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Howe, J.R., Chan, C.L., Lee, D., Blanquart, M., Lee, J.H., Decoster, L., Romero, H.K., Zadina, A.N., Lemieux, M.E., Mills, F., Desplats, P.A., Tye, K.M., Root, C.M. Control of innate olfactory valence by segregated cortical amygdala circuits. (2026) Elife. 14. DOI: 10.7554/eLife.104677

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Tsuda, B., Pate, S.C., Tye, K.M., Siegelmann, H.T., Sejnowski, T.J. Neuromodulators Generate Multiple Context-Relevant Behaviors in Recurrent Neural Networks. (2026) Computación neuronal.:1-36 DOI: 10.1162/NECO.a.1489

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Cressy, J., Jia, C., Salk, J., Tye, K.M. Neural Mechanisms of Social Homeostasis: Dynamic Range Plasticity. (2026) Diario de Neurociencia. 46(8). DOI: 10.1523/JNEUROSCI.0224-25.2025

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Mohanta, S., Tye, K.M. Negative results positive for understanding the neural representation of valence across the brain. (2025) Neurona. 113(18):2879-2882. DOI: 10.1016/j.neuron.2025.08.024

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Lee, C.R., Matthews, G.A., Lemieux, M.E., Wasserlein, E.M., Borio, M., Miranda, R.L., Keyes, L.R., Schneider, G.P., Jia, C., Tran, A., Aloboudi, F., Chan, M.G., Peroni, E., Pereira, G., López-Moraga, A., Pallé, A., Kimchi, E.Y., Padilla-Coreano, N., Wichmann, R., Tye, K.M. Separable dorsal raphe dopamine projections mimic the facets of a loneliness-like state. (2025) Elife. 14. DOI: 10.7554/eLife.105955

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Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive or negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focus on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRN) in mice, which we previously implicated in social motivation alongside an aversive affective state. We show that three prominent DRN projections - to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) - play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRN-CeA projection promoted social behavior and photostimulation of the DRN-BNST projection promoted exploratory behavior, while the DRN-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse receptor expression, poising DRN neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRN photostimulation on downstream neuron excitability depended on region and baseline cell properties, resulting in excitatory responses in BNST cells and diverse responses in CeA and BLP. Finally, in vivo microendoscopic cellular-resolution recordings in the CeA with DRN photostimulation revealed a correlation between social behavior and neurons excited by social stimuli, suggesting that increased dopamine tone may recruit different CeA neurons to social ensembles. Collectively, these circuit features may facilitate a coordinated, but flexible, response in the presence of social stimuli that can be flexibly guided based on the internal social homeostatic need state of the individual.

Tye, K., Jia, C., Tran, A., Aloboudi, F., Say, E., Thao, N., Lee, C., Batra, K., Nguyen, A., Bal, A., Delahanty, J., Chan, M., Keyes, L., Patel, R., Wichmann, R., Taschbach, F., Li, Y., Benna, M., Pereira, T., Li, H., Nono, N. Social Exclusion Amplifies Behavioral Responses to Physical Pain via Insular Neuromodulation. (2025) Res. Cuadrado. DOI: 10.21203/rs.3.rs-6615222/v1

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Allsop, A.S., Tye, K.M., Krystal, J.H. Social Homeostasis: A New Paradigm for Mental Health Diagnosis and Treatment. (2025) Psiquiatría Biológica. 97(10):932-935. DOI: 10.1016/j.biopsych.2025.03.007

Ramot, A., Taschbach, F.H., Yang, Y.C., Hu, Y., Chen, Q., Morales, B.C., Wang, X.C., Wu, A., Tye, K.M., Benna, M.K., Komiyama, T. Motor learning refines thalamic influence on motor cortex. (2025) Naturaleza. DOI: 10.1038/s41586-025-08962-8

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Jia, C., Tran, A., Aloboudi, F., Say, E., Thao, N., Lee, C.R., Batra, K., Nguyen, A., Bal, A., Nono, N.N., Delahanty, J., Chan, M.G., Keyes, L.R., Patel, R.R., Wichmann, R., Taschbach, F., Li, Y., Benna, M., Pereira, T.D., Li, H., Tye, K. Social Exclusion Amplifies Behavioral Responses to Physical Pain via Insular Neuromodulation. (2025) bioRxiv. DOI: 10.1101/2025.05.09.653162

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Coley, A., Tye, K., Batra, K., Delahanty, J., Keyes, L., Pamintuan, R., Ramot, A., Hagemann, J., Lee, C., Liu, V., Adivikolanu, H., Cressy, J., Jia, C., Massa, F., LeDuke, D., Gabir, M., Durubeh, B., Linderhof, L., Patel, R., Wichmann, R., Li, H., Fischer, K., Pereira, T. Predicting Future Development of Stress-Induced Anhedonia From Cortical Dynamics and Facial Expression. (2025) Res. Cuadrado. DOI: 10.21203/rs.3.rs-5537951/v1

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The current state of mental health treatment for individuals diagnosed with major depressive disorder leaves billions of individuals with first-line therapies that are ineffective or burdened with undesirable side effects. One major obstacle is that distinct pathologies may currently be diagnosed as the same disease and prescribed the same treatments. The key to developing antidepressants with ubiquitous efficacy is to first identify a strategy to differentiate between heterogeneous conditions. Major depression is characterized by hallmark features such as anhedonia and a loss of motivation , and it has been recognized that even among inbred mice raised under identical housing conditions, we observe heterogeneity in their susceptibility and resilience to stress . Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity . The mPFC is responsible for higher order functions , such as valence encoding; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol in mice and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic behavior in response to stress. We then performed in vivo 2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population dynamics during a Pavlovian discrimination task. Chronic mild stress mice exhibited a blunted effect in the ratio of mPFC neural population responses to rewards relative to punishments after stress that rebounds following ketamine treatment. Also, a linear classifier revealed that we can decode susceptibility to chronic mild stress based on mPFC valence-encoding properties prior to stress-exposure and behavioral expression of susceptibility. Lastly, we utilized markerless pose tracking computer vision tools to predict whether a mouse would become resilient or susceptible based on facial expressions during a Pavlovian discrimination task. These results indicate that mPFC valence encoding properties and behavior are predictive of anhedonic states. Altogether, these experiments point to the need for increased granularity in the measurement of both behavior and neural activity, as these factors can predict the predisposition to stress-induced anhedonia.

Ransey, E., Thomas, G.E., Wisdom, E., Almoril-Porras, A., Bowman, R., Adamson, E., Walder-Christensen, K.K., White, J.A., Hughes, D.N., Schwennesen, H., Ferguson, C., Tye, K.M., Mague, S.D., Niu, L., Wang, Z.W., Colón-Ramos, D., Hultman, R., Bursac, N., Dzirasa, K. Long-term editing of brain circuits in mice using an engineered electrical synapse. (2025) bioRxiv. DOI: 10.1101/2025.03.25.645291

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Joo, B., Tye, K.M. Stress drives a switch in sex preference. (2025) Ciencia. 387(6730):138-139. DOI: 10.1126/science.adu7946

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Coley, A.A., Batra, K., Delahanty, J.M., Keyes, L.R., Pamintuan, R., Ramot, A., Hagemann, J., Lee, C.R., Liu, V., Adivikolanu, H., Cressy, J., Jia, C., Massa, F., LeDuke, D., Gabir, M., Durubeh, B., Linderhof, L., Patel, R., Wichmann, R., Li, H., Fischer, K.B., Pereira, T., Tye, K.M. Predicting Future Development of Stress-Induced Anhedonia From Cortical Dynamics and Facial Expression. (2024) bioRxiv. DOI: 10.1101/2024.12.18.629202

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The current state of mental health treatment for individuals diagnosed with major depressive disorder leaves billions of individuals with first-line therapies that are ineffective or burdened with undesirable side effects. One major obstacle is that distinct pathologies may currently be diagnosed as the same disease and prescribed the same treatments. The key to developing antidepressants with ubiquitous efficacy is to first identify a strategy to differentiate between heterogeneous conditions. Major depression is characterized by hallmark features such as anhedonia and a loss of motivation , and it has been recognized that even among inbred mice raised under identical housing conditions, we observe heterogeneity in their susceptibility and resilience to stress . Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity . The mPFC is responsible for higher order functions , such as valence encoding; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol in mice and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic behavior in response to stress. We then performed 2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population dynamics during a Pavlovian discrimination task. Chronic mild stress mice exhibited a blunted effect in the ratio of mPFC neural population responses to rewards relative to punishments after stress that rebounds following ketamine treatment. Also, a linear classifier revealed that we can decode susceptibility to chronic mild stress based on mPFC valence-encoding properties prior to stress-exposure and behavioral expression of susceptibility. Lastly, we utilized markerless pose tracking computer vision tools to predict whether a mouse would become resilient or susceptible based on facial expressions during a Pavlovian discrimination task. These results indicate that mPFC valence encoding properties and behavior are predictive of anhedonic states. Altogether, these experiments point to the need for increased granularity in the measurement of both behavior and neural activity, as these factors can predict the predisposition to stress-induced anhedonia.

Howe, J.R., Chan, C.L., Lee, D., Blanquart, M., Romero, H.K., Zadina, A.N., Lemieux, M.E., Mills, F., Desplats, P.A., Tye, K.M., Root, C.M. Control of innate olfactory valence by segregated cortical amygdala circuits. (2024) bioRxiv. DOI: 10.1101/2024.06.26.600895

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Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express and posterior neurons express . Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

Tye, K.M., Miller, E.K., Taschbach, F.H., Benna, M.K., Rigotti, M., Fusi, S. Mixed selectivity: Cellular computations for complexity. (2024) Neurona. DOI: 10.1016/j.neuron.2024.04.017

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Lin, A., Akafia, C., Dal Monte, O., Fan, S., Fagan, N., Putnam, P., Tye, K.M., Chang, S., Ba, D., Allsop, A.S. An unbiased method to partition diverse neuronal responses into functional ensembles reveals interpretable population dynamics during innate social behavior. (2024) bioRxiv. DOI: 10.1101/2024.05.08.593229

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Tye, K., Patel, R., Patarino, M., Kim, K., Pamintuan, R., Taschbach, F., Li, H., Lee, C., Hoek, A., Castro, R., Cazares, C., Miranda, R., Jia, C., Delahanty, J., Batra, K., Keyes, L., Libster, A., Wichmann, R., Pereira, T., Benna, M. Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking. [Preprint] (2024) Res. Cuadrado. DOI: 10.21203/rs.3.rs-4033115/v1

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Kimchi, E.Y., Burgos-Robles, A., Matthews, G.A., Chakoma, T., Patarino, M., Weddington, J.C., Siciliano, C., Yang, W., Foutch, S., Simons, R., Fong, M.F., Jing, M., Li, Y., Polley, D.B., Tye, K.M. Reward contingency gates selective cholinergic suppression of amygdala neurons. (2024) Elife. 12. DOI: 10.7554/eLife.89093

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LeDuke, D.O., Borio, M., Miranda, R., Tye, K.M. Anxiety and depression: A top-down, bottom-up model of circuit function. (2023) Ann N Y Acad Sci. DOI: 10.1111/nyas.14997

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Chen, Z., Zhang, R., Fang, H.S., Zhang, Y.E., Bal, A., Zhou, H., Rock, R.R., Padilla-Coreano, N., Keyes, L.R., Zhu, H., Li, Y.L., Komiyama, T., Tye, K.M., Lu, C. AlphaTracker: a multi-animal tracking and behavioral analysis tool. (2023) Front Behav Neurosci. 17:1111908. DOI: 10.3389/fnbeh.2023.1111908

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Leppla, C.A., Keyes, L.R., Glober, G., Matthews, G.A., Batra, K., Jay, M., Feng, Y., Chen, H.S., Mills, F., Delahanty, J., Olson, J.M., Nieh, E.H., Namburi, P., Wildes, C., Wichmann, R., Beyeler, A., Kimchi, E.Y., Tye, K.M. Thalamus sends information about arousal but not valence to the amygdala. (2022) Psychopharmacology (Berl). DOI: 10.1007/s00213-022-06284-5

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Mills, F., Lee, C.R., Howe, J.R., Li, Shao, Keisler, M.N., Lemieux , M.E., Taschbach , F.H., Keyes, L.R., Borio, M., Chen, H.S., Patel, R.R., Gross, A.l., Delahanty , J., Cazares, C., Maree, L., Wichmann , R., Pereira , T.D., Benna, M.K., Root, C.M., Tye, K.M. Amygdalostriatal transition zone neurons encode sustained valence to direct conditioned behaviors (2022) bioRxiv. DOI: https://doi.org/10.1101/2022.10.28.514263

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In order to respond appropriately to threats in the environment, the brain must rapidly determine whether a stimulus is important and whether it is positive or negative, and then use that information to direct behavioral responses. Neurons in the amygdala have long been implicated in valence encoding and in fear responses to threatening stimuli, but show transient firing responses in response to these stimuli that do not match the timescales of associated behavioral responses. For decades, there has been a logical gap in how behavioral responses could be mediated without an ensemble representation of the internal state of valence that has rapid onset, high signal-to-noise, and is sustained for the duration of the behavioral state. Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of this highly conserved process that is of paramount importance for survival, which does exactly this: represents an internal state (e.g. fear) that can be expressed in multiple motor outputs (e.g. freezing or escape). The ASt is anatomically positioned as a “shortcut” to connect the corticolimbic system (important for evaluation) with the basal ganglia (important for action selection) with the inputs of the amygdala and the outputs of the striatum – ideally poised for evaluating and responding to environmental threats. From in vivo cellular resolution recordings that include both electrophysiology and calcium imaging, we find that ASt neurons are unique in that they are sparse coding, extremely high signal-to-noise, and also maintain a sustained response for negative valence stimuli for the duration of the defensive behavior – a rare but essential combination. We further show that photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors. Using single-nucleus RNA sequencing and in situ RNA labelling we generate a comprehensive profile of cell types and gene expression in the ASt, and find the ASt is genetically distinct from adjacent striatal and amygdalar structures. We also find that the ASt has a greater proportion of neurons expressing Drd2 than neurons expressing Drd1a, a unique feature compared to other regions of the striatum. Using in vivo calcium imaging, we show that that this Drd2+ population robustly encodes stimuli of negative valence, and in loss-of-function experiments find that optogenetic inhibition of Drd2+ ASt neurons causes a striking reduction in cue-conditioned fear responses. Together, our findings identify the ASt as a previously-unappreciated critical missing link for encoding learned associations and directing ongoing behavior.

Padilla-Coreano, N., Tye, K.M., Zelikowsky, M. Dynamic influences on the neural encoding of social valence. (2022) Nature Reviews Neuroscience. DOI: 10.1038/s41583-022-00609-1

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Li, H., Namburi, P., Olson, J.M., Borio, M., Lemieux, M.E., Beyeler, A., Calhoon, G.G., Hitora-Imamura, N., Coley, A.A., Libster, A., Bal, A., Jin, X., Wang, H., Jia, C., Choudhury, S.R., Shi, X., Felix-Ortiz, A.C., de la Fuente, V., Barth, V.P., King, H.O., Izadmehr, E.M., Revanna, J.S., Batra, K., Fischer, K.B., Keyes, L.R., Padilla-Coreano, N., Siciliano, C.A., McCullough, K.M., Wichmann, R., Ressler, K.J., Fiete, I.R., Zhang, F., Li, Y., Tye, K.M. Neurotensin orchestrates valence assignment in the amygdala. (2022) Naturaleza. DOI: 10.1038/s41586-022-04964-y

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Padilla-Coreano, N., Batra, K., Patarino, M., Chen, Z., Rock, R.R., Zhang, R., Hausmann, S.B., Weddington, J.C., Patel, R., Zhang, Y.E., Fang, H.S., Mishra, S., LeDuke, D.O., Revanna, J., Li, H., Borio, M., Pamintuan, R., Bal, A., Keyes, L.R., Libster, A., Wichmann, R., Mills, F., Taschbach, F.H., Matthews, G.A., Curley, J.P., Fiete, I.R., Lu, C., Tye, K.M. Cortical ensembles orchestrate social competition through hypothalamic outputs. [Pubmed] (2022) Naturaleza. DOI: 10.1038/s41586-022-04507-5

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Dwortz, M.F., Curley, J.P., Tye, K.M., Padilla-Coreano, N. Neural systems that facilitate the representation of social rank. (2022) Philos Trans R Soc Lond B Biol Sci. 377(1845):20200444. DOI: 10.1098/rstb.2020.0444

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Lee, C.R., Chen, A., Tye, K.M. The neural circuitry of social homeostasis: Consequences of acute versus chronic social isolation. (2021) Móvil. DOI: 10.1016/j.cell.2021.02.028

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Coley, A.A., Padilla-Coreano, N., Patel, R., Tye, K.M. Valence processing in the PFC: Reconciling circuit-level and systems-level views. (2021) Int Rev Neurobiol. 158:171-212. DOI: 10.1016/bs.irn.2020.12.002

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Tomova, L., Wang, K.L., Thompson, T., Matthews, G.A., Takahashi, A., Tye, K.M., Saxe, R. Acute social isolation evokes midbrain craving responses similar to hunger. (2020) Nature Neuroscience. 23(12):1597-1605. DOI: 10.1038/s41593-020-00742-z

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Tsuda, B., Tye, K.M., Siegelmann, H.T., Sejnowski, T.J. A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex. (2020) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. DOI: 10.1073/pnas.2009591117

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Wu, A., Yu, B., Chen, Q., Matthews, G.A., Lu, C., Campbell, E., Tye, K.M., Komiyama, T. Context-dependent plasticity of adult-born neurons regulated by cortical feedback. (2020) Avances en Ciencia. 6(42). DOI: 10.1126/sciadv.abc8319

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Shemesh, O.A., Linghu, C., Piatkevich, K.D., Goodwin, D., Celiker, O.T., Gritton, H.J., Romano, M.F., Gao, R., Yu, C.J., Tseng, H.A., Bensussen, S., Narayan, S., Yang, C.T., Freifeld, L., Siciliano, C.A., Gupta, I., Wang, J., Pak, N., Yoon, Y.G., Ullmann, J.F.P., Guner-Ataman, B., Noamany, H., Sheinkopf, Z.R., Park, W.M., Asano, S., Keating, A.E., Trimmer, J.S., Reimer, J., Tolias, A.S., Bear, M.F., Tye, K.M., Han, X., Ahrens, M.B., Boyden, E.S. Precision Calcium Imaging of Dense Neural Populations via a Cell-Body-Targeted Calcium Indicator. (2020) Neurona. DOI: 10.1016/j.neuron.2020.05.029

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Tomova, L., Tye, K., Saxe, R. The Neuroscience of Unmet Social Needs. (2019) Social Neuroscience. DOI: 10.1080/17470919.2019.1694580

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Siciliano, C.A., Noamany, H., Chang, C.J., Brown, A.R., Chen, X., Leible, D., Lee, J.J., Wang, J., Vernon, A.N., Vander Weele, C.M., Kimchi, E.Y., Heiman, M., Tye, K.M. A cortical-brainstem circuit predicts and governs compulsive alcohol drinking. (2019) Ciencia. 366(6468):1008-1012. DOI: 10.1126/science.aay1186

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Padilla-Coreano, N., Canetta, S., Mikofsky, R.M., Alway, E., Passecker, J., Myroshnychenko, M.V., Garcia-Garcia, A.L., Warren, R., Teboul, E., Blackman, D.R., Morton, M.P., Hupalo, S., Tye, K.M., Kellendonk, C., Kupferschmidt, D.A., Gordon, J.A. Hippocampal-Prefrontal Theta Transmission Regulates Avoidance Behavior. (2019) Neurona. DOI: 10.1016/j.neuron.2019.08.006

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Mobbs, D., Adolphs, R., Fanselow, M.S., Barrett, L.F., LeDoux, J.E., Ressler, K., Tye, K.M. Viewpoints: Approaches to defining and investigating fear. (2019) Nature Neuroscience. DOI: 10.1038/s41593-019-0456-6

Matthews, G.A., Tye, K.M. Neural mechanisms of social homeostasis. (2019) Ann. N. Y. Acad. Sci. 1457(1):5-25. DOI: 10.1111/nyas.14016

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Siciliano, C.A., Tye, K.M. Leveraging calcium imaging to illuminate circuit dysfunction in addiction. (2019) Alcohol. 74:47-63. DOI: 10.1016/j.alcohol.2018.05.013

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Weele, C.M.V., Siciliano, C.A., Tye, K.M. Dopamine tunes prefrontal outputs to orchestrate aversive processing. (2018) Brain Research. DOI: 10.1016/j.brainres.2018.11.044

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Vander Weele, C.M., Siciliano, C.A., Matthews, G.A., Namburi, P., Izadmehr, E.M., Espinel, I.C., Nieh, E.H., Schut, E.H.S., Padilla-Coreano, N., Burgos-Robles, A., Chang, C.J., Kimchi, E.Y., Beyeler, A., Wichmann, R., Wildes, C.P., Tye, K.M. Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli. (2018) Naturaleza. 563(7731):397-401. DOI: 10.1038/s41586-018-0682-1

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Siciliano, C.A., Mills, F., Tye, K.M. Double threat in striatal dopamine signaling. (2018) Nature Neuroscience. 21(10):1296-1297. DOI: 10.1038/s41593-018-0243-9

Tye, K.M. Neural Circuit Motifs in Valence Processing. (2018) Neurona. 100(2):436-452. DOI: 10.1016/j.neuron.2018.10.001

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Allsop, S.A., Wichmann, R., Mills, F., Burgos-Robles, A., Chang, C.J., Felix-Ortiz, A.C., Vienne, A., Beyeler, A., Izadmehr, E.M., Glober, G., Cum, M.I., Stergiadou, J., Anandalingam, K.K., Farris, K., Namburi, P., Leppla, C.A., Weddington, J.C., Nieh, E.H., Smith, A.C., Ba, D., Brown, E.N., Tye, K.M. Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning. (2018) Móvil. 173(6):1329-1342.e18. DOI: 10.1016/j.cell.2018.04.004

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Tye, K.M., Uchida, N. Editorial overview: Neurobiology of behavior. (2018) Current Opinion in Neurobiology. 49:iv-ix. DOI: 10.1016/j.conb.2018.02.019

Chatterjee, S., Sullivan, H.A., MacLennan, B.J., Xu, R., Hou, Y., Lavin, T.K., Lea, N.E., Michalski, J.E., Babcock, K.R., Dietrich, S., Matthews, G.A., Beyeler, A., Calhoon, G.G., Glober, G., Whitesell, J.D., Yao, S., Cetin, A., Harris, J.A., Zeng, H., Tye, K.M., Reid, R.C., Wickersham, I.R. Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons. (2018) Nature Neuroscience. 21(4):638-646. DOI: 10.1038/s41593-018-0091-7

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Beyeler, A., Chang, C.J., Silvestre, M., Lévêque, C., Namburi, P., Wildes, C.P., Tye, K.M. Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala. (2018) Cell Reports. 22(4):905-918. DOI: 10.1016/j.celrep.2017.12.097

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Wang, W., Wildes, C.P., Pattarabanjird, T., Sanchez, M.I., Glober, G.F., Matthews, G.A., Tye, K.M., Ting, A.Y. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons. (2017) Nature Biotechnology. 35(9):864-871. DOI: 10.1038/nbt.3909

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Wei, D., Allsop, S., Tye, K., Piomelli, D. Endocannabinoid Signaling in the Control of Social Behavior. (2017) Trends in Neurosciences. 40(7):385-396. DOI: 10.1016/j.tins.2017.04.005

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Burgos-Robles, A., Kimchi, E.Y., Izadmehr, E.M., Porzenheim, M.J., Ramos-Guasp, W.A., Nieh, E.H., Felix-Ortiz, A.C., Namburi, P., Leppla, C.A., Presbrey, K.N., Anandalingam, K.K., Pagan-Rivera, P.A., Anahtar, M., Beyeler, A., Tye, K.M. Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment. (2017) Nature Neuroscience. 20(6):824-835. DOI: 10.1038/nn.4553

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Matthews, G.A., Tye, K.M. A New Handle for a Hot Topic: Genetic Markers for Warm-Sensing. (2016) Móvil. 167(1):43-44. DOI: 10.1016/j.cell.2016.09.016

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Nieh, E.H., Vander Weele, C.M., Matthews, G.A., Presbrey, K.N., Wichmann, R., Leppla, C.A., Izadmehr, E.M., Tye, K.M. Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation. (2016) Neurona. 90(6):1286-1298. DOI: 10.1016/j.neuron.2016.04.035

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Namburi, P., Al-Hasani, R., Calhoon, G.G., Bruchas, M.R., Tye, K.M. Architectural Representation of Valence in the Limbic System. (2016) Neuropsychopharmacology. 41(7):1697-715. DOI: 10.1038/npp.2015.358

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Felix-Ortiz, A.C., Burgos-Robles, A., Bhagat, N.D., Leppla, C.A., Tye, K.M. Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. (2016) Neuroscience. 321:197-209. DOI: 10.1016/j.neuroscience.2015.07.041

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Beyeler, A., Namburi, P., Glober, G.F., Simonnet, C., Calhoon, G.G., Conyers, G.F., Luck, R., Wildes, C.P., Tye, K.M. Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval. (2016) Neurona. 90(2):348-361. DOI: 10.1016/j.neuron.2016.03.004

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Matthews, G.A., Nieh, E.H., Vander Weele, C.M., Halbert, S.A., Pradhan, R.V., Yosafat, A.S., Glober, G.F., Izadmehr, E.M., Thomas, R.E., Lacy, G.D., Wildes, C.P., Ungless, M.A., Tye, K.M. Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation. (2016) Móvil. 164(4):617-31. DOI: 10.1016/j.cell.2015.12.040

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Sidor, M.M., Spencer, S.M., Dzirasa, K., Parekh, P.K., Tye, K.M., Warden, M.R., Arey, R.N., Enwright, J.F., Jacobsen, J.P., Kumar, S., Remillard, E.M., Caron, M.G., Deisseroth, K., McClung, C.A. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. (2015) Psiquiatría Molecular. 20(11):1406-19. DOI: 10.1038/mp.2014.167

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Calhoon, G.G., Tye, K.M. Resolving the neural circuits of anxiety. (2015) Nature Neuroscience. 18(10):1394-404. DOI: 10.1038/nn.4101

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Adamantidis, A., Arber, S., Bains, J.S., Bamberg, E., Bonci, A., Buzsáki, G., Cardin, J.A., Costa, R.M., Dan, Y., Goda, Y., Graybiel, A.M., Häusser, M., Hegemann, P., Huguenard, J.R., Insel, T.R., Janak, P.H., Johnston, D., Josselyn, S.A., Koch, C., Kreitzer, A.C., Lüscher, C., Malenka, R.C., Miesenböck, G., Nagel, G., Roska, B., Schnitzer, M.J., Shenoy, K.V., Soltesz, I., Sternson, S.M., Tsien, R.W., Tsien, R.Y., Turrigiano, G.G., Tye, K.M., Wilson, R.I. Optogenetics: 10 years after ChR2 in neurons--views from the community. (2015) Nature Neuroscience. 18(9):1202-12. DOI: 10.1038/nn.4106

Namburi, P., Beyeler, A., Yorozu, S., Calhoon, G.G., Halbert, S.A., Wichmann, R., Holden, S.S., Mertens, K.L., Anahtar, M., Felix-Ortiz, A.C., Wickersham, I.R., Gray, J.M., Tye, K.M. A circuit mechanism for differentiating positive and negative associations. (2015) Naturaleza. 520(7549):675-8. DOI: 10.1038/nature14366

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Nieh, E.H., Matthews, G.A., Allsop, S.A., Presbrey, K.N., Leppla, C.A., Wichmann, R., Neve, R., Wildes, C.P., Tye, K.M. Decoding neural circuits that control compulsive sucrose seeking. (2015) Móvil. 160(3):528-41. DOI: 10.1016/j.cell.2015.01.003

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Janak, P.H., Tye, K.M. From circuits to behaviour in the amygdala. (2015) Naturaleza. 517(7534):284-92. DOI: 10.1038/nature14188

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Sidor, M.M., Davidson, T.J., Tye, K.M., Warden, M.R., Diesseroth, K., McClung, C.A. In vivo optogenetic stimulation of the rodent central nervous system. (2015) JoVE.(95):51483 DOI: 10.3791/51483

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Tye, K.M. Neural circuit reprogramming: a new paradigm for treating neuropsychiatric disease? (2014) Neurona. 83(6):1259-61. DOI: 10.1016/j.neuron.2014.08.022

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Chuong, A.S., Miri, M.L., Busskamp, V., Matthews, G.A., Acker, L.C., Sørensen, A.T., Young, A., Klapoetke, N.C., Henninger, M.A., Kodandaramaiah, S.B., Ogawa, M., Ramanlal, S.B., Bandler, R.C., Allen, B.D., Forest, C.R., Chow, B.Y., Han, X., Lin, Y., Tye, K.M., Roska, B., Cardin, J.A., Boyden, E.S. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. (2014) Nature Neuroscience. 17(8):1123-9. DOI: 10.1038/nn.3752

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Allsop, S.A., Vander Weele, C.M., Wichmann, R., Tye, K.M. Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. (2014) Front Behav Neurosci. 8:241. DOI: 10.3389/fnbeh.2014.00241

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Gunaydin, L.A., Grosenick, L., Finkelstein, J.C., Kauvar, I.V., Fenno, L.E., Adhikari, A., Lammel, S., Mirzabekov, J.J., Airan, R.D., Zalocusky, K.A., Tye, K.M., Anikeeva, P., Malenka, R.C., Deisseroth, K. Natural neural projection dynamics underlying social behavior. (2014) Móvil. 157(7):1535-51. DOI: 10.1016/j.cell.2014.05.017

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Beyeler, A., Eckhardt, C.A., Tye, K.M. Deciphering memory function with optogenetics. (2014) Prog Mol Biol Transl Sci. 122:341-90. DOI: 10.1016/B978-0-12-420170-5.00012-X

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Haws, M.E., Jaramillo, T.C., Espinosa, F., Widman, A.J., Stuber, G.D., Sparta, D.R., Tye, K.M., Russo, S.J., Parada, L.F., Stavarache, M., Kaplitt, M., Bonci, A., Powell, C.M. PTEN knockdown alters dendritic spine/protrusion morphology, not density. (2014) Journal of Comparative Neurology. 522(5):1171-90. DOI: 10.1002/cne.23488

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Lammel, S., Tye, K.M., Warden, M.R. Progress in understanding mood disorders: optogenetic dissection of neural circuits. (2014) Genes, Brain, and Behavior. 13(1):38-51. DOI: 10.1111/gbb.12049

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Felix-Ortiz, A.C., Tye, K.M. Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. (2014) Diario de Neurociencia. 34(2):586-95. DOI: 10.1523/JNEUROSCI.4257-13.2014

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Felix-Ortiz, A.C., Beyeler, A., Seo, C., Leppla, C.A., Wildes, C.P., Tye, K.M. BLA to vHPC inputs modulate anxiety-related behaviors. (2013) Neurona. 79(4):658-64. DOI: 10.1016/j.neuron.2013.06.016

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Nieh, E.H., Kim, S.Y., Namburi, P., Tye, K.M. Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors. (2013) Brain Research. 1511:73-92. DOI: 10.1016/j.brainres.2012.11.001

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The neural circuits underlying emotional valence and motivated behaviors are several synapses away from both defined sensory inputs and quantifiable motor outputs. Electrophysiology has provided us with a suitable means for observing neural activity during behavior, but methods for controlling activity for the purpose of studying motivated behaviors have been inadequate: electrical stimulation lacks cellular specificity and pharmacological manipulation lacks temporal resolution. The recent emergence of optogenetic tools provides a new means for establishing causal relationships between neural activity and behavior. Optogenetics, the use of genetically-encodable light-activated proteins, permits the modulation of specific neural circuit elements with millisecond precision. The ability to control individual cell types, and even projections between distal regions, allows us to investigate functional connectivity in a causal manner. The greatest consequence of controlling neural activity with finer precision has been the characterization of individual neural circuits within anatomical brain regions as defined functional units. Within the mesolimbic dopamine system, optogenetics has helped separate subsets of dopamine neurons with distinct functions for reward, aversion and salience processing, elucidated GABA neuronal effects on behavior, and characterized connectivity with forebrain and cortical structures. Within the striatum, optogenetics has confirmed the opposing relationship between direct and indirect pathway medium spiny neurons (MSNs), in addition to characterizing the inhibition of MSNs by cholinergic interneurons. Within the hypothalamus, optogenetics has helped overcome the heterogeneity in neuronal cell-type and revealed distinct circuits mediating aggression and feeding. Within the amygdala, optogenetics has allowed the study of intra-amygdala microcircuitry as well as interconnections with distal regions involved in fear and anxiety. In this review, we will present the body of optogenetic studies that has significantly enhanced our understanding of emotional valence and motivated behaviors. This article is part of a Special Issue entitled Optogenetics (7th BRES).

Kim, S.Y., Adhikari, A., Lee, S.Y., Marshel, J.H., Kim, C.K., Mallory, C.S., Lo, M., Pak, S., Mattis, J., Lim, B.K., Malenka, R.C., Warden, M.R., Neve, R., Tye, K.M., Deisseroth, K. Diverging neural pathways assemble a behavioural state from separable features in anxiety. (2013) Naturaleza. 496(7444):219-23. DOI: 10.1038/nature12018

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Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections-to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area-each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.

Tye, K.M., Mirzabekov, J.J., Warden, M.R., Ferenczi, E.A., Tsai, H.C., Finkelstein, J., Kim, S.Y., Adhikari, A., Thompson, K.R., Andalman, A.S., Gunaydin, L.A., Witten, I.B., Deisseroth, K. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. (2013) Naturaleza. 493(7433):537-541. DOI: 10.1038/nature11740

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Warden, M.R., Selimbeyoglu, A., Mirzabekov, J.J., Lo, M., Thompson, K.R., Kim, S.Y., Adhikari, A., Tye, K.M., Frank, L.M., Deisseroth, K. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. (2012) Naturaleza. 492(7429):428-32. DOI: 10.1038/nature11617

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The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.

Tye, K.M. Glutamate inputs to the nucleus accumbens: does source matter? (2012) Neurona. 76(4):671-3. DOI: 10.1016/j.neuron.2012.11.008

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Lammel, S., Lim, B.K., Ran, C., Huang, K.W., Betley, M.J., Tye, K.M., Deisseroth, K., Malenka, R.C. Input-specific control of reward and aversion in the ventral tegmental area. (2012) Naturaleza. 491(7423):212-7. DOI: 10.1038/nature11527

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Tye, K.M., Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. (2012) Nature Reviews Neuroscience. 13(4):251-66. DOI: 10.1038/nrn3171

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Tan, K.R., Yvon, C., Turiault, M., Mirzabekov, J.J., Doehner, J., Labouèbe, G., Deisseroth, K., Tye, K.M., Lüscher, C. GABA neurons of the VTA drive conditioned place aversion. (2012) Neurona. 73(6):1173-83. DOI: 10.1016/j.neuron.2012.02.015

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Mattis, J., Tye, K.M., Ferenczi, E.A., Ramakrishnan, C., O'Shea, D.J., Prakash, R., Gunaydin, L.A., Hyun, M., Fenno, L.E., Gradinaru, V., Yizhar, O., Deisseroth, K. Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. (2011) Nature Methods. 9(2):159-72. DOI: 10.1038/nmeth.1808

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Witten, I.B., Steinberg, E.E., Lee, S.Y., Davidson, T.J., Zalocusky, K.A., Brodsky, M., Yizhar, O., Cho, S.L., Gong, S., Ramakrishnan, C., Stuber, G.D., Tye, K.M., Janak, P.H., Deisseroth, K. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. (2011) Neurona. 72(5):721-33. DOI: 10.1016/j.neuron.2011.10.028

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Stuber, G.D., Sparta, D.R., Stamatakis, A.M., van Leeuwen, W.A., Hardjoprajitno, J.E., Cho, S., Tye, K.M., Kempadoo, K.A., Zhang, F., Deisseroth, K., Bonci, A. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. (2011) Naturaleza. 475(7356):377-80. DOI: 10.1038/nature10194

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Berndt, A., Schoenenberger, P., Mattis, J., Tye, K.M., Deisseroth, K., Hegemann, P., Oertner, T.G. High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels. (2011) Actas de la Academia Nacional de Ciencias de los Estados Unidos de América. 108(18):7595-600. DOI: 10.1073/pnas.1017210108

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Tye, K.M., Prakash, R., Kim, S.Y., Fenno, L.E., Grosenick, L., Zarabi, H., Thompson, K.R., Gradinaru, V., Ramakrishnan, C., Deisseroth, K. Amygdala circuitry mediating reversible and bidirectional control of anxiety. (2011) Naturaleza. 471(7338):358-62. DOI: 10.1038/nature09820

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Tye, K.M., Tye, L.D., Cone, J.J., Hekkelman, E.F., Janak, P.H., Bonci, A. Methylphenidate facilitates learning-induced amygdala plasticity. (2010) Nature Neuroscience. 13(4):475-81. DOI: 10.1038/nn.2506

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Hopf, F.W., Bowers, M.S., Chang, S.J., Chen, B.T., Martin, M., Seif, T., Cho, S.L., Tye, K., Bonci, A. Reduced nucleus accumbens SK channel activity enhances alcohol seeking during abstinence. (2010) Neurona. 65(5):682-94. DOI: 10.1016/j.neuron.2010.02.015

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Stuber, G.D., Hopf, F.W., Tye, K.M., Chen, B.T., Bonci, A. Neuroplastic alterations in the limbic system following cocaine or alcohol exposure. (2010) Current Topics in Behavioral Neurosciences. 3:3-27. DOI: 10.1007/7854_2009_23

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Tye, K.M., Cone, J.J., Schairer, W.W., Janak, P.H. Amygdala neural encoding of the absence of reward during extinction. (2010) Diario de Neurociencia. 30(1):116-25. DOI: 10.1523/JNEUROSCI.4240-09.2010

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Tye, K.M., Stuber, G.D., de Ridder, B., Bonci, A., Janak, P.H. Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning. (2008) Naturaleza. 453(7199):1253-7. DOI: 10.1038/nature06963

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Tye, K.M., Janak, P.H. Amygdala neurons differentially encode motivation and reinforcement. (2007) Diario de Neurociencia. 27(15):3937-45. DOI: 10.1523/JNEUROSCI.5281-06.2007

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Kay Tye, doctora

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