Graduate Student Assistant Uniformed Services University Bethesda, Maryland
Abstract Text: Mild traumatic brain injuries (mTBI) are the most common form of TBIs, associated with increased likelihood of long-lasting disabilities including impairments in cognition, mood/emotional regulation and social interactions as well as suicidal and risk-taking behaviors. Recently, the lateral habenula (LHb) has emerged as an anti-reward brain region that is implicated in motivation and reward-risk based decision making, and pathophysiology of stress-related disorders and drug addiction, yet an understanding of LHb circuit mechanisms in mTBI-induced psychopathology remains unknown. Recently, we showed that a repetitive closed head injury mTBI model that induced persistent LHb tonic hyperactivity through a shift in synaptic excitation and inhibition (E/I) balance toward excitation, and insertion of calcium-permeable (CP) AMPARs in LHb neurons and is associated with motivational deficits in self-care grooming behaviors in adult male mice 2-3 weeks post-injury. We also demonstrated that limiting LHb hyperactivity by chemogenetic inhibition of LHb glutamatergic neurons was sufficient to reverse mTBI-induced deficits in self-care grooming behavior in male mice, suggesting a causal link between LHb hyperactivity and mTBI-induced self-grooming deficits. Here, we identified two LHb circuits as major sources for mTBI-induced synaptic E/I imbalance, resulting in LHb hyperactivity. We found that medial prefrontal cortex (mPFC)→LHb synaptic input provided a stronger excitatory drive onto LHb neurons following mTBI in male mice 3-4 weeks post-injury. Given the significant impact of corticotropin releasing factor (CRF) on stress neuronal responses and affective states following mTBI and responsivity of LHb neurons to CRF, we then explored possible circuit-based CRF dysregulation following mTBI using used retrograde and anterograde tracing in CRF-Cre mice. We discovered a novel local CRF circuity within LHb arising from LHbCRF neurons (LHbCRF→LHb circuit). In male but not female mice, chemogenetic activation of LHbCRF neurons increased exploration of the light chamber of the light dark box (LDT) suggesting their possible role in novelty-seeking/risk-taking behavior. We also found that LHbCRF neurons of male mice exhibited enhanced excitability compared to females. In contrast, mTBI induced hypoactivity of LHb neurons in female mice as well as further decreased LHbCRF excitability in female mice. This suggests that mTBI-induced modulation of synaptic drive from LHbCRF→LHb circuit may contribute to sex- and circuit-specific differences in the effects of mTBI on LHb function and possibly different stress coping strategies. In future studies, we are performing additional behavioral testing of motivation and aggression and explore sexual dimorphism in mTBI-induced modulation of both circuits using optogenetics and chemogenetic approaches. Overall, our preliminary data suggest that sex- and circuit-specific dysregulation of LHb activity that may contribute to mood-related negative behavioral outcomes following mTBI.
