The two primary classes of emotional or motivational valence are seeking pleasure and avoiding pain. The ability to distinguish """"""""good"""""""" and """"""""bad"""""""" environmental cues is critical for survival, and perturbations in this ability can result in aberrant behaviors relevant to psychiatric disease. While the amygdala is known to be a region critical for processing motivational valence, a fundamental question in neuroscience is: How can opposing behavioral outputs be mediated by a similar neural mechanism? One likely possibility is that the processing of positive or negative motivation valence occurs with divergence into largely distinct circuits. Electrophysiological recording studies from the last decade provide compelling evidence that the amygdala could act as this initial divergence point. However, this hypothesis has not been directly tested. Here, we propose to directly test the hypothesis that positive and negative valence processing diverges at the basolateral amygdala, which projects to both the fear and reward circuits. We will test whether downstream projection targets define these different populations in both innate and learned associations, explore whether neural activity and synaptic plasticity are occurring preferentially in projection-defined neural populations, and identify novel targets in the fear and reward circuits. Our compelling preliminary data sets demonstrate the feasibility of applying multiple cutting-edge techniques to testing the specific hypotheses regarding causal relationships between specific neural projections and behavior, characterizing the cellular and synaptic mechanisms, and expanding our current knowledge of motivational circuitry. Specifically, this investigator has extensive expertise in projection-specific optogenetic manipulations, electrophysiology, immunohistochemistry and pharmacological manipulations to study the neural basis of motivated behaviors. A successful outcome of the proposed research will establish a major conceptual advance in understanding the neural basis of positive and negative valence.

Public Health Relevance

This New Investigator proposal employs an interdisciplinary arsenal of cutting-edge techniques to tackle a fundamental neuroscience question: How do we distinguish positive and negative environmental cues? The innovative use of optogenetics, imaging, pharmacological and electrophysiological approaches in this proposal will provide a comprehensive answer to this elusive question. Insights about the processing of positive and negative motivational valence have broad implications for basic science to psychiatric disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Rossi, Andrew
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Massachusetts Institute of Technology
Internal Medicine/Medicine
Schools of Arts and Sciences
United States
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Nieh, Edward H; Vander Weele, Caitlin M; Matthews, Gillian A et al. (2016) Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation. Neuron 90:1286-98
Matthews, Gillian A; Nieh, Edward H; Vander Weele, Caitlin M et al. (2016) Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation. Cell 164:617-31
Felix-Ortiz, A C; Burgos-Robles, A; Bhagat, N D et al. (2016) Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex. Neuroscience 321:197-209
Beyeler, Anna; Namburi, Praneeth; Glober, Gordon F et al. (2016) Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval. Neuron 90:348-61
Namburi, Praneeth; Beyeler, Anna; Yorozu, Suzuko et al. (2015) A circuit mechanism for differentiating positive and negative associations. Nature 520:675-8
Janak, Patricia H; Tye, Kay M (2015) From circuits to behaviour in the amygdala. Nature 517:284-92
Nieh, Edward H; Matthews, Gillian A; Allsop, Stephen A et al. (2015) Decoding neural circuits that control compulsive sucrose seeking. Cell 160:528-41
Calhoon, Gwendolyn G; Tye, Kay M (2015) Resolving the neural circuits of anxiety. Nat Neurosci 18:1394-404
Tye, Kay M (2014) Neural circuit reprogramming: a new paradigm for treating neuropsychiatric disease? Neuron 83:1259-61
Beyeler, Anna; Eckhardt, Christine A; Tye, Kay M (2014) Deciphering memory function with optogenetics. Prog Mol Biol Transl Sci 122:341-90

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