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      Divergent projections of the paraventricular nucleus of the thalamus mediate the selection of passive and active defensive behaviors

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          Abstract

          The appropriate selection of passive and active defensive behaviors in threatening situations is essential for survival. Previous studies have shown that passive defensive responses depend on activity of the central nucleus of the amygdala (CeA), whereas active ones primarily rely on the nucleus accumbens (NAc). However, the mechanisms underlying flexible switching between these two types of responses remain unknown. Here, we show in mice that the paraventricular thalamus (PVT) mediates the selection of defensive behaviors through its interaction with the CeA and the NAc. We show that the PVT–CeA pathway drives conditioned freezing responses, whereas the PVT–NAc pathway is inhibited during freezing and instead signals active avoidance events. Optogenetic manipulations revealed that activity in the PVT–CeA or PVT–NAc pathway biases behavior toward the selection of passive or active defensive responses, respectively. These findings provide evidence that the PVT mediates flexible switching between opposing defensive behaviors.

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          Most cited references56

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          Emotion circuits in the brain.

          The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pinpointed the amygdala as an important component of the system involved in the acquisition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emotion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior.
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            Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

            Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors.
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              A Circuit Mechanism for Differentiating Positive and Negative Associations

              The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive 1,2 and negative 3–7 . Different populations of BLA neurons may encode fearful or rewarding associations 8–10 , but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained an enigma. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) underwent opposing synaptic changes following fear or reward conditioning. We found that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impaired fear conditioning and enhanced reward conditioning. We then characterized these functionally-distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. We provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat Neurosci
                Nature neuroscience
                1097-6256
                1546-1726
                17 July 2021
                19 August 2021
                October 2021
                19 February 2022
                : 24
                : 10
                : 1429-1440
                Affiliations
                [1 ]Unit on the Neurobiology of Affective Memory, National Institute of Mental Health, Bethesda, MD, USA.
                [2 ]Central Nervous System Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach Riß, Germany
                [3 ]Rodent Behavioral Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
                [4 ]Section on Behavioral Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
                Author notes

                AUTHOR CONTRIBUTIONS

                J.M. performed all experiments. M.K. assisted with histological procedures and analyzed the monosynaptic rabies tracing data. B.S.B. assisted with the monosynaptic rabies tracing experiments. J.d.H. developed custom tools for analyzing behavior and calcium signals. J.M. and J.d.H analyzed the data. Y.C. contributed to funding acquisition and writing. J.M. and M.A.P. designed the study, interpreted results, and wrote the paper.

                [# ]Correspondence: Mario A. Penzo, Ph.D. Unit on the Neurobiology of Affective Memory, National Institute of Mental Health, Bethesda, MD 20850. mario.penzo@ 123456nih.gov
                Article
                NIHMS1725115
                10.1038/s41593-021-00912-7
                8484052
                34413514
                1d01a60a-c6a7-4337-948a-44d6e52321f4

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