Biology subjects

Delgado-Sallent, C.

Publications and source records attributed to Delgado-Sallent, C..

5 recordsLinked to original sources

bioRxiv2025

Psychedelics Relax Priors and Reshape Orbitofrontal Dynamics

Psychedelics such as psilocybin and ketamine are gaining attention as rapid-acting treatments for psychiatric disorders, yet the mechanisms by which they alter cognition remain unclear. A key hypothesis--the REBUS model--proposes that psychedelics relax high-level priors, allowing bottom-up sensory information to exert greater influence over perception and behavior. Here, we test this model in mice performing a free-response perceptual decision-making task that disambiguates prior-driven and sensory-driven decision strategies. Acute administration of psilocybin or ketamine significantly slowed decision times and improved accuracy. Behavioral modeling that combined drift diffusion and GLM-HMM frameworks revealed that these changes were mediated by increased decision thresholds and a marked shift into sensory-engaged cognitive states. Whole-brain c-Fos mapping identified a distributed decision-making network, with psychedelics selectively modulating cortical and subcortical nodes. Calcium imaging in the orbitofrontal cortex (OFC)--a key region for integrating priors and sensory inputs--revealed preserved decision-related selectivity under psychedelics, while exhibiting reduced neuronal correlations--population-level signatures of weakened top-down influence and relaxed priors. Together, these results provide circuit-level support for the REBUS model, showing that psychedelics reconfigure brain-wide and local dynamics to promote more deliberate, flexible, and sensory-driven decision policies.

neuroscience↗

bioRxiv2025

A State-Dependent Drift Diffusion Model Reveals Mice Actively Explore A Speed-Accuracy Continuum During Decision-Making

Understanding how animals shift between different decision-making strategies is critical for bridging normative models with naturalistic behavior. While drift diffusion models (DDMs) provide a powerful framework for describing evidence accumulation in two-alternative forced choice (TAFC) tasks, they assume fixed parameters across trials--an assumption often violated in practice. Here, we intro- duce a state-dependent DDM framework in which discrete latent states modulate decision parameters from trial to trial. This approach reveals that mice dynamically switch between impulsive and deliberative decision states that differ in accuracy and response latency, suggesting active exploration of the speed-accuracy trade-off. We uncover rare high-bound states in which mice exhibit deliberation times and ac- curacies approaching those observed in humans. These results raise new questions about the cognitive flexibility of rodent decision-making and offer a foundation for studying how internal states and external variables--such as reward history or uncertainty--influence strategy selection. Our method provides a natural interface for integration with neural recordings and dynamical systems models, offering a path toward identifying the circuit-level mechanisms underlying adaptive decision behavior.

animal behavior and cognition↗

bioRxiv2024

A cross-species framework for investigating perceptual evidence accumulation

Cross-species studies are important for a comprehensive understanding of brain functions. However, direct quantitative comparison of behaviors across species presents a significant challenge. To enable such comparisons in perceptual decision-making, we developed a synchronized evidence accumulation task for human and non-human animals, by aligning mechanics, stimuli, and training. The task was readily learned by rats, mice and humans, with each species exhibiting qualitatively similar performance. Quantitative model comparison revealed that all three species employed an evidence accumulation strategy, but differed in speed, accuracy, and key decision parameters. Human performance prioritized accuracy, whereas rodent performance was limited by internal time-pressure. Rats optimized reward rate, while mice appeared to switch between evidence accumulation and other strategies trial-to-trial. Together, these results reveal striking similarities and species-specific priorities in decision-making. Furthermore, the synchronized behavioral framework we present may facilitate future studies involving cross-species comparisons, such as evaluating the face validity of animal models of neuropsychiatric disorders. HighlightsO_LIDevelopment of an evidence accumulation task for rats and mice C_LIO_LISynchronized video game allows direct comparisons with humans C_LIO_LIRat, mouse and human behavior are well fit by the same decision models C_LIO_LIModel parameters reveal species-specific priorities in accumulation strategy C_LI

animal behavior and cognition↗

bioRxiv2023

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and rescue by risperidone

NMDAR hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and perceptual impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory perception and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the new object and its short-term storage were associated with mPFC[->]dHPC high gamma connectivity whereas long-term memory retrieval depended on dHPC[->]mPFC theta connectivity. sPCP impaired short-term and long-term memory, which was associated with increased mPFC and decreased dHPC neural network activities, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and attenuated hippocampal desynchronization. sPCP also impaired auditory perception and its neural correlates (evoked potentials and MMN) in the mPFC, which were also ameliorated by risperidone. Our study suggests that during NMDAR hypofunction the mPFC and the dHPC disconnect possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

neuroscience↗

bioRxiv2021

Phencyclidine-induced psychosis causes hypersynchronization and disruption of connectivity within prefrontal-hippocampal circuits that is rescued by antipsychotic drugs

Neural synchrony and functional connectivity are disrupted in neuropsychiatric disorders such as schizophrenia. However, these alterations and how they are affected by commonly prescribed neuropsychiatric medication have not been characterized in depth. Here, we investigated changes in neural dynamics of circuits involving the prefrontal cortex and the hippocampus during psychosis induced by the NMDAR antagonist phencyclidine and subsequent recovery by three different antipsychotic drugs (APDs), the classical APD haloperidol and two atypical APDs, clozapine and risperidone, in freely moving mice. We found that the psychotomimetic effects of phencyclidine were associated with hypersynchronization and disrupted communication of prefrontal-hippocampal pathways. Major alterations occurred in the prefrontal cortex, where phencyclidine increased oscillatory power at delta, high gamma and high frequencies (<100 Hz) and generated aberrant cross-frequency coupling, suggesting the presence of hypersynchronous cortical microcircuits. Cross-regional coupling and phase coherence were also enhanced, further reflecting that the circuits functional connectivity was increased. Phencyclidine also redirected the intrinsic flow of information at theta frequencies that traveled from the hippocampus to the prefrontal cortex into delta rhythms that traveled in the opposite direction. The three APDs rescued most phencyclidine-induced changes in power, coupling, phase coherence, and directionality, suggesting common cellular mechanisms of antipsychotic action. However, some differential effects were identified, likely resulting from the distinct affinity the three APDs have for dopamine and serotonin receptors. We therefore investigated how serotonin 1A (5-HT1AR) and 2A receptors (5-HT2AR) compare to the actions of the APDs. 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT rescued phencyclidine-induced increased power, coupling and phase coherence but were unable to normalize the circuits theta directionality. This suggests that other targets of the AAPDs working in tandem with 5-HT1ARs and 5-HT2ARs are required to ameliorate this key feature of the circuit.

neuroscience↗