Schneider, K. N. | Search bioRxiv

bioRxiv2025

Brainwide genetic capture for conscious state transitions

Neural circuits underlying unconsciousness remain poorly defined. We test the hypothesis that unconsciousness arises from specific, distributed circuits using general anesthesia in mice as a reproducible model. We identify a cortical-to-subcortical shift in neural activity during isoflurane anesthesia that is organized into nine discrete functional communities mapped at single-cell resolution. The lateral parabrachial nucleus (LPB) emerges as a central hub, exhibiting high interconnectivity, spontaneous firing under anesthesia, and preferential recruitment during reactivation of the brain-wide ensemble confirmed by single unit recordings. Chemogenetic reactivation of the captured brain-wide ensemble induces sedation, slow wave oscillations, hypothermia, and analgesia, which are components of anesthesia-induced unconsciousness. Reactivation of the LPB ensemble alone recapitulates a subset of these effects. Together, we define a global neural substrate for unconsciousness and recapitulate its dissociable autonomic, neurophysiologic, and behavioral effects using brain-wide ensemble manipulations. These results establish a neural circuit framework for anesthesia-induced unconsciousness in the mammalian brain.

neuroscience↗

bioRxiv2022

Individual differences in volitional social motivation in male and female mice following social stress.

BackgroundA key challenge in developing new treatments for neuropsychiatric illness is the disconnect between preclinical models and the complexity of human social behavior. We aimed to integrate voluntary social self-administration into a preclinical rodent stress model, as a platform for the identification of basic brain and behavior mechanisms underlying stress-induced individual differences in social motivation. Here, we introduce an operant social stress (OSS) procedure with male and female mice, where lever presses are reinforced by freely moving social interaction with a familiar social partner across social stress exposure. MethodsOSS is composed of three phases: (i) social self-administration training, (ii) social stress concurrent with daily reinforced social self-administration testing, and (iii) post-stress operant social reward testing under both non-reinforced and reinforced conditions. We resolve social stress-induced changes to social motivation behaviors using hierarchical clustering and aggregated z-scores, capturing the spectrum of individual differences that we describe with a social index score. ResultsOSS captures a range of stress-related dynamic social motivation behaviors inclusive of sex as a biological variable. Both male and female mice lever press for access to a social partner, independent of social partner coat color or familiarity. Social stress attenuates social self-administration in males and promotes social reward seeking behavior in females. Hierarchical clustering does not adequately describe the relative distributions of social motivation following stress, which we find is better described as a non-binary behavioral distribution that we define by introducing the social index score. This index is stable across individual mice. ConclusionWe demonstrate that OSS can be used to detect stable individual differences in stress-induced changes to social motivation in male and female mice. These differences may reflect unique neurobiological, cellular and circuit mechanisms not captured by preclinical models that omit voluntary social behaviors. The inclusion of volitional social procedures may enhance the understanding of behavioral adaptations promoting stress resiliency and their mechanisms under more naturalistic conditions.

neuroscience↗