/jnnp-2022-330109

108. Solaro C Bergamaschi R Rezzani C Mueller M Trabucco E Bargiggia V Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study Clin Neuropharmacol 2013 36 4 114 6 10.1097/WNF.0b013e3182996400 23783007 Solaro C, Bergamaschi R, Rezzani C, Mueller M, Trabucco E, Bargiggia V, et al. Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin Neuropharmacol. 2013;36(4):114–6. 23783007 10.1097/WNF.0b013e3182996400

109. Fan Z Liu D Zhang G Guo X Pharmacological treatment options for cognitive dysfunction induced by multiple sclerosis: a network meta-analysis Front Neurol 2025 16 1649429 10.3389/fneur.2025.1649429 41127289 PMC12537379 Fan Z, Liu D, Zhang G, Guo X. Pharmacological treatment options for cognitive dysfunction induced by multiple sclerosis: a network meta-analysis. Front Neurol. 2025;16:1649429. 41127289 10.3389/fneur.2025.1649429 PMC12537379

110. Mohammadian Nejad E Amouzadeh E Kashipazha D Shamsaei G Cheraghian B The effect of atomoxetine on cognitive function in patients with multiple sclerosis Curr J Neurol 2023 22 3 149 54 38011451 10.18502/cjn.v22i3.13792 PMC10626139 Mohammadian Nejad E, Amouzadeh E, Kashipazha D, Shamsaei G, Cheraghian B. The effect of atomoxetine on cognitive function in patients with multiple sclerosis. Curr J Neurol. 2023;22(3):149–54. 38011451 10.18502/cjn.v22i3.13792 PMC10626139

111. Khoury SJ Healy BC Kivisäkk P Viglietta V Egorova S Guttmann CR A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis Arch Neurol 2010 67 9 1055 61 10.1001/archneurol.2010.222 20837847 PMC2954052 Khoury SJ, Healy BC, Kivisäkk P, Viglietta V, Egorova S, Guttmann CR, et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Arch Neurol. 2010;67(9):1055–61. 20837847 10.1001/archneurol.2010.222 PMC2954052

112. Makhlouf K Weiner HL Khoury SJ Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol) CNS Drugs 2002 16 1 1 8 10.2165/00023210-200216010-00001 11772115 Makhlouf K, Weiner HL, Khoury SJ. Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol). CNS Drugs. 2002;16(1):1–8. 11772115 10.2165/00023210-200216010-00001

113. Makhlouf K Comabella M Imitola J Weiner HL Khoury SJ Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis J Neuroimmunol 2001 117 1–2 156 65 10.1016/S0165-5728(01)00322-8 11431016 Makhlouf K, Comabella M, Imitola J, Weiner HL, Khoury SJ. Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis. J Neuroimmunol. 2001;117(1–2):156–65. 11431016 10.1016/s0165-5728(01)00322-8

114. Tsai CP Lin FC Lee CT Beta2-adrenergic agonist use and the risk of multiple sclerosis: a total population-based case-control study Mult Scler 2014 20 12 1593 601 10.1177/1352458514528758 24732071 Tsai CP, Lin FC, Lee CT. Beta2-adrenergic agonist use and the risk of multiple sclerosis: a total population-based case-control study. Mult Scler. 2014;20(12):1593–601. 24732071 10.1177/1352458514528758

115. Ren J Ascencio M Raimondi T Rainville EC Valenzuela RM Asche CV Association Between Exposure of Ipratropium and Salmeterol and Diagnosis of Multiple Sclerosis: A Matched Case-control Study Clin Ther 2019 41 8 1477 85 10.1016/j.clinthera.2019.04.039 31128979 Ren J, Ascencio M, Raimondi T, Rainville EC, Valenzuela RM, Asche CV. Association Between Exposure of Ipratropium and Salmeterol and Diagnosis of Multiple Sclerosis: A Matched Case-control Study. Clin Ther. 2019;41(8):1477–85. 31128979 10.1016/j.clinthera.2019.04.039

116. de Almeida GM Scola RH Ducci RDP Cirino RHD Cláudia SKK Lorenzoni PJ Does oral salbutamol improve fatigue in multiple sclerosis? A pilot placebo-controlled study Multiple Scler Relat disorders 2020 46 102586 10.1016/j.msard.2020.102586 33296982 de Almeida GM, Scola RH, Ducci RDP, Cirino RHD, Cláudia SKK, Lorenzoni PJ, et al. Does oral salbutamol improve fatigue in multiple sclerosis? A pilot placebo-controlled study. Multiple Scler Relat disorders. 2020;46:102586. 10.1016/j.msard.2020.102586 33296982

117. Dvorak E, Sand I, Sumowski K. J. Experimental Improvement of Attention/Cognitive Speed Does Not Improve Memory in Multiple Sclerosis (P13-3.001). Neurology. 2023;100(17).

118. Di Rezze S Frasca V Inghilleri M Durastanti V Cortese A Giacomelli E Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study Clin Neuropharmacol 2012 35 5 231 4 10.1097/WNF.0b013e3182613dce 22751087 Di Rezze S, Frasca V, Inghilleri M, Durastanti V, Cortese A, Giacomelli E, et al. Duloxetine for the treatment of overactive bladder syndrome in multiple sclerosis: a pilot study. Clin Neuropharmacol. 2012;35(5):231–4. 22751087 10.1097/WNF.0b013e3182613dce

119. Vollmar P Nessler S Kalluri SR Hartung HP Hemmer B The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines Int J Neuropsychopharmacol 2009 12 4 525 36 10.1017/S1461145708009425 18922202 Vollmar P, Nessler S, Kalluri SR, Hartung HP, Hemmer B. The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines. Int J Neuropsychopharmacol. 2009;12(4):525–36. 18922202 10.1017/S1461145708009425

120. Wade DT Young CA Chaudhuri KR Davidson DL A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the Cari Loder regime) in the treatment of multiple sclerosis J Neurol Neurosurg Psychiatry 2002 73 3 246 9 10.1136/jnnp.73.3.246 12185153 PMC1738034 Wade DT, Young CA, Chaudhuri KR, Davidson DL. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the Cari Loder regime) in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;73(3):246–9. 12185153 10.1136/jnnp.73.3.246 PMC1738034

121. Loder C Allawi J Horrobin DF Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems Med Hypotheses 2002 59 5 594 602 10.1016/S0306-9877(02)00261-X 12376086 Loder C, Allawi J, Horrobin DF. Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses. 2002;59(5):594–602. 12376086 10.1016/s0306-9877(02)00261-x

122. Pamphlett R Kum Jew S Uptake of inorganic mercury by human locus ceruleus and corticomotor neurons: implications for amyotrophic lateral sclerosis Acta Neuropathol Commun 2013 1 13 10.1186/2051-5960-1-13 24252585 PMC3893560 Pamphlett R, Kum Jew S. Uptake of inorganic mercury by human locus ceruleus and corticomotor neurons: implications for amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2013;1:13. 24252585 10.1186/2051-5960-1-13 PMC3893560

123. Ahmad I Chowdhury FS Boullerne AI Gow A Feinstein DL MyeliMetric: A Python-Based Toolbox for Standardized G-Ratio Analysis of Axon-Myelin Integrity ASN neuro 2025 18 1 2603411 10.1080/17590914.2025.2603411 41431828 PMC12818378 Ahmad I, Chowdhury FS, Boullerne AI, Gow A, Feinstein DL. MyeliMetric: A Python-Based Toolbox for Standardized G-Ratio Analysis of Axon-Myelin Integrity. ASN neuro. 2025;18(1):2603411. 41431828 10.1080/17590914.2025.2603411 PMC12818378

124. Chowdhury A Luchetti A Fernandes G Filho DA Kastellakis G Tzilivaki A A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking Neuron 2022 110 20 3374 e888 10.1016/j.neuron.2022.08.001 36041433 PMC10508214 Chowdhury A, Luchetti A, Fernandes G, Filho DA, Kastellakis G, Tzilivaki A, et al. A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking. Neuron. 2022;110(20):3374–e888. 36041433 10.1016/j.neuron.2022.08.001 PMC10508214

125. Kempadoo KA Mosharov EV Choi SJ Sulzer D Kandel ER Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory Proc Natl Acad Sci U S A 2016 113 51 14835 40 10.1073/pnas.1616515114 27930324 PMC5187750 Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A. 2016;113(51):14835–40. 27930324 10.1073/pnas.1616515114 PMC5187750

126. Beas BS Wright BJ Skirzewski M Leng Y Hyun JH Koita O The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism Nat Neurosci 2018 21 7 963 73 10.1038/s41593-018-0167-4 29915192 PMC6035776 Beas BS, Wright BJ, Skirzewski M, Leng Y, Hyun JH, Koita O, et al. The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nat Neurosci. 2018;21(7):963–73. 29915192 10.1038/s41593-018-0167-4 PMC6035776

127. Devoto P Flore G Saba P Fà M Gessa GL Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus BMC Neurosci 2005 6 31 10.1186/1471-2202-6-31 15865626 PMC1134661 Devoto P, Flore G, Saba P, Fà M, Gessa GL. Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus. BMC Neurosci. 2005;6:31. 15865626 10.1186/1471-2202-6-31 PMC1134661

128. Morgane PJ Jacobs MS Raphe projections to the locus coeruleus in the rat Brain Res Bull 1979 4 4 519 34 10.1016/0361-9230(79)90037-6 226233 Morgane PJ, Jacobs MS. Raphe projections to the locus coeruleus in the rat. Brain Res Bull. 1979;4(4):519–34. 226233 10.1016/0361-9230(79)90037-6

129. Loizou LA Projections of the nucleus locus coeruleus in the albino rat Brain Res 1969 15 2 563 6 10.1016/0006-8993(69)90185-1 5344392 Loizou LA. Projections of the nucleus locus coeruleus in the albino rat. Brain Res. 1969;15(2):563–6. 5344392 10.1016/0006-8993(69)90185-1

130. Grueschow M Stenz N Thorn H Ehlert U Breckwoldt J Brodmann Maeder M Real-world stress resilience is associated with the responsivity of the locus coeruleus Nat Commun 2021 12 1 2275 10.1038/s41467-021-22509-1 33859187 PMC8050280 Grueschow M, Stenz N, Thorn H, Ehlert U, Breckwoldt J, Brodmann Maeder M, et al. Real-world stress resilience is associated with the responsivity of the locus coeruleus. Nat Commun. 2021;12(1):2275. 33859187 10.1038/s41467-021-22509-1 PMC8050280

131. Lassmann H Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis Front Immunol 2018 9 3116 10.3389/fimmu.2018.03116 30687321 PMC6335289 Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2018;9:3116. 30687321 10.3389/fimmu.2018.03116 PMC6335289

132. Kutzelnigg A Lucchinetti CF Stadelmann C Bruck W Rauschka H Bergmann M Cortical demyelination and diffuse white matter injury in multiple sclerosis Brain 2005 128 Pt 11 2705 12 10.1093/brain/awh641 16230320 Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(Pt 11):2705–12. 16230320 10.1093/brain/awh641

133. Keren NI Taheri S Vazey EM Morgan PS Granholm AC Aston-Jones GS Histologic validation of locus coeruleus MRI contrast in post-mortem tissue NeuroImage 2015 113 235 45 10.1016/j.neuroimage.2015.03.020 25791783 PMC4649944 Keren NI, Taheri S, Vazey EM, Morgan PS, Granholm AC, Aston-Jones GS, et al. Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. NeuroImage. 2015;113:235–45. 25791783 10.1016/j.neuroimage.2015.03.020 PMC4649944

134. D’Souza L, Mallikarjun S, Stezin A. Quantification of Neuromelanin as a Neuroimaging Biomarker for Parkinson’s Disease. Can J Neurol Sci Le J canadien des Sci neurologiques. 2025;10:1–9. 10.1017/cjn.2025.10490 41367207

135. Cassidy CM Therriault J Pascoal TA Cheung V Savard M Tuominen L Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease Neuropsychopharmacology 2022 47 5 1128 36 10.1038/s41386-022-01293-6 35177805 PMC8938499 Cassidy CM, Therriault J, Pascoal TA, Cheung V, Savard M, Tuominen L, et al. Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease. Neuropsychopharmacology. 2022;47(5):1128–36. 35177805 10.1038/s41386-022-01293-6 PMC8938499

136. Liu Y Xiao B Huang P Li Y Wang X Zhang Y Integration of Volumetric, Iron, and Neuromelanin Magnetic Resonance Imaging Measures Effectively Differentiates Parkinson’s Disease from Multiple System Atrophy Mov Disord 2026 41 3 750 60 10.1002/mds.70153 41467326 Liu Y, Xiao B, Huang P, Li Y, Wang X, Zhang Y, et al. Integration of Volumetric, Iron, and Neuromelanin Magnetic Resonance Imaging Measures Effectively Differentiates Parkinson’s Disease from Multiple System Atrophy. Mov Disord. 2026;41(3):750–60. 41467326 10.1002/mds.70153

137. Castellanos G Fernández-Seara MA Lorenzo-Betancor O Ortega-Cubero S Puigvert M Uranga J Automated neuromelanin imaging as a diagnostic biomarker for Parkinson’s disease Mov Disord 2015 30 7 945 52 10.1002/mds.26201 25772492 Castellanos G, Fernández-Seara MA, Lorenzo-Betancor O, Ortega-Cubero S, Puigvert M, Uranga J, et al. Automated neuromelanin imaging as a diagnostic biomarker for Parkinson’s disease. Mov Disord. 2015;30(7):945–52. 25772492 10.1002/mds.26201

138. Tarasiuk J Kapica-Topczewska K Czarnowska A Chorazy M Kochanowicz J Kulakowska A Co-occurrence of Fatigue and Depression in People With Multiple Sclerosis: A Mini-Review Front Neurol 2021 12 817256 10.3389/fneur.2021.817256 35242093 PMC8886154 Tarasiuk J, Kapica-Topczewska K, Czarnowska A, Chorazy M, Kochanowicz J, Kulakowska A. Co-occurrence of Fatigue and Depression in People With Multiple Sclerosis: A Mini-Review. Front Neurol. 2021;12:817256. 35242093 10.3389/fneur.2021.817256 PMC8886154