Biology subjects

Langdon, A. J.

Publications and source records attributed to Langdon, A. J..

3 recordsLinked to original sources

bioRxiv2026

Psilocybin asymmetrically modulates outcome-based choice and cortical processing under uncertainty

Emerging clinical research with psilocybin highlights the value of the psychedelic experience on successful treatment of a multitude of psychiatric disorders. While the psychedelic trip or clinical support procedures cannot be modeled in rodents, neural processes critical to meta-learning and flexible modification of previously learned strategies can be quantified during psilocybin exposure. Here we applied computational modeling and single unit recordings from medial prefrontal cortex to characterize the effect of psilocybin using a value-based probabilistic choice task. Psilocybin improved choice selection in uncertain contexts and shifted reinforcement learning rate bidirectionally, enhancing updating from rewarded, while reducing updating from unrewarded, actions. These behavioral changes coincided with selective shifts in the neural encoding of task features including enhanced neural representation of rewarded, and diminished representation of unrewarded, outcomes. Collectively these data indicate that psilocybin improves choice selection in uncertain contexts by reweighing cortical coding in a way that favors learning from positive new information over prospective actions.

neuroscience↗

bioRxiv2024

Reductions of Grin2a in adolescent dopamine neurons confers aberrant salience and related psychosis phenotype

Psychosis is a hallmark of schizophrenia. It involves a collection of symptoms that are typically associated with disrupted dopamine signaling and emerges during adolescence or early adulthood. Most schizophrenia-associated genes, however, involve glutamatergic or other ubiquitous targets that do not explain the latent expression of psychosis or dopaminergic abnormalities. Here, we describe an etiologically relevant model for the adolescent onset of dopamine-related dysfunction in schizophrenia. We focused on GRIN2A, the gene encoding the GluN2A subunit of the NMDA receptor, as both the common loss-of-function variants and the rare missense variants in this gene are risk factors for schizophrenia. We find that GluN2A levels distinctly decline in dopamine neuron-containing regions throughout adolescence while remaining stable in other regions. This suggested that adolescent dopamine neurons may be particularly vulnerable to further reductions in GluN2A caused by a damaging variant of GRIN2A. Consistent with this idea, we find that selective knockout of Grin2a in adolescent rat dopamine neurons results in a psychosis-relevant behavioral phenotype. This manipulation also reduced dopamine release in response to unexpected outcomes in young adults, reflective of prediction error signaling abnormalities observed in the clinical population. These data provide mechanistic insight into how GRIN2A mutations may contribute to the delayed onset of dopamine-related symptoms and provide a model for identifying course altering treatments for schizophrenia.

neuroscience↗

bioRxiv2022

Audiovisual cues must be predictable and win-paired to drive risky choice

Risky or maladaptive decision making is thought to be central to the etiology of both drug and gambling addiction. Salient audiovisual cues paired with rewarding outcomes, such as the jackpot sound on a win, can enhance disadvantageous, risky choice in both rats and humans, yet it is unclear which aspects of the cue-reward contingencies drive this effect. Here, we implemented six variants of the rat Gambling Task (rGT), in which animals can maximise their total sugar pellet profits by avoiding options paired with higher per-trial gains but disproportionately longer and more frequent time-out penalties. When audiovisual cues were delivered concurrently with wins, and scaled in salience with reward size, significantly more rats preferred the risky options as compared to the uncued rGT. Similar results were observed when the relationship between reward size and cue complexity was inverted, and when cues were delivered concurrently with all outcomes. Conversely, risky choice did not increase when cues occurred randomly on 50% of trials, and decision making actually improved when cues were coincident with losses alone. As such, cues do not increase risky choice by simply elevating arousal, or amplifying the difference between wins and losses. It is instead important that the cues are reliably associated with wins; presenting the cues on losing outcomes as well as wins does not diminish their ability to drive risky choice. Computational analyses indicate reductions in the impact of losses on decision making in all rGT variants in which win-paired cues increased risky choice. These results may help us understand how sensory stimulation can increase the addictive nature of gambling and gaming products.

animal behavior and cognition↗