Traumatic brain injury (TBI) contributes to almost 30% of all injury-related deaths in the United States, but the majority of TBI injuries are mild (mTBI). Anxiety, depression and social impairments are frequently reported as long-term consequences of mTBI that are likely mediated by dysfunction of brain dopamine (DA) and serotonin (SERT) signaling in reward circuits induced by mTBI. The lateral habenula, LHb, is a highly conserved diencephalic structure that is unequivocally important in encoding negative reward information and conveying aversive motivational signals through its prominent inhibitory influence on midbrain DA neurons and raphe SERT neurons. Compared to the growing literature of LHb studies aimed at understanding the contribution of the LHb to development of depression, anxiety and drug withdrawal, the role of LHb in long-term effects of experimental brain injuries on dysregulation of the brain reward circuits is unclear. In this proposal, we aim to demonstrate that dysfunction of LHb neural circuits (specifically focusing on the entopeduncular nucleus (EP)-LHb circuitry) following mTBI contributes to dysregulation of brain reward pathways underlying social anhedonia using state?of?the?art physiological, optogenetic and chemogenetic approaches. We also explore alterations in dynorphin-kappa opioid receptor (DYN/KOR) system induced by mTBI that can contribute to dysregulation of LHb neural circuits and mediate part of the negative affective and anhedonic states of social withdrawal following mTBI. The results of this research will advance our understanding of dysregulation of DYN/KOR signaling in LHb neural systems critical to mood and reward regulation in a cell- and circuit-specific manner following mTBI and help to develop more effective therapeutic intervention to reverse the long- term changes in the function of reward pathways after mTBI.
The goal of this pre-clinical proposed study is to identify mild traumatic brain injury (mTBI)-associated changes in the neural reward circuitry to provide insights into how mTBI rewires reward circuits to induce maladaptive mood-related behavioral responses and identify novel targets for potential therapeutics.
