Author ORCID Identifier

https://orcid.org/0009-0002-8494-9880

Date of Award

2026

Document Type

Thesis (Ph.D.)

Department or Program

Psychological & Brain Sciences

First Advisor

Katherine Nautiyal

Second Advisor

Kyle Smith

Third Advisor

Wilder Doucette

Abstract

Mood disorders represent a substantial and growing global health crisis, with ~10 million adults in the US meeting criteria for a major depressive disorder (MDD). Current first-line treatments such as SSRIs require long-term daily administration and fail a significant proportion of patients, driving renewed interest in rapid-acting alternatives. Psilocybin, a serotonergic psychedelic, shows growing clinical evidence of efficacy in treating depressive and anxiety disorders, often producing therapeutic effects persisting weeks to months following a single dose. Yet, the neural mechanisms underlying these enduring effects remain poorly understood and have been largely attributed to the serotonin 2A receptor (5-HT2AR) based on its role in mediating the acute hallucinogenic experience. However, psilocybin’s active metabolite psilocin binds many serotonin receptor subtypes, and this polypharmacology is likely a critical feature of its clinical efficacy. This dissertation investigates the role of the serotonin 1B receptor (5-HT1BR), a non-hallucinogenic, inhibitory Gi/o-coupled receptor implicated in depressive-like phenotypes and neuroplasticity, as a key mediator of psilocybin’s acute neural response and therapeutic-like behavioral effects in preclinical mouse models. Additionally, this dissertation identifies meaningful biological and experimental factors that moderate psilocybin’s effects with the aim of refining preclinical models to improve translational relevance. Chapter 1 demonstrates that 5-HT1BR is necessary for some of psilocybin’s enduring behavioral effects. Using transgenic and pharmacological loss-of-function models, we show that mice lacking 5-HT1BR exhibit attenuated anxiolytic and antidepressant-like responses to psilocybin, as well as altered brain-wide neural activity. We further identify neural circuits through which 5-HT1BR may modulate the response to psilocybin, implicating subcortical limbic structures including the amygdala in mediating these effects. In Chapter 2, we address the substantial variability in preclinical psilocybin research using a large multi-cohort dataset and data-driven approaches to identify factors shaping psilocybin’s behavioral effects. Strain and age most strongly moderate acute responses, while sex, stress model, and 5-HT1BR signaling are key predictors of post-acute outcomes, reframing preclinical variability as meaningful biological modulation rather than irreproducibility. Chapter 3 demonstrates that 5-HT1BR on forebrain excitatory neurons modulate psilocybin’s anxiolytic effects, and act as a circuit-level brake on excitatory propagation to drive widespread network decorrelation. Together, these studies establish 5-HT1BR as a critical non-hallucinogenic mediator of psilocybin’s therapeutic effects, reveal crucial biological factors to consider in preclinical models, and open new therapeutic avenues for the treatment of depressive disorders.

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