Biology subjects

Heshmati, M.

Publications and source records attributed to Heshmati, M..

5 recordsLinked to original sources

bioRxiv2026

Social agency buffers pain sensitivity during a critical window following spared nerve injury

BackgroundSocial buffering of pain, where social contact blunts pain intensity, is well established. However, the degree to which agency over social contact, rather than passive social exposure alone, modifies pain intensity or social behavior is unclear. MethodsUsing a social operant self-administration procedure in which mice lever-press for access to their pair-housed partner, we show that voluntary social engagement gates pain after spared nerve injury (SNI). After 8 days of training, mice underwent SNI and then regained access to social self-administration either 1 day (Early) or 5 days (Delayed) following surgery. We compared these mice to groups without social self-administration access, non-contingent social-access, and food self-administration. We assessed changes in pain, or mechanical allodynia, via the von Frey test. ResultsEarly access to social self-administration after SNI preserved pre-injury social reinforcement and buffered pain. Delayed access similarly preserved social reinforcement but failed to buffer allodynia, revealing an early post-injury critical window for social buffering of pain. Females were more sensitive to both SNI and disrupted social access, while males maintained social reward-seeking after SNI when given early access and showed robust social buffering of pain. Non-contingent (involuntary) social self-administration did not modify pain, nor did food self-administration. ConclusionsThere is an early critical window during which voluntary social interactions buffer pain after nerve injury. These results highlight social reward agency and proximity to injury as key variables, since pain outcomes do not generalize to food reward, non-contingent social reward, or delayed access to social reward.

neuroscience↗

bioRxiv2026

Subcortical recruitment dissociates isoflurane emergence from distinct wakeful states in mice

Emergence from general anesthesia, defined by a recovery of consciousness to the wakeful state, is a clinically consequential state transition that remains a passive process dependent on drug clearance. Despite the critical use of anesthesia, the neural circuitry underlying behavioral recovery remains poorly defined. Here, we map whole-brain neural activity during emergence from isoflurane anesthesia in mice using Fos immunolabeling, tissue clearing, and light-sheet microscopy. This approach enables unbiased quantification of neural activity at cellular resolution across the intact whole brain and supports subsequent network analysis. Rather than resembling wakefulness, emergence exhibits widespread cortical suppression alongside selective activation of discrete subcortical nuclei. This pattern of activity includes both previously implicated arousal-related regions and lesser-studied structures linked to respiratory, autonomic, interoceptive, and cerebellar function. By comparing emergence to two behaviorally distinct wakeful control states, we find that control state selection substantially shapes interpretation of whole-brain activity maps. This establishes dual-state comparisons as a broadly useful strategy for state-dependent circuit mapping. Functional network analysis further elucidates candidate central regions that strongly covary together during emergence, with the most integrated region being the ventral orbital cortex. This approach allows for targeted causal investigation, linking brain-wide circuit discovery with future hypothesis-driven mechanistic interrogation. Together, we find that emergence from isoflurane anesthesia reflects selective subcortical recruitment rather than broad global reactivation toward wakefulness. Significance StatementMillions of people undergo general anesthesia each year. While anesthetic unconsciousness is induced rapidly, emergence from altered consciousness is unpredictable. Neural mechanisms that underlie behavioral emergence remain poorly defined. Using whole-brain Fos mapping at cellular resolution, we found that emergence from isoflurane anesthesia is characterized by widespread cortical suppression alongside selective activation of discrete subcortical, autonomic, hindbrain, and cerebellar nuclei. This selective systems-level activity pattern identifies behavioral emergence as more than a simple global return toward wakefulness and highlights underappreciated neural circuitry involved in post-anesthetic recovery. Network analysis of the Fos maps further identifies candidate regions for targeted causal investigation of emergence-related regions.

neuroscience↗

bioRxiv2025

Synthetic modulation of brain-wide anesthesia-activated neural ensembles using a transgenic mouse system

BackgroundGeneral anesthesia is commonly used to produce unconsciousness across species, though the underlying neural substrates remain poorly understood. Here we test the hypothesis that isoflurane anesthesia produces unconsciousness by targeting discrete cell types and neural circuits distributed brain-wide, rather than by brain-wide non-specific binding or binding exclusively within single brain regions. MethodsWe take advantage of a transgenic mouse system that expresses chemogenetic designer receptors exclusively activated by a designer drug (DREADDs) in an inducible Cre-dependent manner driven by Fos immediate early gene expression. Since Fos peaks with metabolic activity, we use this system to insert DREADDs brain-wide into neurons that are active under isoflurane anesthesia. We then test the effects of chemogenetic manipulation of brain-wide anesthesia-activated neural ensembles on behavior, in the absence of isoflurane. ResultsUsing iDisco+ intact brain clearing and light sheet microscopy, we describe brain-wide expression of the captured neurons revealing sparse, heterogeneous and spatially distributed cells. We quantify dense labeling across mesolimbic pathways that include the amygdala, hypothalamus, thalamus, and hindbrain nuclei, implicating these regions as candidate mediators of the anesthetic state. Chemogenetic manipulation of the brain-wide activated neural ensembles reproduces key components of anesthesia, including immobility and thermal anti-nociception. We observe significantly increased isoflurane sensitivity, though not a complete loss of consciousness as measured by the righting reflex, suggesting alternative mechanisms contribute to unconsciousness that are not captured by specific neural signatures. ConclusionsWe provide causal evidence that isoflurane anesthesia engages discrete, distributed brain-wide circuitry, recapitulating dissociable components of general anesthesia. Significance StatementOver 300 million people worldwide undergo general anesthesia each year, yet the neural circuit mechanisms that produce unconsciousness remain unresolved. This fundamental gap limits the development of safer anesthetic strategies and hinders efforts to understand long-term cognitive consequences. Here we define the intact brain-wide neural signatures of isoflurane anesthesia-induced unconsciousness using a transgenic mouse system. We capture brain-wide neurons that are activated by isoflurane, manipulate those ensembles using chemogenetic tools and characterize their spatial representations at the cellular resolution using light sheet microscopy. Together, our data provides causal evidence that anesthesia engages discrete, distributed brain-wide circuitry, offering a systems-level framework for understanding how unconsciousness is generated.

neuroscience↗

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↗