Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Abstract

The serotonin 2 receptor (5HT2R) agonist psilocybin has demonstrated rapid and long-lasting efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. Psilocybin may accomplish this by inducing rapid and stable dendritic plasticity. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in cognitive and behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by rapidly and persistently altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. Leveraging tensor component analysis to identify neurons that modulate activity on multiple temporal scales, we found that a single-dose of psilocybin induced cortical ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The extent of suppression of fear-active neurons and recruitment of extinction-active neurons were both predictive of psilocybin-enhanced fear extinction. These results both align with hypotheses that psilocybin enhances behavioral flexibility by recruiting new populations of neurons and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.

Resetting the Hippocampal Buffer: A Neurocognitive Account of Psychedelic Therapy for Anxiety-Related Psychopathology

“…Likewise, psychedelics can acutely attenuate hippocampal activity (Hesselgrave et al, 2021;Mason et al, 2020) and impair the formation of hippocampal-dependent memory (i.e., episodic memory in humans; Barrett et al, 2018;Zhang et al, 2017) while sparing or even enhancing the formation of a corticaldependent memory process called familiarity (knowing that a stimulus was recently processed without necessarily retrieving details such as where or when one first encountered the stimulus; Doss et al, 2023). Although the hippocampus supports extinction learning (Fullana et al, 2018;Milad & Quirk, 2012), psychedelics can acutely enhance extinction learning (Cameron et al, 2018;Kelly et al, 2023;Rogers et al, 2024;Werle et al, 2024;Woodburn et al, 2024), perhaps by inhibiting the amygdala (Kelly et al, 2023;Pędzich et al, 2022) and driving other circuitry such as DMN regions (e.g., vmPFC and retrosplenial cortex; Rogers et al, 2024;Werle et al, 2024). Given the hippocampus' role in the processing of contextual information (Smith & Bulkin, 2014) and the tendency for extinction learning to be context-dependent (i.e., extinction learned in one context can fail in other contexts; Maren et al, 2013), extinction memories formed under psychedelics may therefore be context-general.…”

“…Through heightened cortical plasticity and reduced contextual constraints, interactions between the SN, ECN, and DMN may normalize, resulting in attenuated hyperactivity of the SN, less frequent recruitment of the ECN in response to salient environmental stimuli, and thus, greater capacity for the SN to deploy the DMN (Carhart-Harris et al, 2013Madsen et al, 2021;Stoliker et al, 2023;Timmermann et al, 2023), especially vmPFC, to adaptively regulate amygdala responses to salient external cues (Figure 1b). Finally, because hippocampal function is disrupted, fear extinction learning may be coded in context-independent semi-permanent semantic memory stores of the DMN (Rogers et al, 2024;Werle et al, 2024). Such cortical learning (cf.…”

“…While psychedelic therapy currently consists of patients lying on a couch, wearing eyeshades, listening to music, and having minimal interactions with the therapist (Johnson et al, 2008), early psychedelic research combined moderate or even low doses of psychedelics with psychotherapy, a tradition known as psycholytic therapy (Passie et al, 2022). If extinction learning is enhanced by the acute effects of psychedelics (Cameron et al, 2018;Kelly et al, 2023;Rogers et al, 2024;Werle et al, 2024;Woodburn et al, 2024) and such learning is hippocampal-independent, then exposure to anxiety-related cues during acute effects may produce a context-general extinction memory. Likewise, if cortical learning during acute effects is enhanced (Doss et al, 2023), presenting information that could disrupt anxietymaintaining beliefs might be warranted, especially with repetition given that the cortex learns with repetition (also note that extinction involves repeated presentation; Elward et al, 2023;Elward & Vargha-Khadem, 2018;Verfaellie et al, 2008;Yonelinas, 2002).…”

Psilocybin facilitates fear extinction: importance of dose, context, and serotonin receptors

“…However, this dosing strategy makes it difficult to discern whether psilocybin’s effect was due to a change in extinction learning or in the consolidation and retrieval of the initial fear memory. More recent studies suggest that psilocybin (1 - 2 mg/kg) reduces conditioned freezing when administered 30 minutes prior to extinction 32,33 , and that this effect can persist 24 hours later 32 , but used contextual and trace fear conditioning paradigms. Thus, despite tantalizing hints from these recent studies, much remains unknown regarding psilocybin’s effect on cued fear extinction.…”

Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors

“…However, this dosing strategy makes it difficult to discern whether psilocybin’s effect was due to a change in extinction learning or in the consolidation and retrieval of the initial fear memory. More recent studies suggest that psilocybin (1–2 mg/kg) reduces conditioned freezing when administered 30 min prior to extinction − and that this effect can persist 24 h later, but for different contextual and trace fear conditioning paradigms. Thus, despite tantalizing hints from these recent studies, much remains unknown regarding psilocybin’s effect on fear extinction.…”