Neuroplasticity After Stroke: Clinical Evidence and Its Implication for Effective Rehabilitation Strategies.

Stress-related disorders such as post-traumatic stress disorder (PTSD) impose substantial personal and societal costs, with UK healthcare expenditure exceeding £11 billion annually (), and disability weights approaching those of major chronic illnesses (). Over half of individuals with PTSD also meet criteria for major depressive disorder (MDD) (), and this high rate of comorbidity has raised important questions regarding traditional nosological boundaries – both in terms of symptomatology and underlying mechanisms (; ; ). High genetic correlation and shared inflammatory signatures raise the possibility of partially convergent pathophysiology (; ). Inflammation-induced impairments in neuroplasticity, neurotransmission, and blood–brain barrier integrity have been implicated in both disorders (; ; ), and mitochondrial dysfunction has emerged as a potential mechanistic bridge (; ). Inflammatory cytokines such as IFN-γ can disrupt mitochondrial biogenesis (), while mitochondrial stress can itself amplify inflammation through release of damage-associated molecular patterns (DAMPs) () and activation of Toll-Like Receptor 9/Nuclear Factor Kappa B (TLR9/NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) pathways (; ). The overlap in inflammatory pathways between depression and PTSD presents an opportunity for cross-disease insights that could improve both early diagnostics and therapeutic strategies. Experimental approaches in rodents offer a tractable framework to parse these shared and dissociable processes. Here, we compare two procedures in rats – one with relevance to PTSD, and the other to depression – to disentangle convergent and divergent stress-induced mechanisms. Due to its capacity to distinguish between associative fear memory and non-associative fear sensitisation, the stress-enhanced fear learning (SEFL) procedure (; ) has emerged as a prominent rodent analogue of trauma. By comparing SEFL with a chronic unpredictable stress (CUS) model with relevance to depression (), we aim to determine whether mitochondrial and inflammatory markers differentiate distinct stress-responsive behavioural phenotypes, and whether PTSD- and depression-relevant behavioural outcomes reflect overlapping or dissociable biological processes that may be relevant to the development of stress-related psychopathology and/or stress-induced behavioural adaptation. A key objective of this study was to examine whether trauma timing – recent versus remote exposure – influences PTSD-relevant outcomes. As no behavioural differences were observed between recent and remote trauma groups, these cohorts were pooled for subsequent analyses; however, the initial comparison allowed us to assess whether temporal proximity to trauma produced detectable behavioural effects. We further investigated potential sex differences, given the increased prevalence of PTSD and depression in women () and the potential influence of hormonal state on fear learning and extinction (; ). Based on these findings, we anticipated that susceptibility to SEFL and CUS differ between males and females.