Divergent Routing of Positive and Negative Information from the Amygdala during Memory Retrieval

Although the basolateral amygdala (BLA) is known to play a critical role in the formation of memories of both positive and negative valence, the coding and routing of valence-related information is poorly understood. Here, we recorded BLA neurons during the retrieval of associative memories and used optogenetic-mediated phototagging to identify populations of neurons that synapse in the nucleus accumbens (NAc), the central amygdala (CeA), or ventral hippocampus (vHPC). We found that despite heterogeneous neural responses within each population, the proportions of BLA-NAc neurons excited by reward predictive cues and of BLA-CeA neurons excited by aversion predictive cues were higher than within the entire BLA. Although the BLA-vHPC projection is known to drive behaviors of innate negative valence, these neurons did not preferentially code for learned negative valence. Together, these findings suggest that valence encoding in the BLA is at least partially mediated via divergent activity of anatomically defined neural populations.National Institute of Mental Health (U.S.) (Grant R01-MH102441-01)National Institutes of Health (U.S.) (Grant DP2-DK-102256-01

A light- and calcium-gated transcription factor for imaging and manipulating activated neurons

Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high-to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- A nd motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium.Massachusetts Institute of TechnologyStanford UniversityJPB FoundationPicower Institute for Learning and Memory (Engineering Award)National Institute of Mental Health (U.S.) (R01-MH102441-01)National Institutes of Health (U.S.) (Director's New Innovator Award DP2-DK-102256-01

Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state.McKnight Foundation (New York Stem Cell Foundation-Robertson Investigator and McKnight Scholar)JPB FoundationWhitehall FoundationKlingenstein FoundationBrain & Behavior Research Foundation (NARSAD Young Investigator Award)Alfred P. Sloan FoundationWhitehead Institute for Biomedical Research (Whitehead Career Development Chair)National Institutes of Health (U.S.) (R01-MH102441-01 (NIMH))National Institutes of Health (U.S.) (NIH grant U54-CA112967)National Institute on Aging (RF1-AG047661-01 (NIA))National Institutes of Health (U.S.) (NIH Director’s New Investigator Award DP2- DK-102256-01 (NIDDK))Medical Research Council (Great Britain) (MC-A654-5QB70)National Institute of General Medical Sciences (U.S.) (NIGMS T32GM007484