Biology subjects

Sohal, V. S.

Publications and source records attributed to Sohal, V. S..

16 recordsLinked to original sources

bioRxiv2026

Smells like γ-synchrony: Insula-prefrontal communication depends on γ-synchrony and supports modality-specific changes in behavioral strategies

The prefrontal cortex is critical for many aspects of flexible behavior, but how it interacts with other brain regions to perform this function remains largely unknown. The insula is bidirectionally coupled with prefrontal cortex and known to be necessary for many aspects of cognition. Here we examined how the medial insular cortex (mIC) and medial prefrontal cortex (mPFC) interact to promote flexible behavior. Disrupting mIC-mPFC connectivity interferes with the ability of mice to learn shifts from texture cue-based behavioral strategies to odor-based ones (but not vice-versa). Using genetically encoded voltage indicators, we find a corresponding increase of in-phase gamma-frequency synchronization between mIC and mPFC parvalbumin-expressing inhibitory neurons during texture-to-odor shifts. Finally, we confirmed that optogenetically perturbing this synchronization disrupts texture-to-odor (but not odor-to-texture) shifts. These results establish a critical role for gamma synchronization in insula-prefrontal communication, and show that this communication plays a sensory modality-specific role in flexible behavior.

neuroscience↗

bioRxiv2026

Psilocybin selectively rescues cognitive flexibility impairments caused by aberrant prefrontal error signaling

Psychedelic drugs show remarkable potential for treating psychiatric disorders, but the mechanisms underlying their therapeutic effects remain relatively unknown. Here, we demonstrate that psilocybin can powerfully ameliorate deficits in cognitive flexibility, but this effect depends on the specific circuit-level cause of those deficits. Using optogenetic models of cognitive inflexibility in mice, psilocybin rescued deficits caused by aberrant mesocortical signaling but failed to rescue deficits arising from disrupted interhemispheric gamma synchrony. Aberrant mesocortical signaling drove abnormally elevated activity in prefrontal cortex-mediodorsal thalamus (PFC-MD) projection neurons during post-error exploration, and psilocybin attenuated this pathological activity both acutely and 24 hours later. Patch-clamp electrophysiology revealed that psilocybin induces lasting plasticity in PFC-MD neurons, potentiating thalamic inputs while suppressing dopamine- and NMDA-receptor-dependent afterdepolarizations that could otherwise sustain aberrant post-error signaling. These findings reveal cellular and circuit mechanisms that could explain psilocybins therapeutic specificity and establish a precision medicine framework approach for psychedelic treatment.

neuroscience↗

bioRxiv2025

Circuit inhibition promotes the dynamic reorganization of prefrontal task encoding to support cognitive flexibility

The mammalian prefrontal cortex encodes variables related to goal-directed behavior, and enables flexibility during environmental changes, making it critical to understand how the dynamic updating vs. stable maintenance of different encodings contribute to behavioral adaptation. We addressed this by comparing prefrontal encoding during successful adaptation vs. maladaptive perseveration. Specifically, we studied mutant (Dlx5/6+/-) mice, which have dysfunctional parvalbumin-expressing inhibitory interneurons and perseverate in a rule shifting task. We measured mPFC activity patterns using microendoscopic calcium imaging, then used linear classifiers and neural networks to compare representational geometries in wild-type mice and Dlx5/6+/- mutants before, during, and after benzodiazepine treatment, which persistently rescues their rule shift learning. The encoding of correct vs. incorrect trial outcomes rapidly shifts as mice successfully learn new cue-reward associations, but becomes more stable when mutant mice perseverate. We also find activity patterns that normally distinguish learning of the initial association vs. rule shift, but become diminished during perseveration. Finally, during perseveration, outdated representations are inappropriately reinstated, not just passively maintained. These results reveal prefrontal contributions to flexible behavior driven by the dynamic reorganization of abstract rule representations, rather than stable reinforcement signals.

neuroscience↗

bioRxiv2025

Hippocampal input-driven plasticity of prefrontal interneurons reveals a circuit basis for impaired spatial working memory.

Long-range projections from ventral hippocampus (vHPC) to medial prefrontal cortex (mPFC) support cognitive functions including spatial working memory (SWM). vHPC input targets multiple prefrontal interneuron classes, yet how hippocampal input recruits these populations in vivo, whether this recruitment is plastic, and how such plasticity influences cognition remain unknown. Here, we combined optical stimulation of mouse vHPC inputs with calcium recordings from discrete mPFC interneuron populations, revealing persistent activity-induced reweighting of hippocampal recruitment across prefrontal inhibitory microcircuits. Ex vivo electrophysiology and computational modeling implicated weakened monosynaptic hippocampal drive onto vasoactive intestinal polypeptide (VIP)-expressing interneurons in this circuit reconfiguration. Prior vHPC input stimulation and the schizophrenia-associated Df(16)A+/- mutation, which also yielded reduced hippocampal input onto VIP interneurons, produced convergent alterations in task-related VIP interneuron activity associated with poorer SWM task learning. These findings implicate hippocampal input to VIP interneurons as a key locus of plasticity capable of reconfiguring inhibitory microcircuit activity linked to impaired working memory task learning. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/665987v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@e26cb0org.highwire.dtl.DTLVardef@14d9d6borg.highwire.dtl.DTLVardef@9a0fc2org.highwire.dtl.DTLVardef@80afd1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

neuroscience↗

bioRxiv2025

Synaptic plasticity of prefrontal long-range inhibition regulates cognitive flexibility

While glutamatergic synaptic plasticity is believed to be a fundamental mechanism mediating learning, the behavioral significance of plasticity at cortical GABAergic synapses remains less well understood. Furthermore, despite recent discoveries of long-range projections from neocortical GABAergic neurons, details about how they function are also sparse. Here we combine behavioral optogenetics with patch-clamp electrophysiology to link plasticity at long-range GABAergic synapses with higher-order cognitive functions. Specifically, learning extradimensional rule shifts potentiates callosal GABAergic synapses from prefrontal parvalbumin-expressing (PV) neurons onto corticothalamic neurons. Disrupting this potentiation by inhibiting callosal PV terminals during rule shifts induces perseveration, whereas reinstating this potentiation with subsequent gamma-frequency callosal PV terminal stimulation restores flexible behavior. This shows how a novel plasticity locus can regulate brain circuits underlying normal cognition and pathological states.

neuroscience↗

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2025

Loss of the autism associated gene Tbr1 disrupts prediction and encoding by prefrontal ensembles during socioemotional behaviors

Disruptions in many genes linked to autism spectrum disorder (ASD) affect synaptic function and socioemotional behaviors in mice. However, exactly how synaptic dysfunction alters neural activity patterns underlying behavior remains unknown. We addressed this using mice lacking the high confidence ASD gene Tbr1 in cortical layer 5 (L5) projection neurons (Tbr1 cKO mice). These mice have known deficits in synaptic input to L5 neurons and social behavior. We also find some abnormalities in anxiety-related avoidance. Calcium imaging of prefrontal L5 neurons revealed that despite reduced overall activity, cKO mice recruit normal numbers of neurons into prefrontal ensembles encoding social and anxiety-related behaviors. However, the stability, inter-neuronal coordination, and reactivation of social ensembles were diminished in cKO mice. Furthermore, in cKO mice, ensembles no longer predicted approach-avoidance decisions. These results reveal new aspects of how prefrontal ensembles encode socioemotional behaviors, and malfunction in the setting of ASD-linked gene disruption.

neuroscience↗

bioRxiv2024

Cell type-specific dynamics of prefrontal gamma synchrony during flexible behavior

Cognitive dysfunction in conditions such as schizophrenia involves disrupted communication between the prefrontal cortex (PFC) and mediodorsal thalamus (MD). Parvalbumin interneurons (PVI) are known to regulate PFC microcircuits and generate gamma-frequency ([~]40Hz) oscillations - fast, synchronized neural rhythms that are recruited during many executive functions, necessary for cognitive flexibility, and deficient in schizophrenia. While targeting PVI-mediated gamma oscillations holds great therapeutic promise, their nature and specific functions, e.g., for regulating PFC[->]MD communication, remain elusive. Using dual-color voltage indicators and optogenetics, we reveal that PVIs dynamically entrain MD-projecting PFC neurons both locally and contralaterally, giving rise to multiple distinct circuit-specific patterns of distributed synchronization that are recruited in a behaviorally-specific manner to support particular aspects of flexible behavior. Thus, gamma oscillations are not unitary phenomena characterized by one microcircuit-wide pattern of entrainment. Rather, they comprise diverse motifs, defined by specific cell types and phase relationships, that are dynamically recruited for specific functions.

neuroscience↗

bioRxiv2022

Long-range inhibition synchronizes and updates prefrontal task activity

Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates, and humans to update their behavior to adapt to changes in the environment, e.g., during cognitive tasks1-5. Within medial prefrontal cortex, inhibitory neurons expressing parvalbumin are important for updating strategies in a rule shift task6-8. Nevertheless, causal mechanisms through which parvalbumin neurons recruit specific circuits to produce prefrontal network dynamics that switch from maintaining to updating task-related patterns of activity remain unknown. Here we identify a new long-range inhibitory projection from prefrontal parvalbumin neurons to the contralateral cortex that mediates this process. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts, selectively inhibiting these callosal parvalbumin projections disrupts rule shift learning, desynchronizes gamma-frequency activity that is necessary for learning8, and suppresses changes in prefrontal activity patterns that normally accompany rule shifts. Thus, callosal parvalbumin projections switch prefrontal circuits from maintaining to updating behavioral strategies by synchronizing callosal communication and preventing it from inappropriately maintaining outdated neural representations. These findings may explain how deficits in prefrontal parvalbumin neurons and gamma synchrony cause impaired behavioral flexibility in schizophrenia9-10, and identify long-range projections from prefrontal parvalbumin neurons as a key circuit locus for understanding and treating these deficits.

neuroscience↗

bioRxiv2021

Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated if alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast spiking, somatostatin-expressing (SOM+) subtype of inhibitory neurons in layer V of the orbitofrontal cortex (OFC) two months after injury. These neurons exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons. By contrast, fast spiking, parvalbumin-expressing (PV+) interneurons did not show changes in intrinsic excitability or synaptic output. Impairments in SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.

neuroscience↗

bioRxiv2021

Rhythmic auditory stimulation rescues cognitive flexibility in mutant mice with impaired gamma synchrony

Neural synchronization at gamma ([~]40 Hz) frequencies is believed to contribute to brain function and be deficient in disorders including Alzheimers disease and schizophrenia. Gamma-frequency sensory stimulation has been proposed as a non-invasive treatment for deficient gamma synchrony and associated cognitive deficits, and has been shown to be effective in mouse models of Alzheimers disease. However, both the mechanism and applicability of this approach remain unclear. Here we tested this approach using mutant (Dlx5/6+/-) mice which have deficits in gamma synchrony and the ability to learn to shift between rules which use different types of cues to indicate reward locations. 40 Hz auditory stimulation rescues rule shifting in Dlx5/6+/- mice. However, this improvement does not outlast the period of stimulation, and is not associated with normalized gamma synchrony, measured using genetically encoded voltage indicators. These results show how gamma-frequency sensory stimulation may improve behavior without fully restoring normal circuit function.

neuroscience↗

bioRxiv2021

Convergence of clinically relevant manipulations on dopamine-regulated prefrontal activity underlying stress-coping responses

BackgroundDepression is a pleiotropic condition that can be produced or ameliorated by diverse genetic, environmental, and pharmacological manipulations. In this context, identifying patterns of circuit activity on which many of these manipulations converge would be important, because studying these patterns could reveal underlying biological processes related to depression and/or new therapies. In particular, the prefrontal cortex and dopaminergic signaling have both been implicated in depression. Nevertheless, how dopamine influences disease-relevant patterns of prefrontal circuit activity remains unknown. MethodsWe used calcium imaging in brain slices to identify depression-relevant patterns of activity in prefrontal microcircuits, and measure how these are modulated by dopamine D2 receptors (D2Rs). Then, we used optogenetic and genetic manipulations to test how dopamine and D2Rs contribute to stress-coping behavior in a paradigm commonly used to assay how manipulations promote or ameliorate depression-like states. ResultsPatterns of correlated activity in prefrontal microcircuits are enhanced by D2R stimulation as well as by two mechanistically distinct antidepressants: ketamine and fluoxetine. Conversely, this D2R-driven effect was disrupted in two etiologically distinct models of depression: a genetic susceptibility model and chronic social defeat. Phasic stimulation of dopamine afferents to prefrontal cortex increased effortful responses to tail suspension stress. Conversely, deleting prefrontal D2R receptors reduced the duration of individual struggling episodes. ConclusionsCorrelated prefrontal microcircuit activity represents a point of convergence for multiple depression-related manipulations. Prefrontal D2Rs enhance this activity. Through this mechanism, prefrontal dopamine signaling may promote network states associated with antidepressant actions that manifest as effortful responses to stress.

neuroscience↗

bioRxiv2021

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

The prefrontal cortex (PFC) is postulated to exert top-down control by modulating information processing throughout the brain to promote specific actions based on current goals. However, the pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down prefrontal control of information processing in the hippocampus remains sparse. Here we describe novel monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal representations of objects. Correspondingly, stimulation of PFC-to-hippocampus GABAergic projections promotes object exploration. Together, these results elucidate a novel top-down pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

neuroscience↗

bioRxiv2020

Dynamic correlations help prefrontal ensembles transmit information about social behavior

New technologies have made it possible to measure activity from many neurons simultaneously. Nevertheless, most studies still analyze the activity of simultaneously recorded neurons one-at-a-time, then group together neurons which increase their activity during similar behaviors into an ensemble. This notion of an ensemble ignores the ability of neurons to act collectively, and encode and transmit information in ways that are not reflected by their individual activity levels. We used microendoscopic GCaMP imaging to measure prefrontal activity while mice were either alone or engaged in social interaction. We developed new approaches, using neural network classifiers and surrogate (shuffled) datasets, to characterize how neurons synergistically transmit information about social behavior. Surrogate datasets which preserve behaviorally-specific patterns of coactivity (correlations) outperform those which preserve behaviorally-driven changes in activity levels but not correlated activity. This shows that prefrontal neurons act collectively to transmit information about socialization, because social behavior elicits increases in correlated activity that are not explained simply by the activity levels of the underlying neurons. Notably, this ability of correlated activity to enhance the information transmitted by neuronal ensembles is lost in mice lacking the autism-associated gene Shank3. These results show that synergy is an important concept for the coding of social behavior which can be disrupted in disease states, reveal a specific mechanism underlying this synergy (social behavior increases correlated activity within specific ensembles), and outlines methods for studying how neurons within an ensemble can work together to encode information.

neuroscience↗

bioRxiv2019

Interhemispheric gamma synchrony between parvalbumin interneurons supports behavioral adaptation

Organisms must learn novel strategies to adapt to changing environments. Synchrony, which enhances neuronal communication, might create dynamic brain states, facilitating such adaptation. Although synchronization is common in neural systems, its functional significance remains controversial. We studied the role of gamma-frequency (~40 Hz) synchronization, promoted by parvalbumin interneurons, in mice learning multiple new cue-reward associations. Voltage imaging revealed cell type-specific increases of interhemispheric gamma synchrony within prefrontal parvalbumin interneurons, when mice received feedback that previously-learned associations were no longer valid. Disrupting this synchronization by delivering out-of-phase optogenetic stimulation caused mice to perseverate on outdated associations, an effect not reproduced by stimulating in-phase or out-of-phase at other frequencies. Gamma synchrony was specifically required when new associations utilized familiar cues that were previously irrelevant to behavioral outcomes, not when associations involved novel cues, or for reversing previously learned associations. Thus, gamma synchrony is indispensable for reappraising the behavioral salience of external cues.

neuroscience↗

bioRxiv2019

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis (TS) gene, Tsc1, which inhibits mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. These changes also occur when only one allele of Tsc1 is deleted, making these findings relevant to individuals with TS. Notably, treatment with rapamycin, which inhibits MTOR, reverses these changes in adult mice. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to some neuropsychiatric symptoms observed in TS. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

neuroscience↗