Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury–Induced Motivational Deficits

• DOI: 10.1089/neu.2022.0224
• Publication Date: 2022-08-16T15:24:28Z
• Authors: William J. Flerlage; Ludovic D. Langlois; Milan Rusnak; Sarah C. Simmons; Shawn Gouty; Regina C. Armstrong; Brian M. Cox; Aviva J. Symes; Mumeko C. Tsuda; Fereshteh S. Nugent
• Keywords: Anhedonia

Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One the important regions that control motivation mood is lateral habenula (LHb), whose hyperactivity associated with depression. Here, we used repetitive closed-head mTBI model deficits adult male mice explored alterations LHb activity motivated behavior 10-18 days post-injury. We found increased proportion spontaneous tonically active neurons yet decreased displaying bursting activity. Additionally, diminished glutamatergic GABAergic synaptic onto neurons, while excitation inhibition (E/I) balance was shifted toward through greater suppression transmission. Behaviorally, latency grooming sucrose splash test self-care following mTBI. To show whether limiting could restore motivational behavior, then tested effects Gi (hM4Di)-DREADD-mediated test. chemogenetic sufficient reverse mTBI-induced delays behavior. Overall, our study provides first evidence for persistent neuronal dysfunction due an altered integration causal correlates dysregulated states