Biology subjects

Conn, K.

Publications and source records attributed to Conn, K..

5 recordsLinked to original sources

bioRxiv2026

Appetite for change: How psilocybin reshapes food reward learning through striatal dopamine function

Psilocybin has emerged as a promising therapeutic agent for psychiatric disorders characterised by cognitive rigidity and disrupted reward processing, including anorexia nervosa. While its pro-cognitive effects have been mechanistically probed almost exclusively through serotonin receptor subtype antagonism, the downstream contributions of dopaminergic systems to these outcomes remain poorly understood. Here, we examined how psilocybin (1.5 mg/kg) alters cognitive flexibility across multiple operant paradigms in female rats and whether ventral striatal dopamine, nutritional state or prior activity-based anorexia (ABA) exposure moderate these effects. In food-restricted rats, psilocybin improved reversal learning with an apparent temporal delay relative to our previously published ad libitum fed cohort. In vivo fiber photometry revealed that psilocybin broadly amplified nucleus accumbens core (NAc) dopamine transients time-locked to both expected and unexpected outcomes during probabilistic reversal learning across 7 days. Computational modelling identified psilocybin-specific increases in learning rate and reductions in prior value weighting, consistent with strengthened feedback-driven updating. In touchscreen paradigms, psilocybin enhanced discrimination accuracy and accelerated reversal learning acquisition when administered prior to initial discrimination, but impaired serial reversal accuracy when administered after initial discrimination. ABA exposure constrained psilocybin's pro-cognitive effects, abolishing discrimination accuracy benefits, suggesting that metabolic disruption and stress alter the neural substrates required for psilocybin-enhanced neuroplasticity and reward learning. These findings provide the first direct evidence that psilocybin modulates striatal dopamine signalling in a behaving animal and demonstrate that current nutritional state and prior experience with pathological weight loss and reward learning moderate its cognitive effects.

neuroscience↗

bioRxiv2025

Psilocybin modulates social behaviour in male and female mice in a time-dependent manner

With the resurgence of psychedelic research and the growing interest in their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable (SABV) on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5 mg/kg) in C57BL/6J mice on various aspects of social behaviours. We show an intriguing connection between huddling behaviour and body temperature acutely elicited by psilocybin that was restricted to females. We also observe temporally distinct patterns of social behaviour alterations in female mice, whereby enhanced preference for social novelty was observed after acute effects subsided (4 h post-administration), which was maintained for [~]24 h. Longer-term, the impact of psilocybin was reversed and promoted preference for familiar over novel conspecifics when assessed 7d post-administration, which was associated with prolonged nucleus accumbens dopamine signalling during familiar sniffing. In males, psilocybin reduced stress-related behaviours at 24 h and increased preference for familiar conspecifics, along with blunted novelty-evoked dopamine responses at both 24 h and 7 days post-treatment. Both 5-HT1A and 5-HT2A receptors were involved in modulating these behaviours, though in sex-specific ways. These findings highlight that the prosocial effects of psychedelics are not universal and emphasize the importance of sex-informed approaches in both preclinical research and clinical application. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/695064v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@5f9786org.highwire.dtl.DTLVardef@1d4e2b5org.highwire.dtl.DTLVardef@16ff7c3org.highwire.dtl.DTLVardef@1f32e33_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

A genetic signature of resistance to activity-based anorexia in striatal projecting cortical neurons

ObjectiveConverging evidence from neuroimaging studies and genome-wide association study (GWAS) suggests the involvement of prefrontal cortex (PFC) and striatum dysfunction in the pathophysiology of anorexia nervosa (AN). However, identifying the causal role of circuit-specific genes in the development of AN-like phenotype remains challenging and requires the combination of novel molecular tools and preclinical models. MethodsWe used the activity-based anorexia (ABA) rat model in combination with a novel viral-based translating ribosome affinity purification (TRAP) technique to identify transcriptional differences within a specific neural pathway that we have previously demonstrated to mediate pathological weight loss in ABA rats (i.e. medial prefrontal cortex neurons that project to the nucleus accumbens shell). We compared actively transcribed genes in rats susceptible to weight loss to the subpopulation of rats resistant to weight loss under the same experimental conditions. ResultsWe reveal 1424 differentially expressed genes between Susceptible and Resistant rats, highlighting important transcriptional changes associated with ABA within this pathway. The changes observed were independent of current calorie deficit and associated with metabolic, mitochondrial and neural functions. Further, we show that genes upregulated in Resistant rats were involved in mitochondrial function, while downregulated genes were associated with cytoskeletal, postsynaptic and axonal functions, supporting the hypothesis that hyperexcitability of cortico-striatal circuit function is a critical mediator of pathological weight loss in ABA. DiscussionThese findings represent an essential first step in understanding how circuit-specific gene expression patterns may contribute to susceptibility to ABA and provide potential molecular targets for manipulation in this animal model of AN. Public SignificanceThis study identifies specific brain gene activity patterns that may explain why some individuals are more vulnerable to extreme weight loss, as seen in anorexia nervosa. Using an advanced molecular technique in a well-established animal model, key differences in a neural pathway linked to cognitive control were observed. These findings pave the way for more targeted treatments that could prevent or reverse this dangerous condition. SummaryO_LITranscriptional differences within medial prefrontal cortex to nucleus accumbens shell (mPFC-AcbSh) neurons distinguish rats highly susceptible to activity-based anorexia (ABA) from those resistant to pathological weight loss. C_LIO_LIResistant rats showed upregulation of mitochondrial function genes, while Susceptible rats had upregulation of genes related to synaptic structure and signalling, implicating excitability of this circuit in driving maladaptive weight loss behaviour. C_LIO_LITranscriptomic changes align with human genome-wide association study (GWAS) findings and support links between anorexia nervosa and both metabolic and psychiatric comorbidities. C_LIO_LIThe study highlights potential molecular targets for future gene manipulation and therapeutic intervention. It also provides a foundation for creating refined genetic animal models that integrate multiple AN-associated variants to better reflect the polygenic nature of the disorder. C_LI

neuroscience↗

bioRxiv2024

Psilocybin increases optimistic engagement over time: computational modelling of behavior in rats

Psilocybin has shown promise as a novel pharmacological intervention for treatment of depression, where post-acute effects of psilocybin treatment have been associated with increased positive mood and decreased pessimism. Although psilocybin is proving to be effective in clinical trials for treatment of psychiatric disorders, the information processing mechanisms affected by psilocybin are not well understood. Here, we fit computational models of underlying decision-making mechanisms to behaviour in rats. The model revealed that rats treated with psilocybin achieve more rewards through increased task engagement, mediated by modification of forgetting rates and reduced loss aversion. These findings suggest that psilocybin may afford an optimism bias that arises through altered belief updating, with translational potential for clinical populations characterised by lack of optimism.

animal behavior and cognition↗

bioRxiv2023

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms.

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

neuroscience↗