Biology subjects

Rondeau, J.

Publications and source records attributed to Rondeau, J..

5 recordsLinked to original sources

bioRxiv2026

An adaptive noradrenergic-prefrontal circuit for innate avoidance of heights

Innate preferences determine how animals interact with the environment, but how experience refines the neural processes underlying those intrinsic motivations is not well understood. Here we develop a virtual pole descent task which permitted in which mice can repeat many trials without habituation of height-dependent avoidance. Mice adjusted their choices based on recent trial outcomes without externally imposed behavioral reinforcement or punishment. Using this paradigm, we found that noradrenergic signaling enhances height avoidance while experience refines the prefrontal cortex population representation of the task. Inhibiting locus coeruleus norepinephrine neurons reduced safe choices in apparently tall visual height stimuli, while stimulating their projections to prelimbic cortex enhanced safe decision-making. Anticipatory norepinephrine in prelimbic cortex correlated with height avoidance across animals and reflected trial outcome history. Miniscope calcium imaging revealed prelimbic neurons tracked progress in the task. At the population level, experience induced improvements in the decoding of position which correlated strongly with behavioral improvements. With experience, neural trajectories became less variable during the task and reliability of representations correlated with behavioral improvement. Together these results reveal that innate threat experience can induce prefrontal cortical refinement without externally imposed reinforcement. Innate behavioral preference is thus maintained while the neural processes underlying it evolve, suggesting flexibility in neural circuits for interacting with hardwired environmental motivations.

neuroscience↗

bioRxiv2026

Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Psilocybin has antidepressant effects, but its 5-HT2AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.

neuroscience↗

bioRxiv2026

MDMA enhances prefrontal plasticity and representational drift during fear extinction

Fear extinction requires dynamic updating of cortical representations, yet the neural mechanisms underlying successful extinction remain poorly understood. Some psychoactive substances induce structural plasticity in medial prefrontal cortex (mPFC), possibly underlying their therapeutic potential. Here we investigated whether MDMA, which enhances fear extinction, induces prefrontal structural and functional plasticity, and measured its effects on ensemble representations during extinction. Longitudinal two-photon microscopy revealed that MDMA increased spine density and spinogenesis across prefrontal subregions. Miniscope Ca{superscript 2} imaging in infralimbic cortex (IL) during fear extinction revealed that IL became more correlated with the suppression of freezing behavior, consistent with a strengthening of its role in extinction. Longitudinal cell registration demonstrated accelerated representational drift across days in MDMA-treated mice; this effect was strongest in a functionally defined subpopulation of neurons that showed suppression of activity to conditioned cues. These findings demonstrate that MDMA facilitates structural and functional neuroplasticity, potentially underlying its enhancement of extinction learning.

neuroscience↗

bioRxiv2024

Classification of psychedelic drugs based on brain-wide imaging of cellular c-Fos expression

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results support a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.

neuroscience↗

bioRxiv2023

Frontal cortex norepinephrine, serotonin, and dopamine dynamics in an innate fear-reward behavioral model

Animals must survive by foraging for food in an uncertain and dangerous world. Neural circuits for naturalistic decision-making under these conditions must balance competing motivational demands for approaching reward and avoiding danger. To enable flexible switching between motivational states, neuromodulators are released and alter neural excitability and plasticity. The question of how neuromodulators encode motivational state is thus fundamental to systems neuroscience, yet the dynamics of neuromodulators during naturalistic decision making are not fully understood. Here, we developed a naturalistic approach/avoidance task in mice involving a tradeoff between seeking reward versus safety in the presence of looming predation risk. We utilized fiber photometry, computational behavior tracking, and local pharmacology in this task. Silencing medial prefrontal cortex (mPFC) reduced looming defensive behaviors. Moreover, by using fiber photometry combined with GPCR-based sensors, we found that cortical norepinephrine (NE) plays a more prominent role in encoding looming threats while dopamine (DA) represents reward and threat. In contrast, serotonin (5HT) dynamic negatively correlates to both emotional valences. To begin to understand neuromodulatory interactions, we used ex vivo slice physiology to understand 5HT impact on spontaneous firing of locus coeruleus NE neurons. In conclusion, monoamines such as NE, DA, 5HT can converge in their encoding of naturalistic motivated behaviors as well as dissociate from one another. By utilizing this novel innate reward-threat task, we can better understand neurochemical signaling events during natural behavior, and may contribute to the understanding of neural mechanisms underlying emotional decision-making and its implications for psychiatric disorders.

neuroscience↗