Biology subjects

Mineur, Y. S.

Publications and source records attributed to Mineur, Y. S..

6 recordsLinked to original sources

bioRxiv2026

A ventral tegmental area GABAergic projection to the ventral pallidum regulates value-based decision making in mice

Activity of the mesolimbic system is essential for adaptive performance of reward-related behaviors. Within this system, dopaminergic (DAergic) neurons play a critical role in driving motivation to obtain rewards and encoding predictions and error signals during reinforcement learning. However, activity of DAergic neurons shifts from reward presentation to predictive cues following cue-reward learning, leaving open questions about the mechanism of subjective reward value representation. Our previous studies suggest that activity of a GABAergic circuit originating from the ventral tegmental area (VTA) and projecting to the ventral pallidum (VP) scales with unconditioned reward value, independent of effort or associative cue-reward learning. Here, we demonstrate that activity in this pathway consistently reflects unconditioned reward value across extended cue-reward training, unlike DA activity, which undergoes dynamic changes toward the cue and away from a predicted reward. VTA-to-VP GABA activity tracks internal-state-dependent reward value, showing minimal response to water drinking in sated mice and strong activity after overnight dehydration. In a two-option probabilistic operant reward task (PRT), optogenetic activation of this pathway upon reward consumption biased decision-making toward the stimulation-paired option, even when its reward was of lesser value. These findings identify a previously uncharacterized circuit that encodes reward value and contributes to value-based decision-making. Significance StatementAdaptive behavior depends on accurate representation of reward value. While dopamine (DA) signals shift from rewards to predictive cues during learning, the neural encoding of unconditioned reward value has remained elusive. We identify a GABAergic projection from the VTA to the VP that stably encodes unconditioned reward value across extended training, yet tracks changes in internal state such as thirst. Unlike DA activity, this pathway consistently reflects reward consumption and, when stimulated, biases choice toward otherwise less-preferred options. These findings uncover a stable but state-sensitive mechanism of reward value encoding, providing a new framework for understanding value-based decision-making and its disruption in neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Noradrenergic inputs to the basolateral amygdala have bidirectional effects on coping behavior and neuronal activity in mice

Norepinephrine (NE) signaling is disrupted in stress disorders, with insufficient NE signaling implicated in major depressive disorder and hyperactive NE signaling associated with post-traumatic stress disorder, suggesting that adequate mood regulation requires optimal NE levels. The basolateral amygdala (BLA) is a hub for stress processing and receives dense noradrenergic innervation from the locus coeruleus (LC), the primary noradrenergic nucleus in the brain. The relationship between LC activity and cognitive/behavioral function during fear conditioning has been described as an inverted U, in which moderate LC activity, and subsequent NE release, is required for adaptive coping to threats, while hyperactive LC-NE signaling drives maladaptive behavioral responses. We used fiber photometry to measure NE signaling in the mouse BLA during acute behavioral responses to escapable and inescapable stressors, and then used an optogenetic approach to stimulate the noradrenergic terminals in the BLA at different frequencies to evaluate effects on coping behavior and cFos expression in the LC-BLA circuit. We found that low-frequency stimulation of the circuit inhibited both passive coping and BLA neuronal activity, while high-frequency stimulation had the opposite effect; the behavioral effects were not mediated by sex, but the cFos effects were specific to males. This study represents an expansion of the inverted U framework to encompass LC-BLA signaling driving acute behavioral responses to stress. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/677150v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1b642a7org.highwire.dtl.DTLVardef@d20eedorg.highwire.dtl.DTLVardef@d22aa7org.highwire.dtl.DTLVardef@1ee4291_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBLA NE levels signal behavioral transitions between coping responses to stress C_LIO_LILow-frequency stimulation of BLA NE terminals inhibits passive coping and BLA cFos C_LIO_LIHigh-frequency stimulation of BLA NE terminals promotes passive coping and BLA cFos C_LIO_LIBehavioral effects are similar across sexes, but cFos alterations are male- specific C_LI

neuroscience↗

bioRxiv2025

An Anterior Cingulate Cortex Neuronal Ensemble Controls Contextual Opioid Analgesic Tolerance

Opioids are first-line treatments for pain; however, tolerance leads to decreased efficacy and escalated dosing, increasing the risk of opioid use disorder and overdose. Despite well-established cellular and molecular adaptations, opioid analgesic tolerance can be rapidly reversed in settings where these drugs are not expected. The specific neuronal populations that orchestrate this expectation-based tolerance are not known. In this study, we used a contextual tolerance training method, whole-brain clearing, and immunostaining to identify brain regions involved in contextual tolerance and to pinpoint a neuronal ensemble in the anterior cingulate cortex (ACC) that is activated by contextual analgesic tolerance. We observed that calcium activity in principal neurons of the ACC is suppressed by fentanyl in opioid-naive mice and during contextual reversal, but not during contextual tolerance. Chemogenetic silencing of the ACC induced analgesic tolerance reversal in the opioid-associated context without affecting thermal nociception in opioid-free mice. Conversely, chemogenetic activation of the ACC contextual tolerance-active neuronal ensemble triggered analgesic tolerance in an unassociated context. This research highlights the role of ACC neuronal ensembles in mediating expectation-driven, contextual opioid analgesic tolerance without affecting basal nociception. Modulating ACC activity could provide a promising strategy to improve pain relief while maintaining the essential ability to detect harmful stimuli.

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bioRxiv2024

Molecular Specification of Claustro-Amygdalar and Paleocortical Neurons and Connectivity

The ventropallial excitatory neurons (ExNs) in the claustro-amygdalar complex and piriform cortex (PIR; part of paleocortex) form crucial reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that result in adaptive behaviors. Early-life disruptions in these circuits are linked to neuropsychiatric disorders, highlighting the importance of understanding their development. Our study uncovers that transcription factors SOX4, SOX11, and TFAP2D play a pivotal role in the development, identity, and PFC connectivity of these neurons. Using mouse models, we demonstrate that the absence of transcription factors SOX4 and SOX11 in post-mitotic ExNs dramatically reduces the size of the basolateral amygdala complex (BLC), claustrum, and PIR. SOX4 and SOX11 control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including humans, identified conserved Tfap2d expression in developing ExNs of BLC, claustrum, paleocortex including PIR, and the associated transitional areas of the frontal, insular and temporal cortex. While the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat behaviors, differences emerge in the manifestation of Tfap2d dosage, particularly in terms of changes observed in BLC size and the connectivity pattern between the BLC and PFC. This underscores the significance of Tfap2d dosage in orchestrating developmental shifts in BLC-PFC connectivity and behavioral modifications reminiscent of symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial ventropallial ExNs and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

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bioRxiv2023

Acetylcholine signaling in the medial prefrontal cortex mediates the ability to learn an active avoidance response following learned helplessness training

Increased brain levels of acetylcholine (ACh) are observed in subsets of patients with depression and increasing ACh levels chronically can precipitate stress-related behaviors in humans and animals. Conversely, optimal ACh levels are required for cognition and memory. We hypothesize that ACh signaling is important for encoding both appetitive and stress-relevant memories, but that excessive increases in ACh result in a negative encoding bias in which memory formation of a stressful event is aberrantly strengthened, potentially contributing to the excessive focus on negative experience that could lead to depressive symptoms. The medial prefrontal cortex (mPFC) is critical to control the limbic system to filter exteroceptive cues and stress-related circuits. We therefore evaluated the role of ACh signaling in the mPFC in a learned helplessness task in which mice were exposed to repeated inescapable stressors followed by an active avoidance task. Using fiber photometry with a genetically-encoded ACh sensor, we found that ACh levels in the mPFC during exposure to inescapable stressors were positively correlated with later escape deficits in an active avoidance test in males, but not females. Consistent with these measurements, we found that both pharmacologically- and chemogenetically-induced increases in mPFC ACh levels resulted in escape deficits in both male and female mice, whereas chemogenetic inhibition of ACh neurons projecting to the mPFC improved escape performance in males, but impaired escape performance in females. These results highlight the adaptive role of ACh release in stress response, but also support the idea that sustained elevated ACh levels contribute to maladaptive behaviors. Furthermore, mPFC ACh signaling may contribute to depressive symptomology differentially in males and females.

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bioRxiv2019

Cumulative effects of social stress on reward-guided actions and prefrontal cortical activity

When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood. Here we characterize the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice, using a head-fixed sucrose preference task and two-photon calcium imaging. Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the Cg1 and M2 subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient animals after the first defeat session, and continue to diverge following successive stress episodes before reaching persistent abnormal levels. Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility raises the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity.

neuroscience↗