Biology subjects

Khatri, S. N.

Publications and source records attributed to Khatri, S. N..

3 recordsLinked to original sources

bioRxiv2025

Estrogen Receptor Beta Localized on Ventral Tegmental Area Dopamine Neurons Regulates Nicotine Self-Administration Acquisition in Ovary-Intact Female Rats

Women exhibit greater nicotine use vulnerability than men. High estradiol (E2) exacerbates nicotine use outcomes in women, effects which have been modeled in preclinical nicotine self-administration (SA) studies. Nicotine SA is maintained by dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NA). E2 exerts its effects by binding to estrogen receptors (ER), including ER, ER{beta}, and G-protein coupled ER-1 (GPER-1)s. E2 action at ERs specifically has been shown to potentiate DA neuronal excitability within the VTA. Further, we have shown that ovariectomy decreases both nicotine use during SA and VTA ER{beta} protein. Despite clear evidence of mechanistic relationships between E2, ERs, DA, and nicotine, no studies to date have functionally evaluated the specific role of ER{beta} located on VTA DA cells in driving nicotine consumption during SA in females. There are currently no tools that allow for evaluations of relationships between nicotine neurobiology and ERs with cell-type specificity, as ER{beta} is also localized on other (non-DA) cell types within the VTA. As such, the goals of the present studies were (1) to build and validate a novel adeno-associated viral construct that produces long-term knockdown of ER{beta} specifically on VTA DA neurons, and (2) to determine if VTA DA ER{beta} viral knockdown reduces nicotine SA in ovary-intact female rats. Here we show that ER{beta} regulates VTA DA neuron excitability, and that ER{beta} knockdown in VTA DA neurons reduces DA neuron firing frequency. We also show that VTA ER{beta} knockdown in DA neurons reduces nicotine SA acquisition in ovary-intact female rats. Together, our results demonstrate a critical role of ER{beta} in driving nicotine use in females, underscoring the need for future studies to evaluate neurobehavioral mechanisms of smoking through the lens of sex differences.

neuroscience↗

bioRxiv2025

Tonic GABAA receptor currents in Cerebellar Purkinje cells of wild-type and DMDmdx mice

Cerebellar Purkinje cells (PCs) fire spontaneously in the absence of excitatory input and depend heavily on inhibition to modify their firing activity. Previous work in the field has described phasic inhibition arising primarily from molecular layer interneuron-PC (MLI-PC) synapses extensively, however little work explores other sources of inhibition in PCs. Several types of neurons throughout the brain and within the cerebellum receive significant inhibition through tonic currents, a low amplitude current resulting from ambient GABA acting upon extrasynaptic GABAA receptors. Through the use of ex vivo electrophysiology and single cell RNA analysis, we investigated the role of tonic inhibition in PCs. We find that PCs have a significant tonic current mediated by {delta}-subunit containing GABAA receptors, which accounts for roughly half of the total inhibitory current. We also examined PC tonic GABA currents in DMDmdx mice, a mouse model of Duchenne Muscular Dystrophy with [~]50% reduction in phasic inhibitory currents. We find that tonic inhibition is dramatically upregulated in DMDmdx PCs, suggesting a possible compensatory mechanism to account for the loss in phasic inhibition. Furthermore, roughly 80% of the total inhibition is derived from tonic currents in this condition. These data suggest that under physiological conditions, PCs are subject to both tonic and phasic inhibition, and that adjustments in the balance of inhibition may be a physiological mechanism for PC function. These data reveal an expanded range of inhibitory currents in PC which may be critical to regulating PC activity in both normal and pathophysiological states.

neuroscience↗

bioRxiv2023

Xylazine co-self-administration suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl "high", alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 g/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, IP) induced unique sex-specific withdrawal symptomatology whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05. 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, SC) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across timepoints in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes, and induced a unique withdrawal syndrome in females which was not altered by acute naloxone treatment.

animal behavior and cognition↗