Optogenetic insights on the relationship between anxiety-related behaviors and social deficits

Many psychiatric illnesses are characterized by deficits in the social domain. For example, there is a high rate of co-morbidity between autism spectrum disorders and anxiety disorders. However, the common neural circuit mechanisms by which social deficits and other psychiatric disease states, such as anxiety, are co-expressed remains unclear. Here, we review optogenetic investigations of neural circuits in animal models of anxiety-related behaviors and social behaviors and discuss the important role of the amygdala in mediating aspects of these behaviors. In particular, we focus on recent evidence that projections from the basolateral amygdala (BLA) to the ventral hippocampus (vHPC) modulate anxiety-related behaviors and also alter social interaction. Understanding how this circuit influences both social behavior and anxiety may provide a mechanistic explanation for the pathogenesis of social anxiety disorder, as well as the prevalence of patients co-diagnosed with autism spectrum disorders and anxiety disorders. Furthermore, elucidating how circuits that modulate social behavior also mediate other complex emotional states will lead to a better understanding of the underlying mechanisms by which social deficits are expressed in psychiatric disease

Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation

Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience.National Institute of Mental Health (U.S.) (Grant R01-MH102441-01

Functionally distinct dopamine signals in nucleus accumbens core and shell in the freely moving rat

Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine.Lundbeck FoundationUniversity of Copenhagen (2016 Excellence Programme for Interdisciplinary Research (DSIN))National Institute on Drug Abuse (P01 DA031656

Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment

Though growth hormone (GH) is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience

Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli

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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

A cortical-brainstem circuit predicts and governs compulsive alcohol drinking

© 2019 American Association for the Advancement of Science. All rights reserved. What individual differences in neural activity predict the future escalation of alcohol drinking from casual to compulsive? The neurobiological mechanisms that gate the transition from moderate to compulsive drinking remain poorly understood. We longitudinally tracked the development of compulsive drinking across a binge-drinking experience in male mice. Binge drinking unmasked individual differences, revealing latent traits in alcohol consumption and compulsive drinking despite equal prior exposure to alcohol. Distinct neural activity signatures of cortical neurons projecting to the brainstem before binge drinking predicted the ultimate emergence of compulsivity. Mimicry of activity patterns that predicted drinking phenotypes was sufficient to bidirectionally modulate drinking. Our results provide a mechanistic explanation for individual variance in vulnerability to compulsive alcohol drinking