Neurotensin orchestrates valence assignment in the amygdala
Nature. 2022-07-20; :
DOI: 10.1038/s41586-022-04964-y
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Li H(#)(1), Namburi P(#)(2), Olson JM(#)(2)(3), Borio M(1)(2), Lemieux ME(1)(2), Beyeler A(2)(4), Calhoon GG(2)(5), Hitora-Imamura N(2)(6)(7), Coley AA(1), Libster A(1)(2), Bal A(1)(8), Jin X(9)(10), Wang H(11), Jia C(1)(12), Choudhury
SR(10), Shi X(10)(13), Felix-Ortiz AC(2), de la Fuente V(2)(14)(15), Barth VP(2)(16), King HO(2)(17), Izadmehr EM(2), Revanna JS(1)(18), Batra K(1)(19), Fischer KB(1), Keyes LR(1), Padilla-Coreano N(1), Siciliano CA(2)(20), McCullough
KM(21)(22), Wichmann R(1)(2), Ressler KJ(21)(22), Fiete IR(13), Zhang F(10)(13)(23), Li Y(11), Tye KM(24)(25)(26).
Author information:
(1)Salk Institute for Biological Studies, La Jolla, CA, USA.
(2)The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
(3)Neuroscience Program, Department of Psychology, Volen National Center for Complex Systems, Brandeis University, Waltham, MA, USA.
(4)University of Bordeaux, Neurocentre Magendie, INSERM 1215, Bordeaux, France.
(5)Neuroscience Program, Bates College, Lewiston, ME, USA.
(6)Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
(7)Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
(8)Behavioral Neuroscience, Department of Psychology, Michigan State University, East Lansing, MI, USA.
(9)Society of Fellows, Harvard University, MA, USA.
(10)Broad Institute of MIT and Harvard, Cambridge, MA, USA.
(11)State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Peking-Tsinghua Center for Life Science, IDG/McGovern Institute for Brain Research at PKU, Beijing, China.
(12)Neuroscience Graduate Program, University of California San Diego, La Jolla, CA, USA.
(13)McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
(14)Instituto de Fisiología, Biología Molecular y Neurociencias
(IFIBYNE-UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
(15)Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
(16)Department of Electrical and Computer Engineering, Technical University of Munich, Munich, Germany.
(17)Whitehead Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
(18)Biological Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
(19)Department of Electrical and Computer Engineering, University of California San Diego, La Jolla, CA, USA.
(20)Vanderbilt Center for Addiction Research, Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
(21)Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA.
(22)Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
(23)Stanley Center for Psychiatric Research, Cambridge, MA, USA.
(24)Salk Institute for Biological Studies, La Jolla, CA, USA. .
(25)The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. .
(26)Systems Neuroscience Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA. . (#)Contributed equally
The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning1-7. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity8-11 with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative
learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT
projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.