Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions.

SUMMARY 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.

SummaryThe 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.PaperClip

Despite abundant evidence that dopamine (DA) modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioral functions 1,2 , the precise circuit computations remain elusive. One potentially unifying model by which DA can underlie a diversity of functions is to modulate the signal-to-noise ratio (SNR) in subpopulations of mPFC neurons [3][4][5][6] , where neural activity conveying sensory information (signal) is amplified relative to spontaneous firing (noise). Here, we demonstrate that DA increases the SNR of responses to aversive stimuli in mPFC neurons projecting to the dorsal periaqueductal gray (dPAG). Using electrochemical approaches, we reveal the precise time course of pinch-evoked DA release in the mPFC, and show that mPFC DA biases behavioral responses to aversive stimuli. Activation of mPFC-dPAG neurons is sufficient to drive place avoidance and defensive behaviors. mPFC-dPAG neurons displayed robust shock-induced excitations, as visualized by single-cell, projection-defined microendoscopic calcium imaging. Finally, photostimulation of DA terminals in the mPFC revealed an increase in SNR in mPFC-dPAG responses to aversive stimuli. Together, these data highlight how mPFC DA can route sensory information in a valence-specific manner to different downstream circuits.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#termsReprints and permissions information is available at www.nature.com/reprints.

Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems.

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.

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.

While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psychostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxycodone, in drug naïve rats using fast-scan cyclic voltammetry and rapid (1 min) microdialysis coupled with mass spectrometry. In addition to measuring rapid dopamine transmission, microdialysis HPLC-MS measures changes in GABA, glutamate, monoamines, monoamine metabolites, and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug-evoked dopamine transmission differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid-induced neurotransmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior.