Biology subjects

Nautiyal, K. M.

Publications and source records attributed to Nautiyal, K. M..

6 recordsLinked to original sources

bioRxiv2026

Identifying factors that contribute to the behavioral effects of psilocybin in preclinical mouse models

Psychedelic drugs offer a potentially promising avenue for novel therapeutics for the treatment of psychiatric conditions, including for mood and anxiety disorders. Emerging clinical studies have prompted increased preclinical research into mechanisms of action. However, post-acute behavioral outcomes in rodents remain inconsistent and difficult to reproduce across laboratories. To address this, we collected a large dataset of behavioral responses to psilocybin in mice (N=693) and used data-driven analyses to identify biological and experimental factors that modulated behavioral readouts. We examined the effects of sex, age, strain, stress protocol, and 5-HT1B signaling on the response to a single high dose of psilocybin measured in acute (head twitch responding and locomotion) or post-acute (sucrose preference, elevated plus maze, novelty-suppressed feeding) behavioral outcomes. We found that psilocybin displays a robust acute behavioral response and a more variable post-acute behavioral profile with a most robust response in sucrose preference. Sex, stress model, and 5-HT1BR activation emerged as key modulators of post-acute antidepressant-like and anxiolytic effects. Random forest classification was narrowly able to predict drug treatment based on post-acute behavioral outcomes and biological and experimental factors. These findings suggest that the heterogeneity seen in the response to psilocybin in mice reflects meaningful biological and experimental variables. Accounting for these factors may enhance translational relevance by identifying the conditions under which therapeutic-like effects are most robust and can support more reproducible models for understanding the neural mechanisms underlying the persisting behavioral effects of psilocybin.

neuroscience↗

bioRxiv2025

The serotonin 1B receptor modulates striatal activity differentially based on behavioral context

The dorsomedial striatum (DMS) is critical for goal-directed behavior and has been implicated in both motivating and inhibiting behavioral responses. The DMS circuitry is complex as it integrates multiple inputs from the cortex, thalamus, and other subcortical structures including midbrain dopamine neurons. Though less studied, serotonin neurons from the dorsal raphe nucleus also richly innervate the DMS, which expresses the majority of the 14 receptor subtypes for serotonin. In particular, slice electrophysiology shows that the serotonin 1B receptor (5-HT1BR) impacts DMS physiology and plasticity, and behavioral experiments show that 5-HT1BR expression modulates impulsivity and other DMS-dependent reward-related behaviors. In these studies, our goal was to investigate the effects of 5-HT1BR on the DMS in vivo during goal-directed behavior in mice. Using a genetic 5-HT1BR loss-of-function model, we examined the calcium activity of individual medium spiny neurons (MSNs) in the DMS during operant tasks of responding and waiting. We found that knockout of 5-HT1BRs resulted in a significant reduction of excitatory calcium responses and an increase in the proportion of cells with inhibitory calcium responses following receipt of a reward. This suggests that serotonin may recruit MSN activity in response to reward via actions at 5-HT1BRs. On the other hand, in a behavioral paradigm designed to test impulsivity, we found that serotonin may inhibit DMS calcium activity through 5-HT1BRs. Specifically, mice lacking 5-HT1BR expression had a larger proportion of cells showing increased calcium responses during the waiting period of the trial, compared to controls. These results point to the importance of in vivo studies to understand the functional role of DMS serotonin in reward-related behavior. Overall our results demonstrate that serotonin can modulate the DMS in a behavioral state-specific manner, potentially providing a mechanism for how serotonin effects on behavior are context-dependent.

neuroscience↗

bioRxiv2024

The non-hallucinogenic serotonin 1B receptor is necessary for the antidepressant-like effects of psilocybin in mice

Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR mediates some of the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotion to psilocybin. We also measured the persisting effects of psilocybin on anhedonia and anxiety-like behavior using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B is involved in mediating the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a mediator of the behavioral and neural effects of psilocybin in mice.

neuroscience↗

bioRxiv2024

Asymptomatic neonatal herpes simplex virus infection in mice leads to long-term cognitive impairment

Neonatal herpes simplex virus (nHSV) is a devastating infection impacting approximately 14,000 newborns globally each year. Infection is associated with high neurologic morbidity and mortality, making early intervention and treatment critical. Clinical outcomes of symptomatic nHSV infections are well-studied, but little is known about the frequency of, or outcomes following, sub-clinical or asymptomatic nHSV. Given the ubiquitous nature of HSV infection and frequency of asymptomatic shedding in adults, subclinical infections are underreported, yet could contribute to long-term neurological damage. To assess potential neurological morbidity associated with subclinical nHSV infection, we developed a low-dose (100 PFU) HSV infection protocol in neonatal C57BL/6 mice. At this dose, HSV DNA was detected in the brain by PCR but was not associated with acute clinical symptoms. However, months after initial inoculation with 100 PFU of HSV, we observed impaired mouse performance on a range of cognitive and memory performance tasks. Memory impairment was induced by infection with either HSV-1 or HSV-2 wild-type viruses, but not by a viral mutant lacking the autophagy-modulating Beclin-binding domain of the neurovirulence gene {gamma}34.5. Retroviral expression of wild type {gamma}34.5 gene led to behavioral pathology in mice, suggesting that {gamma}34.5 expression may be sufficient to cause cognitive impairment. Maternal immunization and HSV-specific antibody treatment prevented offspring from developing neurological sequelae following nHSV-1 infection. Altogether, these results support the idea that subclinical neonatal infections may lead to cognitive decline in adulthood, with possible profound implications for research on human neurodegenerative disorders such as Alzheimers Disease.

microbiology↗

bioRxiv2020

DIY-NAMIC behavior: A high-throughput method to measure complex phenotypes in the homecage

Complex behavioral assessment is becoming increasingly necessary in order to comprehensively assess in vivo manipulations in rodent models. Using operant behavioral paradigms provides rich data sets allowing for the careful analysis of behavioral phenotypes. However, one major limitation in these studies is the expense and work-load that are required using traditional methods. The equipment for commercial operant boxes can be prohibitively expensive, and the daily experimenter effort and mouse costs required for these studies is extensive. Rodents are generally trained on task-specific paradigms for months, tested every day for 5-7 days per week. Additionally, appetitive paradigms usually require food restriction and are also commonly run in the non-active light phase of the rodent circadian rhythm. These limitations make operant behavioral testing especially difficult during adolescence, a time period of interest with regards to the development of adult-like phenotypes and a high-risk period for the development of neuropsychiatric disorders, including those which involve impulsive behavior. In order to address these issues, we developed an automated, inexpensive, open-source method which allows the implementation of most standard operant paradigms in the homecage of rodents in shorter time frames without food restriction, and with much less experimenter effort. All construction and code for the DIY Nautiyal Automated Modular Instrumental Conditioning (DIY-NAMIC) system are open source. We demonstrate their utility here by measuring impulsive behavior in a pharmacology experiment, as well as in adolescent mice.Significance statement Rigorous behavioral assessment is critical to understand the neural basis of neuropsychiatric disorders using animal models. Operant behavioral paradigms provide the ability to measure complex phenotypes, however, traditional methods generally require time-consuming daily training for many weeks. We designed, built, and tested an open-source automated homecage system for appetitive instrumental conditioning that enables testing in shorter timeframes with reduced experimenter effort.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗

bioRxiv2020

A role for reward sensitivity in the serotonergic modulation of impulsivity

Impulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is integral to understanding and treating disorders with dysregulated impulsive behavior. Our approach was to first determine what behavioral and cognitive phenotypes are associated with increased impulsive behavior, and then probe if they could causally contribute to increasing impulsivity. We used a mouse model for disordered impulsivity - mice lacking the serotonin 1B receptor (5-HT1BR) which have deficits specific to impulsive action, and not other components of impulsive behavior. Here we report, that in addition to increased impulsive action, mice lacking expression of 5-HT1BR also have increased goal-directed responding and motivation, with no differences in extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression did show an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more to cues that predict reward, compared to controls. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action is a result of increased reward valuation. Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Additionally this work supports a role for reward valuation as an important substrate in impulsive action which may drive clinically-relevant increases in impulsivity.

neuroscience↗