Valerie Tsai

All Publications

• Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors NATURE NEUROSCIENCE Enriquez-Traba, J., Arenivar, M., Yarur-Castillo, H. E., Noh, C., Flores, R. J., Weil, T., Roy, S., Usdin, T. B., Lagamma, C. T., Wang, H., Tsai, V. S., Kerspern, D., Moritz, A. E., Sibley, D. R., Lutas, A., Moratalla, R., Freyberg, Z., Tejeda, H. A. 2024

  Abstract

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

  View details for DOI 10.1038/s41593-024-01819-9

  View details for Web of Science ID 001372773000001

  View details for PubMedID 39653808

  View details for PubMedCentralID 6528838

• Individual Differences in Volitional Social Self-Administration and Motivation in Male and Female Mice Following Social Stress. Biological psychiatry Navarrete, J., Schneider, K. N., Smith, B. M., Goodwin, N. L., Zhang, Y. Y., Salazar, A. S., Gonzalez, Y. E., Anumolu, P., Gross, E., Tsai, V. S., Heshmati, M., Golden, S. A. 2024

  Abstract

  A key challenge in developing treatments for neuropsychiatric illness is the disconnect between preclinical models and the complexity of human social behavior. We integrate voluntary social self-administration into a rodent model of social stress as a platform for the identification of fundamental brain and behavior mechanisms underlying stress-induced individual differences in social motivation.Here, we introduced an operant social stress procedure in male and female mice composed of 3 phases: 1) social self-administration training, 2) social stress exposure concurrent with reinforced self-administration testing, and 3) poststress operant testing under nonreinforced and reinforced conditions. We used social-defeat and witness-defeat stress in male and female mice.Social defeat attenuated social reward seeking in males but not females, whereas witness defeat had no effect in males but promoted seeking behavior in females. We resolved social stress-induced changes to social motivation by aggregating z-scored operant metrics into a cumulative social index score to describe the spectrum of individual differences exhibited during operant social stress. Clustering does not adequately describe the relative distributions of social motivation following stress and is better described as a nonbinary behavioral distribution defined by the social index score, capturing a dynamic range of stress-related alterations in social motivation inclusive of sex as a biological variable.We demonstrated that operant social stress can detect stable individual differences in stress-induced changes to social motivation. The inclusion of volitional behavior in social procedures may enhance the understanding of behavioral adaptations that promote stress resiliency and their mechanisms under more naturalistic conditions.

  View details for DOI 10.1016/j.biopsych.2024.01.007

  View details for PubMedID 38244753

  View details for PubMedCentralID PMC11255129

• Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner. Molecular psychiatry Yarur, H. E., Casello, S. M., Tsai, V. S., Enriquez-Traba, J., Kore, R., Wang, H., Arenivar, M., Tejeda, H. A. 2023; 28 (11): 4801-4813

  Abstract

  The medial prefrontal cortex (mPFC) controls behavior via connections with limbic excitatory afferents that engage various inhibitory motifs to shape mPFC circuit function. The dynorphin (Dyn) / kappa-opioid receptor (KOR) system is highly enriched in the mPFC, and its dysregulation is implicated in neuropsychiatric disorders. However, it is unclear how the Dyn / KOR system modulates excitatory and inhibitory circuits that are integral for mPFC information processing and behavioral control. Here, we provide a circuit-based framework wherein mPFC Dyn / KOR signaling regulates excitation-inhibition balance by toggling which afferents drive mPFC neurons. Dyn / KOR regulation of afferent inputs is pathway-specific. Dyn acting on presynaptic KORs inhibits glutamate release from afferent inputs to the mPFC, including the basolateral amygdala (BLA), paraventricular nucleus of the thalamus, and contralateral cortex. The majority of excitatory synapses to mPFC neurons, including those from the ventral hippocampus (VH), do not express presynaptic KOR, rendering them insensitive to Dyn / KOR modulation. Dyn / KOR signaling also suppresses afferent-driven recruitment of specific inhibitory sub-networks, providing a basis for Dyn to disinhibit mPFC circuits. Specifically, Dyn / KOR signaling preferentially suppresses SST interneuron- relative to PV interneuron-mediated inhibition. Selective KOR action on afferents or within mPFC microcircuits gates how distinct limbic inputs drive spiking in mPFC neurons. Presynaptic Dyn / KOR signaling decreases KOR-positive input-driven (e.g. BLA) spiking of mPFC neurons. In contrast, KOR-negative input recruitment of mPFC neurons is enhanced by Dyn / KOR signaling via suppression of mPFC inhibitory microcircuits. Thus, by acting on distinct circuit elements, Dyn / KOR signaling shifts KOR-positive and negative afferent control of mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function. Together, these findings highlight the utility of targeting the mPFC Dyn / KOR system as a means to treat neuropsychiatric disorders characterized by dysregulation in mPFC integration of long-range afferents with local inhibitory microcircuits.

  View details for DOI 10.1038/s41380-023-02226-5

  View details for PubMedID 37644172

  View details for PubMedCentralID PMC10914606

• Sex differences in appetitive and reactive aggression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Aubry, A. V., Joseph Burnett, C., Goodwin, N. L., Li, L., Navarrete, J., Zhang, Y., Tsai, V., Durand-de Cuttoli, R., Golden, S. A., Russo, S. J. 2022; 47 (10): 1746-1754

  Abstract

  Aggression is an evolutionarily conserved, adaptive component of social behavior. Studies in male mice illustrate that aggression is influenced by numerous factors including the degree to which an individual finds aggression rewarding and will work for access to attack and subordinate mice. While such studies have expanded our understanding of the molecular and circuit mechanisms of male aggression very little is known about female aggression, within these established contexts. Here we use an ethologically relevant model of male vs. female aggression by pair housing adult male and female outbred CFW mice with opposite sex cage mates. We assess reactive (defensive) aggression in the resident intruder (RI) test and appetitive (rewarding) aggression in the aggression conditioned place preference (CPP) and operant self-administration (SA) tests. Our results show dramatic sex differences in both qualitative and quantitative aspects of reactive vs. appetitive aggression. Males exhibit more wrestling and less investigative behavior during RI, find aggression rewarding, and will work for access to a subordinate to attack. Females exhibit more bites, alternate between aggressive behaviors and investigative behaviors more readily during RI, however, they do not find aggression to be rewarding or reinforcing. These results establish sex differences in aggression in mice, providing an important resource for the field to better understand the circuit and molecular mechanisms of aggression in both sexes.

  View details for DOI 10.1038/s41386-022-01375-5

  View details for PubMedID 35810200

  View details for PubMedCentralID PMC9372130