Biology subjects

Tsai, V. S.

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

4 recordsLinked to original sources

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↗

bioRxiv2024

The transcriptional response of cortical neurons to concussion reveals divergent fates after injury

Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how different neuron types respond to this kind of injury. In this study, we follow neuronal populations over several months after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. We show that neurons that activate ATF3 upregulate stress-related genes while repressing many genes, including commonly used markers for these cell types. Using an inducible reporter linked to ATF3, we genetically mark damaged cells to track them over time. Notably, we find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and retains the ability to fire action potentials. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive kinase MAP3K12, also known as dual leucine zipper kinase (DLK), is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our novel approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.

neuroscience↗

bioRxiv2023

Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors

Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, we show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.

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↗