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Daily high doses of atorvastatin alter neuronal morphology in a juvenile songbird model.

Statins are highly effective and widely prescribed cholesterol lowering drugs. However, statins cross the blood-brain barrier and decrease neural cholesterol in animal models, raising concern that long-term statin use may impact cholesterol-dependent structures and functions in the brain. Cholesterol is a fundamental component of cell membranes and experimentally decreasing membrane cholesterol has been shown to alter cell morphology in vitro. In addition, brain regions that undergo adult neurogenesis rely on local brain cholesterol for the manufacture of new neuronal membranes. Thus neurogene…

Alpha-melanocyte-stimulating hormone promotes functional recovery in peripheral olfactory dysfunction by modulating bulbar neuroinflammation and enhancing neuronal maturation.

Although olfactory dysfunction (OD) is common worldwide, there is insufficient information about its pathophysiology and treatment. Alpha-melanocyte-stimulating hormone (α-MSH) has anti-inflammatory and neuroprotective properties and has been suggested to promote neurogenesis. This study investigated whether α-MSH improves regeneration, inflammatory responses, trophic factor expression, and olfactory behavior in a rat model of intranasal zinc sulfate (ZnSO4) induced peripheral OD. Therefore, male Sprague Dawley rats were assigned to Control, OD, α-MSH, and OD+α-MSH groups and evaluated at days…

Gastrodiae rhizoma attenuates brain aging via promoting neuritogenesis and neurodifferentiation.

BACKGROUND: Gastrodiae Rhizoma (Tianma), the dried tuber of Gastrodia elata Bl. (Orchidaceae), is listed as a top-grade herbal medicine in S … vivo model. Animal behaviors including nesting and burrowing and Morris water maze were conducted. Neurogenesis in the hippocampus was assessed by immunohistochemistry and confocal microscopy, and the aging-related proteins were assessed by Western blot analysis. The potential neuritogenesis activity of the partially purified fraction of Gastrodiae Rhizoma (T …

Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice.

Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male m…

Association between exploratory activity and social individuality in genetically identical mice living in the same enriched environment.

We previously reported that inbred, genetically identical mice living in one enriched environment develop individual behavioral trajectories, indicating increasingly different levels of spatial exploratory behavior as quantified by roaming entropy. Cumulative roaming entropy (cRE) correlated positively with adult hippocampal neurogenesis, a type of plasticity involved in the flexible integration of new information into existing contexts (Freund et al., 2013). The study on which we report here was done in parallel to that first experiment, but here we acquired detailed observational data on the…

SIRT1 mediates brain metabolic and developmental consequences of methionine synthase deficiency in inborn errors of cobalamin metabolism.

Inborn errors of vitamin B12 metabolism (IECM) resulting from impaired methionine synthase (MTR) activity cause severe cognitive and neurolo … 1 expression. At the functional level, we observe disrupted Wnt signaling associated with decreased neurogenesis, increased astrocytosis, and cognitive impairment. SRT2104 treatment restores mitochondrial and energy metabolism, normalizes Wnt signaling and neurogenesis markers, and rescues learning and memory performance. These findings identify SIRT1 as a the …

N-Stearidonoylethanolamine Restores CA1 Synaptic Integrity and Reduces Astrocytic Reactivity After Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) disrupts hippocampal network function through coordinated alterations in glial reactivity, synaptic integrity, and adult neurogenesis. Effective therapeutic approaches targeting these interconnected processes remain limited. Lipid-derived molecules capable of modulating these mTBI-induced disturbances are emerging as promising neuroprotective candidates. Here, we investigated the effects of N-stearidonylethanolamine (SDEA), an ω-3 ethanolamide, in a mouse model of mTBI. SDEA treatment attenuated astrocytic reactivity, restored Arc expression, and improved den…

Restoration of Memory Along With Neurogenic Enhancement by Therapeutic Botulinum Neurotoxin in a Preclinical Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra (SN), leading to motor impairments, while hippocampal dysfunction contributes to memory deficits. Botulinum neurotoxin (BoNT), a therapeutic modulator of acetylcholine (ACh) release, its cognitive effects remain underexplored. We investigated the effect of BoNT on spatial learning, memory, microglia and hippocampal neurogenesis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Behavioral tests, including the open field, novel object recognition, and Morris w…

Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrate dysregulation of genes associated with autism and cognitive impairment. This includes perturbation of REST transcript…

Translational biomarkers of hypoxic brain injury uncovered in CSF secreting human choroid plexus organoids.

The choroid plexus-cerebrospinal fluid (ChP-CSF) interface regulates a microenvironment supporting neural stem cell growth, strongly affecte … involved in energy metabolism and mitochondrial function. We found that H2AZ and ITM2B, involved in neurogenesis and neurite growth, were the key proteins downregulated in hypoxic iCSF and ChP organoids, respectively. Positive correlation analysis between hypoxia-induced mRNA expression of the neuronal progenitor biomarkers SOX2 and PAX6. Mature neuron MAP2 an …

ZEB1 и Neural Stem Cells: Insights to Microlia-Conditioned Smid-Driven Neuroinflammation.

Нейроинфламмация является ключевым ответом на нездоровый гомеостаз CNS, в основном через активированную микроглию, и чрезмерное воспаление с микроглией может негативно повлиять на нейрогенез. ZEB1 играет ключевую роль в развитии нейрогенеза и мозга, оказывая влияние на поддержание, распространение и дифференциацию нейронных стволовых клеток (NSC). Цель этого исследования состояла в том, чтобы оценить, каким образом вырубление ZEB1 влияет на поведение НСК в провокационной среде. NSC были изолированы от субвентричной зоны крыс, и ZEB1 был достигнут с помощью ZEB1 SIRNA. Для стимулирования подстр

Совпадение в аннотации оригинала
Neuroinflammation is a key response to disturbed CNS homeostasis, largely mediated by activated microglia, and excessive microglia-driven inflammation can negatively impact neurogenesis. ZEB1 plays a crucial role in neurogenesis and brain development by influencing neural stem cell (NSC) maintenance, proliferation, and differentiation. This study aimed to ev…

Neonatal brain injury unravels transcriptional and signaling changes underlying the reactivation of cortical progenitors.

Germinal activity persists throughout life within the ventricular-subventricular zone (V-SVZ) of the postnatal forebrain due to the presence … in the dorsal V-SVZ. Fate mapping of V-SVZ NSCs demonstrates their contribution to de novo cortical neurogenesis. Transcriptional analysis of glutamatergic progenitors shows parallel changes in methyltransferase 14 (Mettl14) and Wnt/β-catenin signaling. In agreement, manipulations through genetic and pharmacological activation of Mettl14 and the Wnt/β-catenin …

Protein Phosphatase 2ACα Regulates ATR-Mediated Endogenous DNA Damage Response Against Microcephaly.

Protein phosphatase 2A (PP2A) is an abundant heterotrimeric holoenzyme in eukaryotic cells coordinating with specific kinases to regulate spatial-temporal protein dephosphorylation in various biological processes. However, the function of PP2A in cortical neurogenesis remains largely unknown. Here, we report that neuronal-specific deletion of Pp2acα in mice displayed microcephaly, with significantly smaller brains and defective learning and memory ability. Mechanistically, neuronal Pp2acα deficiency resulted in elevated endogenous DNA damage and activation of ATR/CHK1 signaling. It was further…

Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease.

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifier Sap130 , and adhesion protein Pcdha9, revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating m…

A defined roadmap of radial glia and astrocyte differentiation from human pluripotent stem cells.

Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, g…

Rack1 is essential for corticogenesis by preventing p21-dependent senescence in neural stem cells.

Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation, and survival. Disruptions lead to neurodevelopmental disorders, including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenes…

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in c…

The cytokine ciliary neurotrophic factor (CNTF) activates hypothalamic urocortin-expressing neurons both in vitro and in vivo.

Ciliary neurotrophic factor (CNTF) induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examine…

Melanocortins as potential therapeutic agents in severe hypoxic conditions.

Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of circulatory shock, myocardial ischemia, ischemic stroke, traumatic brain injury, respiratory arrest, renal ischemia, intestinal ischemia and testicular ischemia, as well as in experimental heart transplantation. Moreover, melanocortins improve functional recovery and stimulate neurogenesis in experimental models of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediate…

Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction.

Increasing evidence shows that neural stem/progenitor cells (NSPCs) can be activated in the nonconventional neurogenic zones such as the cortex following ischemic stroke. However, the precise origin, identity, and subtypes of the ischemia-induced NSPCs (iNSPCs), which can contribute to cortical neurogenesis, is currently still unclear. In our present study, using an adult mouse cortical infarction model, we found that the leptomeninges (pia mater), which is widely distributed within and closely associated with blood vessels as microvascular pericytes/perivascular cells throughout central nervo…