Biology subjects

Coimbra, B.

Publications and source records attributed to Coimbra, B..

10 recordsLinked to original sources

bioRxiv2026

Valence-specific ensembles in the laterodorsal tegmentum encode salient stimuli and modulate motivated behavior

The laterodorsal tegmentum (LDT) is a brainstem hub that integrates sensory and motivational signals to regulate adaptive behavior. While LDT neurons are known to modulate reward and aversion, whether salient stimuli recruit distinct neuronal ensembles within this structure remains unknown. Here, combined cell-type-specific calcium imaging, activity-dependent genetic tagging (TRAP2), and optogenetic reactivation to investigate how rewarding and aversive stimuli recruit and functionally define LDT neurons. Notably, single exposures to cocaine or shock in TRAP2;Ai14 mice labeled spatially and neurochemically distinct ensembles, with minimal overlap. We used fiber photometry and TRAP2 system to tag active neuronal ensembles in the LDT during cocaine (coca-LDT) and foot shock (shock-LDT) exposure, expressing GCaMP8m (green) in these neurons and, simultaneously, sRGECO (red) in the whole LDT. Our results demonstrate coca-LDT activation by physical aversive events and valenced odours, with reduced activity in response to rewarding liquids. Shock-LDT showed activation by physical aversive events, odours, and shock-predictive cues. Additionally, optogenetic reactivation of cocaine-TRAPed ensembles in a two-choice operant task biased action selection toward stimulation-paired responses, whereas shock-TRAPed ensemble activation did not drive avoidance. These findings identify functionally segregated LDT ensembles recruited by opposing motivational stimuli and reveal a causal role for reward-activated brainstem ensembles in shaping behavior. This functional segregation may contribute to the brains ability to differentiate stimulus types and, to some extent, valence experiences. Our results may provide evidence on how the LDT influences decision-making processes in addiction and anxiety disorders, potentially paving the way for novel therapeutic approaches.

neuroscience↗

bioRxiv2026

Dissociable neuronal substrates for positive and negative valence stimuli in the nucleus accumbens

The nucleus accumbens (NAc) responds to both natural and artificial rewards and to aversive stimuli; however, it remains unclear whether these opposing valence signals engage distinct neuronal ensembles. Here we used Fos-CreERT2-based activity-dependent tagging to label NAc neuronal ensembles activated by cocaine or foot shock. We found that cocaine ensemble consisted predominantly of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), whereas foot shock ensemble similarly recruited D1- and D2-MSNs. One-photon calcium imaging in freely moving mice revealed that acute cocaine primarily excited D1-MSNs while inhibiting the majority of D2-MSNs, whereas foot shock induced excitatory responses in both types of MSNs. Optogenetic reactivation of the cocaine-ensemble elicited a strong behavioural preference, whereas reactivation of the shock-ensemble produced no significant behavioural effect. Together, these findings demonstrate that cocaine recruits a functionally specific NAc ensemble distinct from that recruited by shock, providing mechanistic insight into the valence-specific neuronal substrates underlying reward and aversion processing.

neuroscience↗

bioRxiv2026

The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits

INTRODUCTIONAccumulation of pathological Tau precipitates neuronal malfunction in Alzheimers disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified. METHODSWe used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses. RESULTSLoss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs. DISCUSSIONOur findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.

neuroscience↗

bioRxiv2025

Adaptive changes of cholinergic projections to the nucleus accumbens bidirectionally mediate cocaine reinforcing effects

The laterodorsal tegmentum (LDT) sends critical inputs to distinct reward circuit regions, including the nucleus accumbens (NAc), but their functional role in addiction-related behaviors remains underexplored. Here, we demonstrate that LDT-NAc cholinergic projections undergo cocaine-induced adaptations and modulate cocaine-related behaviors. Using cell type-specific tracing, we show that LDT neurons preferentially innervate NAc medium spiny neurons and cholinergic interneurons. Large-scale in vivo recordings reveal that cocaine pre-exposure induces persistent alterations in both LDT and NAc neuronal dynamics and modifies responses to subsequent cocaine challenge. Remarkably, pre-exposure to cocaine triggers population-specific adaptations in the LDT, selectively enhancing excitability of LDT-NAc-projecting cholinergic neurons while reducing that of non-projecting cholinergic cells. Behaviorally, optogenetic activation of LDT-NAc cholinergic projections enhances cocaine conditioning, whereas their inhibition diminishes cocaines reinforcing effects. Our findings identify LDT-NAc cholinergic inputs as key substrates of cocaine-induced plasticity, and critical mediators of cocaines rewarding properties, introducing a novel component to addiction circuitry.

neuroscience↗

bioRxiv2024

Association between maternal depressive symptoms and hair cortisol concentration during pregnancy with corpus callosum integrity in newborns

BackgroundMaternal prenatal depressive symptoms are linked to neurodevelopmental impairments in offspring. Maternal cortisol levels are hypothesized to moderate this association, but its relationship with depressive symptoms is inconsistent. This study examined how maternal prenatal depressive symptoms and cortisol levels predict infant brain development, focusing on neonatal corpus callosum (CC) integrity. MethodsUsing data from the FinnBrain Birth Cohort Study, we analyzed 37 mother-infant dyads. MRI data were collected from 2 to 5 weeks old infants, and DTI imaging estimated fractional anisotropy (FA) in CC regions (Genu, Body, and Splenium). Maternal cortisol levels were assessed through hair cortisol concentration (HCC) from a 5cm hair segment, reflecting cortisol over the last five months of pregnancy. A factor score of maternal depressive symptoms was computed from EPDS questionnaire data collected at gestational weeks 14, 24, and 34. We employed multivariate regression models with a Bayesian approach for statistical testing, controlling for maternal and infant attributes. ResultsResults indicated that maternal prenatal depressive symptoms and HCC interact negatively in predicting infants FA across all CC regions. Infants exposed to high prenatal depressive symptoms and low HCC (1 SD below the mean) showed higher FA in all CC regions. ConclusionsThese findings highlight the complex dynamics between maternal prenatal cortisol levels and depressive symptoms, revealing a nuanced impact of those factors on the structural integrity of infants CC.

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bioRxiv2024

Dynamic representation of appetitive and aversive stimuli in nucleus accumbens shell D1- and D2-medium spiny neurons

The nucleus accumbens (NAc) is a key brain region for motivated behaviors, yet how distinct neuronal populations encode appetitive or aversive stimuli remains undetermined. Using microendoscopic calcium imaging, we tracked NAc shell D1- or D2-medium spiny neurons (MSNs) activity during exposure to stimuli of opposing valence and associative learning. Despite drift in individual neurons coding, both D1- and D2-population activity was sufficient to discriminate opposing valence unconditioned stimuli, but not predictive cues. Notably, D1- and D2-MSNs were similarly co-recruited during appetitive and aversive conditioning, supporting a concurrent role in associative learning. Conversely, when contingencies changed, there was an asymmetric response in the NAc, with more pronounced changes in the activity of D2-MSNs. Optogenetic manipulation of D2-MSNs provided causal evidence of the necessity of this population in the extinction of aversive associations. Our results reveal how NAc shell neurons encode valence, Pavlovian associations and their extinction, and unveil new mechanisms underlying motivated behaviors.

neuroscience↗

bioRxiv2023

Nucleus accumbens neurons dynamically encode positive and aversive associative learning

To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in Pavlovian associations, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks. Sucrose was used as a positive unconditioned stimulus (US) and foot shock was used as a negative US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general decrease in activity in response to CS and to US across learning, with dynamic, and partially overlapping, activity responses to CS and US. During the aversive Pavlovian conditioning, D1- and D2-neurons showed an increase in the activity in response to the CS and to the US (shock). Our data supports a synchronous role for D1- and D2-neurons in appetitive and aversion processing.

neuroscience↗

bioRxiv2022

Involvement of nucleus accumbens D2-MSN projections to the ventral pallidum in anxious-like behavior

The nucleus accumbens (NAc) is a crucial brain region for emotionally-relevant behaviors. The NAc is mainly composed of medium spiny neurons (MSN) expressing either dopamine receptor D1 (D1-MSNs) or D2 (D2-MSNs). D1-MSNs project to the ventral tegmental area (VTA) and ventral pallidum (VP), while D2-MSNs project only to the VP. In this work, we selectively manipulated D1-MSN projections to the VP and VTA, and D2-MSN projections to the VP during classical anxiety behavioral paradigms in naive mice. We found that optogenetic activation of D1-MSN to VP or VTA did not trigger significant anxious-like behaviors. Interestingly, optical activation of D2-MSN-VP projections significantly increased anxious-like behavior in all of the tests performed. This phenotype was associated with a decrease in the activity of VP putative GABAergic neurons. Importantly, pre-treating D2-MSN-VP animals with the GABA modulator diazepam prevented the optically-triggered anxious-like behavior. Overall, our results suggest that D2-MSN-VP projections contribute for the development of anxious-like behavior, through modulation of GABAergic activity in the VP.

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bioRxiv2020

Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior

The nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs. Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition. In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.

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bioRxiv2018

Criticality between cortical states

Since the first measurements of neuronal avalanches [1], the critical brain hypothesis has gained traction [2]. However, if the brain is critical, what is the phase transition? For several decades it has been known that the cerebral cortex operates in a diversity of regimes [3], ranging from highly synchronous states (e.g. slow wave sleep [4], with higher spiking variability) to desynchronized states (e.g. alert waking [5], with lower spiking variability). Here, using independent signatures of criticality, we show that a phase transition occurs in an intermediate value of spiking variability. The critical exponents point to a universality class different from mean-field directed percolation (MF-DP). Importantly, as the cortex hovers around this critical point [6], it follows a linear relation between the avalanche exponents that encompasses previous experimental results from different setups [7, 8] and is reproduced by a model.

neuroscience↗