Research Projects

The increasing global incidence of comorbid psychological stress and metabolic dysfunction, exemplified by the co-occurrence of post-traumatic stress disorder (PTSD), depression, and obesity, presents a significant challenge in neuroscience. These conditions synergistically disrupt brain function, yet the molecular mechanisms underlying this interaction remain poorly understood. Emerging evidence identifies matrix metalloproteinase-9 (MMP-9), an extracellular protease involved in synaptic remodelling, as a critical mediator of neural impairments under both chronic stress and high-fat diet (HFD) conditions. MMP-9 is known to degrade synaptic adhesion molecules, particularly nectin-1 and nectin-3, thereby contributing to synaptic destabilisation, impaired plasticity, and behavioural dysfunction. This project proposes that MMP-9 overexpression under combined metabolic and psychological stress represents a key convergent mechanism driving synaptic pathology. The central hypothesis is that co-exposure to HFD and acute stress induces MMP-9 overactivation, leading to cleavage of nectin-1 and nectin-3, resulting in cognitive and emotional impairments. The project will test whether silencing MMP-9 via intracerebroventricular (ICV) delivery of short hairpin RNA (shRNA) and/or systemic administration of selective MMP-9 inhibitors (JNJ0960/SB-3CT) can restore synaptic integrity and ameliorate behavioural deficits. Hypothesis/Model: The proposed model posits that MMP-9 acts as a molecular switch driving synaptic disintegration in response to dual stressors. Gene silencing or pharmacological inhibition of MMP-9 is expected to preserve nectin-mediated synaptic adhesion, thus preventing or reversing behavioural and structural deficits. The objectives of the project are: 1. To establish the model of brain dysfunction by combined dietary modulation and psychological stress in a mouse. 2. To assess whether targeted inhibition of MMP-9 using short hairpin RNA (shRNA) delivered via the intracerebroventricular (ICV) route can prevent or reverse synaptic disruption and behavioural deficits. 3. To investigate the efficacy of selective pharmacological MMP-9 inhibitors JNJ0960/SB-3CT in reversing the synaptic disruption and behavioural deficits. 4. To assess downstream molecular and physiological outcomes following MMP-9 modulation. Experimental Approach: Male C57BL/6 mice will be exposed to a 12-week high-fat diet followed by foot shock stress. Behavioural assessments (OFT, LDBT, TST, and freezing behaviour) will be conducted at 24 hours and 7 days post-stress. Molecular endpoints include mRNA and protein expression of MMP-9, nectin-1, nectin-3, synaptic markers, and HPA axis readouts (corticosterone). A subset of mice will receive stereotaxic ICV injections of AAV-packaged MMP-9-targeting shRNA or scrambled controls. Another subset will be treated with selective MMP-9 inhibitors (JNJ0960 or SB-3CT). The efficacy of interventions will be confirmed by qPCR, immunofluorescence, Western blotting and immunohistochemistry. Significance: This study pioneers a dual therapeutic strategy, gene silencing and pharmacological inhibition, targeting MMP-9 in a dual-stressor model, closely mimicking real-world comorbidities. If successful, the findings will (i) establish MMP-9 as a viable molecular target in stress-metabolic brain disorders; (ii) provide preclinical validation for CNS-targeted shRNA and pharmacological therapies; and (iii) open translational avenues for treating obesity-linked cognitive and emotional dysfunctions. The project bridges an important gap in Indian neuroscience research by integrating behavioural neuroscience, molecular neurobiology, and gene therapy. It also represents the first Indian study to utilise ICV-delivered shRNA and pharmacological MMP-9 inhibition for therapeutic intervention in a comorbid brain disorder model, thereby advancing both mechanistic understanding and translational potential in neuropsychiatric therapeutics.