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

Abstract

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

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior

“…Here, we evaluated the effects of mTBI on LHb spontaneous LHb activity (Figure 1A-B, D), LHb neuronal excitability (Figure 2A-B) and intrinsic excitability (Figure 2C-D) in LHb slices from sham and mTBI male and adult mice ~4 weeks post-injury. mTBI increased the overall LHb spontaneous tonic activity while decreasing spontaneous LHb neuronal firing in bursting mode in cell-attached voltage-clamp recordings in male mice as we previously reported 39 , but also resulted in similar changes in female mice (Figure 1B, males: **p<0.01, Figure 1D, females: *p<0.05, Chi squared test). Consistently, LHb neurons of mTBI male and female mice also exhibited significantly higher neuronal excitability in intact synaptic transmission compared to those from sham mice although mTBI-induced LHb hyperexcitability was more pronounced in male mice (Figure 2 A, males: F (1, 836) = 63.46, ****p<0.0001; Figure 2B, females: F (1, 680) = 24.60, ****p<0.0001; sex effect in comparison between mTBI male group from Figure 2A and mTBI female group from Figure 2B: F (1, 806) = 63.69, ****p<0.0001, 2-way ANOVA).…”

“…Given the significant lack of preclinical mTBI studies in females as well as studies focused on mTBI-related reward circuit dysfunction in both biological sexes 15,38 , we have developed a preclinical model of mTBI using repetitive closed injury mouse model of mTBI which induces behavioral deficits in motivational self-care grooming in sucrose splash test 39 and social interaction test 40 as well as persistent LHb hyperactivity through a shift in synaptic excitation and inhibition (E/I) balance toward excitation, and via plasma membrane insertion of calcium-permeable (CP) AMPARs in LHb neurons in male mice 39 . We demonstrated that limiting LHb hyperactivity by chemogenetic inhibition of LHb neurons was sufficient to reverse mTBI-induced delays in self-care grooming behavior in male mice supporting a causal link between LHb hyperactivity and mTBI-induced self-grooming deficits 39 . TBI patients also experience neuroendocrine dysfunction [41][42][43][44] with dysregulation of the hypothalamic pituitary axis (HPA) stress neuromodulator, corticotropin releasing factor (CRF), that has significant impact on stress neuronal responses and affective states following mTBI [45][46][47][48][49] .…”

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

“…One of these compounds, J60, was developed by an NIH team who showed it has acceptable behavioral and other effects in mice (Bonaventura et al, 2019), a finding that has been replicated by several other groups (Desloovere et al, 2021; Flerlage et al, 2022; Fleury Curado et al, 2021; Giannotti et al, 2021; Heinsbroek et al, 2021; Huang et al, 2021; Lewis et al, 2020; Li and Hollis, 2021; Salimi-Nezhad et al, 2023; Zhang et al, 2020). J60 efficiently crosses the blood-brain-barrier, it binds directly to central DREADD receptors after i.p.…”

Tachykinin receptor 3 in the lateral habenula alleviates pain and anxiety comorbidity in mice

“…Maternal deprivation induces LHb hyperactivity through glutamatergic synaptic potentiation that shifts the excitation/inhibition (E/I) balance towards excitation and shows changes in the relative weights of both increased excitatory and decreased inhibitory synaptic inputs onto LHb neurons, and thus produces anxiety-like and depression-like behaviors in adolescent male rats ( 76 ). Another study showed that mild traumatic brain injury diminishes spontaneous glutamatergic and GABAergic synaptic activity onto LHb neurons, while the E/I balance is shifted toward excitation through increased suppression of GABAergic transmission ( 77 ). In the present study, the GABAergic transmission onto LHb neurons were not recorded.…”