630. Identification of brain structures involved in fear memory-induced depressive-like behaviours
Abstract
Abstract Background Post-traumatic stress disorder (PTSD) is a psychiatric condition that develops from experiencing trauma. It is characterised by dysregulated fear-memory processing, leading to overconsolidated, generalised and persistent fear. Within the amygdala-hippocampus-prefrontal cortex fear circuit alterations have been observed, including amygdala hyperactivity, hippocampal atrophy and impaired prefrontal cortex-mediated extinction control. However, around 50% of PTSD patients also develop major depressive disorder (MDD), indicating further disruption of emotional and motivational circuits. Despite greater functional impairment and poorer treatment response in patients with comorbid PTSD and MDD, little is known about the neurobiology underlying this comorbidity. Preclinical findings suggested that inhibition of a hippocampal fear engram, encoding highly intense fear, decreased not only the recall of fear memories but also improved depressive-like behaviour. However, the specific brain structures that are responsible for fear-induced depressive-like behaviours remain unknown. Aims & Objectives This study aims to identify brain structures involved in maladaptive fear memory–induced depressive-like behaviour. Method Adult male and female C57BL/6J mice will undergo stereotaxic surgery for co-infusion of AAV-Fos::CreERT2 and a Cre-dependent DREADD (hM4Di-Gi) targeting the dorsal hippocampus. Subsequently, the animals will either undergo a low- (3 x 0.45 mA) or high-intensity (3 x 0.8 mA) contextual fear conditioning protocol to model adaptive or maladaptive fear, respectively. Depressive-like behaviour will be assessed using the forced swim test. Chemogenetic inhibition of fear-memory engrams via DREADDs will causally test the contribution of engram activity to behavioural outcomes. Whole-brain c-Fos mapping will identify downstream brain structures engaged by maladaptive fear memory immediately after the FST. Results - Discussion & Conclusions By identifying brain structures through which maladaptive fear leads to depressive-like behaviour, this study highlighted potential targets for pharmacological interventions aimed at promoting neural plasticity and normalising dysfunctional networks.