Biology subjects

Couto, J.

Publications and source records attributed to Couto, J..

8 recordsLinked to original sources

bioRxiv2025

Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy

The immune response to Mycobacterium tuberculosis is accompanied by metabolic adaptations that fuel host immunity, but that are exploited by the pathogen to ensure persistence and growth. Nuclear receptors, such as liver-X-receptors (LXR), orchestrate macrophage immunometabolic adaptations to infection and globally associate with tuberculosis (TB) protection. Here, we show that the "signalling by nuclear receptors" (SNR) pathway is detected in the whole blood of TB patients and that its expression correlates with disease severity. Accordingly, we also show that the activation of the LXR pathway progressively increases in the lungs of M. tuberculosis-infected C57BL/6 and C3HeB/FeJ mice. Pharmacologic activation of LXR, specifically at the chronic stage of infection, improved infection outcomes and significantly prolonged the survival of the highly susceptible C3HeB/FeJ mice. Common to both mouse models and to in vitro macrophage infections, LXR activation enhanced bacterial control together with an increase in extracellular cholesterol levels. We propose that progressive LXR activation is required to fine-tune host cholesterol availability during M. tuberculosis infections and restrict access to this nutrient during chronic stages of infections. Collectively, we identify the SNR pathway as a potential biomarker of TB severity and timely LXR activation as a candidate host-directed therapy.

immunology↗

bioRxiv2025

Specific anterior-posterior brain-wide input patterns support specialized visuospatial processing in the mouse retrosplenial cortex

The retrosplenial cortex (RSC) is a key integrative hub involved in spatial orientation, navigation, and cognitive processes. In rodents, RSC neurons carry rich sensory and navigational signals and are interconnected with sensory, motor, thalamic, and hippocampal circuits--supporting multimodal integration. However, the circuitry that supports this integration remain unclear. Here, we combined 2-photon calcium imaging in navigating mice with brain-wide retrograde tracing to investigate how visual and positional information are represented and distributed across RSC subregions. We found a clear anterior-posterior gradient: anterior RSC neurons exhibited sharper, more reliable position tuning and preferred fast-moving visual stimuli, while posterior RSC neurons showed broader tuning and preferential responses to slower motion. These functional differences were paralleled by distinct patterns of long-range input: anterior RSC received denser projections from motor, parietal, and hippocampal-associated areas--regions implicated in position encoding--whereas posterior RSC was more strongly innervated by visual cortices. Our findings reveal that the RSC contains functionally and anatomically distinct subregions specialized for processing different visuospatial features, suggesting a modular organization that supports integration of contextual and sensory information during navigation.

neuroscience↗

bioRxiv2025

Anterior cingulate cortex mixes retrospective cognitive signals and ongoing movement signatures during decision-making

In dynamic environments, animals must closely monitor the effects of their actions to inform switches in behavioral strategy. Anterior cingulate cortex (ACC) neurons track decision outcomes in these environments. Yet, it remains unclear whether ACC neurons similarly monitor behavioral history in static environments and, if so, whether these signals are distinct from movement representations. We recorded large-scale ACC activity in freely moving mice making visual evidence-accumulation decisions. Many ACC neurons exhibited nonlinear mixed selectivity for previous choices and outcomes (trial history) and were modulated by movements. Trial history could be stably decoded from population activity and accounted for a separable component of neural activity than posture and movements. Trial history encoding was conserved across different subjects and was unaffected by fluctuating behavioral biases. These findings demonstrate that trial history monitoring in ACC is implemented in a conserved population code that is independent of the volatility of subjects task environment.

neuroscience↗

bioRxiv2024

A failure to discriminate social from non-social touch at the circuit level may underlie social avoidance in autism

Social touch is critical for communication and to impart emotions and intentions. However, certain autistic individuals experience aversion to social touch, especially when it is unwanted. We used a novel social touch assay and Neuropixels probes to compare neural responses to social vs. non-social interactions in three relevant brain regions: vibrissal somatosensory cortex, tail of striatum, and basolateral amygdala. We find that wild type (WT) mice showed aversion to repeated presentations of an inanimate object but not of another mouse. Cortical neurons cared most about touch context (social vs. object) and showed a preference for social interactions, while striatal neurons changed their preference depending on whether mice could choose or not to interact. Amygdalar and striatal neurons were preferentially modulated by forced object touch, which was the most aversive. In contrast, the Fmr1 knockout (KO) model of autism found social and non-social interactions equally aversive and displayed more aversive facial expressions to social touch when it invaded their personal space. Importantly, when Fmr1 KO mice could choose to interact, neurons in all three regions did not discriminate social valence. Thus, a failure to differentially encode social from non-social stimuli at the circuit level may underlie social avoidance in autism.

neuroscience↗

bioRxiv2023

Large scale, simultaneous chronic neural recordings from multiple brain areas

Understanding how brain activity is related to animal behavior requires measuring multi-area interactions on multiple timescales. However, methods to perform chronic, simultaneous recordings of neural activity from many brain areas are lacking. Here, we introduce a novel approach for independent chronic probe implantation that enables flexible, simultaneous interrogation of neural activity from many brain regions during head restrained or freely moving behavior. The approach, that we called indie (independent dovetail implants for electrophysiology), enables repeated retrieval and reimplantation of probes. The chronic implantation approach can be combined with other modalities such as skull clearing for cortex wide access and optogenetics with optic fibers. Using this approach, we implanted 6 probes chronically in one hemisphere of the mouse brain. The implant is lightweight, allows flexible targeting with different angles, and offers enhanced stability. Our approach broadens the applications of chronic recording while retaining its main advantages over acute recordings (superior stability, longitudinal monitoring of activity and freely moving interrogations) and provides an appealing venue to study processes not accessible by acute methods, such as the neural substrate of learning across multiple areas.

neuroscience↗

bioRxiv2023

DREDge: robust motion correction for high-density extracellular recordings across species

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

neuroscience↗

bioRxiv2023

Engaged decision-makers align spontaneous movements to stereotyped task demands

Existing work demonstrates that animals alternate between engaged and disengaged states during perceptual decision-making. To understand the neural signature of these states, we performed cortex-wide measurements of neural activity in mice making auditory decisions. The trial-averaged magnitude of neural activity was similar in the two states. However, the trial-to-trial variance in neural activity was higher during disengagement. To understand this increased variance, we trained separate linear encoding models on neural data from each state. The models demonstrated that although task variables and task-aligned movements impacted neural activity similarly during the two states, movements that are independent of task events explained more variance during disengagement. Behavioral analyses uncovered that during disengagement, movements become uncoupled to task events. Taken together, these results argue that the neural signature of disengagement, though obscured in trial-averaged neural activity, is evident in trial-to-trial variability driven by changing patterns of spontaneous movements.

neuroscience↗

bioRxiv2020

Investigating the origin and consequences of endogenous default options in repeated economic choices.

Classical value-based decision theories state that economic choices are solely based on the value of available options. Experimental evidence suggests, however, that individuals choices are biased towards default options, prompted by the framing of decisions. Although the effects of default options created by exogenous framing - such as how choice options are displayed - are well-documented, little is known about the potential effects and properties of endogenous framing, that is, originating from an individuals internal state. In this study, we investigated the existence and properties of endogenous default options in a task involving choices between risky lotteries. By manipulating and examining the effects of three experimental features - time pressure, time spent on task and relative choice proportion towards a specific option -, we reveal and dissociate two features of endogenous default options which bias individuals choices: a natural tendency to prefer certain types of options (natural default), and the tendency to implicitly learn a default option from past choices (learned default). Additional analyses suggest that while the natural default may bias the standard choice process towards an option category, the learned default effects may be attributable to a second independent choice process. Overall, these investigations provide a first experimental evidence of how individuals build and apply diverse endogenous default options in economic decision-making and how this biases their choices.

neuroscience↗