Lateral habenula circuit dysfunction in mild traumatic brain injury - Abstract Mild traumatic brain injury (mTBI) is a significant risk factor for debilitating, treatment-resistant neuropsychiatric disorders like depression, anxiety, and PTSD. Our preliminary data strongly suggest that mTBI-induced dysfunction of the lateral habenula (LHb), a key anti-reward brain region, causally contributes to associated motivational and mood deficits. We've developed a sex-balanced repetitive mTBI mouse model that faithfully recapitulates these deficits, demonstrating persistent LHb synaptic and neuronal dysfunction, including hyperactivity, altered excitation/inhibition balance, and increased bursting. Crucially, chemogenetic inhibition of LHb glutamatergic neurons reversed motivational deficits in male mice, establishing a causal link between LHb hyperactivity and these impairments. Our preliminary optogenetic data also reveal that mTBI potentiates medial prefrontal cortical (mPFC) projections to the LHb, indicating persistent mPFC → LHb circuit dysfunction. Furthermore, increased GFAP-immunolabeled area in the LHb post-mTBI points to altered astrocytic activity. Despite these critical observations, the specific roles of cortico-habenular circuits and LHb astrocyte-neuron interactions in mTBI-related mood dysregulation remain largely unexplored. We hypothesize that mTBI induces persistent cortico-habenular microcircuit dysfunction, leading to long-term deficits in motivated behaviors, partly through altered LHb astrocyte-neuronal interaction in both male and female mice. To rigorously test this, we'll leverage our validated mTBI model in male and female mice, combining advanced methodologies including viral strategies, optogenetics, retrobead electrophysiology, in vitro GCaMP recordings, cutting-edge astrocyte modulation tools, and intersectional chemogenetics. Our research will pursue two main aims: 1) Determine the synaptic and behavioral effects of mTBI on specific mPFC → LHb microcircuits, examining projection-specific alterations to downstream targets and delineating their behavioral contributions. 2) Investigate the synaptic and behavioral effects of mTBI on LHb astrocytic regulation of LHb activity, to dissect how astrocytic dysfunction contributes to altered LHb neuronal/synaptic activity, population dynamics, and the development of mTBI-related depressive- and PTSD-like behaviors. This work is expected to uncover novel circuit mechanisms and astrocytic roles in mTBI-induced deficits in motivated and defensive behaviors, providing crucial evidence for causal links between their dysregulation and the pathological motivational and decision-making deficits observed in depression, anxiety, and PTSD following mTBI.
