Prelimbic cortex-associated stress sensitisation and region-specific mitochondrial adaptations across preclinical approaches relevant to PTSD and depression.

Mitochondrial dysfunction is increasingly implicated in stress-related disorders, including post-traumatic stress disorder (PTSD) and depression, but its relationship to inflammatory signalling and circuit-level vulnerability remains unclear. Here, we investigated region-specific mitochondrial adaptations across two experimental approaches of stress in rodents: stress-enhanced fear learning (SEFL) and chronic unpredictable stress (CUS), modelling PTSD- and depression-like phenotypes, respectively. Behavioural data were analysed using a novel, data-driven clustering approach to define stress-responsive phenotypes (e.g., susceptible, resilient, depressive), alongside quantification of mitochondrial oxidative phosphorylation (OXPHOS) markers across the hippocampus, basolateral amygdala, and prefrontal cortex (prelimbic and infralimbic subregions), and circulating plasma inflammatory markers. Hippocampal mitochondrial adaptations diverged between experimental approaches, with SEFL-susceptible animals showing broad upregulation of OXPHOS complexes, whereas CUS-depressive animals exhibited more restrictive mitochondrial alterations. In contrast, the basolateral amygdala showed convergent mitochondrial adaptations across models, with increased Complex V expression observed in vulnerable phenotypes. Within the prefrontal cortex, stress effects were regionally dissociable, with the prelimbic cortex showing SEFL-specific, phenotype-dependent mitochondrial alterations, implicating it as a putative node in stress sensitisation in PTSD-like phenotypes. Plasma TNF-α levels were significantly elevated in a phenotype- and time-dependent manner and were associated with regional mitochondrial adaptations, consistent with a role for systemic inflammatory signalling in modulating stress-related neurobiological plasticity and energy states. These data support a multi-level model in which behavioural phenotypes reflect underlying inflammatory-mitochondrial states distributed across hippocampal, amygdala, and prefrontal circuits, providing a potential explanatory framework linking systemic inflammatory signalling, circuit-specific mitochondrial function, and vulnerability to PTSD- and depressive-like pathology.