Biology subjects

Tsuda, M. C.

Publications and source records attributed to Tsuda, M. C..

3 recordsLinked to original sources

bioRxiv2025

Neuroanatomical and behavioral characterization of corticotropin releasing factor-expressing lateral Habenula neurons in mice

The lateral habenula (LHb) is a critical hub for stress-related behaviors, yet the sources of its corticotropin-releasing factor (CRF) inputs remain poorly defined. Using high-resolution imaging, RNAscope, and viral tracing, we identified a novel, intrinsic population of CRF-expressing LHb neurons (LHbCRF). These neurons are primarily VGLUT2+, though a rostral subpopulation co-expresses GAD2. While chemogenetic activation of LHbCRF neurons did not impact place preference or anxiety-like behaviors, it selectively biased defensive strategies toward passive action-locking during the Visual Looming Shadow Test (VLST). Notably, this activation prolonged escape latencies in males and post-escape shelter stays in females. Electrophysiological and optogenetic characterization revealed significant sexual dimorphism: male LHbCRF neurons are more numerous and intrinsically excitable, whereas female LHbCRF neurons exhibit stronger local excitatory connectivity. These findings establish LHbCRF neurons as a sexually dimorphic circuit component that could modulate sex-specific defensive strategies under threat via divergent cellular and synaptic mechanisms between the sexes.

neuroscience↗

bioRxiv2024

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

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at [~]8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb normalizes mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

neuroscience↗

bioRxiv2020

Potentiation of glutamatergic synaptic transmission onto lateral habenula neurons following early life stress and intravenous morphine self-administration in rats

Early life stress (ELS) presents an important risk factor for drug addiction and comorbid depression and anxiety through persistent effects on the mesolimbic dopamine (DA) pathways1. Using an ELS model for child neglect (a single 24 h episode of maternal deprivation, MD) in rats, recent published works from our lab show that MD induces dysfunction in ventral tegmental area (VTA) DA neurons 2-4 and its negative controller, the lateral habenula (LHb) 5-7. In regard to LHb, MD-induced potentiation of glutamatergic synaptic transmission onto LHb neurons shifts the coordination of excitation/inhibition (E/I) balance towards excitation, resulting in an increase in the overall spontaneous neuronal activity with elevation in bursting and tonic firing, and intrinsic excitability of LHb neurons in early adolescent male rats 5-7. Here, we explored how MD affects intravenous morphine self-administration (MSA) acquisition and sucrose preference as well as glutamatergic synaptic function in LHb neurons of adult male rats self-administering morphine. We found that MD-induced increases in LHb neuronal and glutamatergic synaptic activity and E/I ratio persisted into adulthood. Moreover, MD significantly reduced morphine intake, triggered anhedonia-like behavior in the sucrose preference test (SPT), and was associated with persistent glutamatergic potentiation 24h after the last MSA session. MSA also triggered postsynaptic glutamatergic potentiation in LHb neurons of control rats during this time period. Our data highlights that ELS-induced glutamatergic plasticity in LHb may dampen the positive reinforcing properties of natural rewards and opioids, and contribute to the development of anhedonic and dysphoric states associated with opioids.

neuroscience↗