The activity of Ventral Tegmental Area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors, however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior, but not conditioned anticipatory behavior in response to reward-predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release, but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons, as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors.

Phasic activation of dopaminergic neurons is associated with reward-predicting cues and supports learning during behavioral adaptation. While non-contingent activation of dopaminergic neurons in the ventral tegmental are (VTA) is sufficient for passive behavioral conditioning, it remains unknown whether the phasic dopaminergic signal is truly reinforcing. In this study, we first targeted the expression of channelrhodopsin-2 (ChR2) to dopaminergic neurons of the VTA and optimized optogenetically-evoked dopamine transients. Second, we showed that phasic activation of dopaminergic neurons in freely moving mice causally enhances positive reinforcing actions in a food-seeking operant task. Interestingly, such effect was not found in the absence of food reward. We further found that phasic activation of dopaminergic neurons is sufficient to reactivate previously extinguished food-seeking behavior in the absence of external cues. This was also confirmed using a single-session reversal paradigm. Collectively, these data suggest that activation of dopaminergic neurons facilitates the development of positive reinforcement during reward-seeking and behavioral flexibility.

Dopamine (DA) controls many vital physiological functions and is critically involved in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. The major function of the plasma membrane dopamine transporter (DAT) is the rapid uptake of released DA into presynaptic nerve terminals leading to control of both the extracellular levels of DA and the intracellular stores of DA. Here, we present a newly developed strain of rats in which the gene encoding DAT knockout Rats (DAT-KO) has been disrupted by using zinc finger nuclease technology. Male and female DAT-KO rats develop normally but weigh less than heterozygote and wild-type rats and demonstrate pronounced spontaneous locomotor hyperactivity. While striatal extracellular DA lifetime and concentrations are significantly increased, the total tissue content of DA is markedly decreased demonstrating the key role of DAT in the control of DA neurotransmission. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, the partial Trace Amine-Associated Receptor 1 (TAAR1) agonist RO5203648 ((S)-4-(3,4-Dichloro-phenyl)-4,5-dihydro-oxazol-2-ylamine) and haloperidol. DAT-KO rats also demonstrate a deficit in working memory and sensorimotor gating tests, less propensity to develop obsessive behaviors and show strong dysregulation in frontostriatal BDNF function. DAT-KO rats could provide a novel translational model for human diseases involving aberrant DA function and/or mutations affecting DAT or related regulatory mechanisms. Here, we present a newly developed strain of rats in which the gene encoding the dopamine transporter (DAT) has been disrupted (Dopamine Transporter Knockout rats [DAT-KO rats]). DAT-KO rats display functional hyperdopaminergia accompanied by pronounced spontaneous locomotor hyperactivity. Hyperactivity of DAT-KO rats can be counteracted by amphetamine, methylphenidate, and a few other compounds exerting inhibitory action on dopamine-dependent hyperactivity. DAT-KO rats also demonstrate cognitive deficits in working memory and sensorimotor gating tests, less propensity to develop compulsive behaviors, and strong dysregulation in frontostriatal BDNF function. These observations highlight the key role of DAT in the control of brain dopaminergic transmission. DAT-KO rats could provide a novel translational model for human diseases involving aberrant dopamine functions.

Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and invigorate social interactions. However, the neurocircuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors and is comprised of molecularly-diverse neurons with widespread projections. Here, we identify a steroid-responsive subset of neurotensin (Nts) expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially-engaged reward circuit. Using in vivo 2-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to non-social appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach, and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically-relevant stimuli and co-opt midbrain reward circuits to promote prosocial behavior critical for species survival.

While reward-dependent facilitation of phasic dopamine signaling is well documented at both the cell bodies and terminals, little is known regarding fast dopamine transmission under aversive conditions. Exposure to aggressive confrontation is extremely aversive and stressful for many species including rats. The present study used fast-scan cyclic voltammetry and multiunit recording to determine if aggressive encounters and subsequent social defeat affect burst firing of ventral tegmental area (VTA) dopamine neurons and accumbal dopamine transients in defeated rats. Significant increases in the frequency of transient dopamine release were observed during interactions with an aggressive rat but not with a familiar cage mate. In agreement with voltammetric results, significant increases in burst frequency were detected in the VTA dopamine firing patterns during an aggressive confrontation; however, the number of spikes per burst remained unchanged. We found that neurons with lower burst rates under homecage conditions did not switch from non-bursting to bursting types, while neurons with higher burst levels showed amplified increases in bursting. This study demonstrates for the first time that aggressive confrontations in defeated rats are associated with increases in phasic dopamine transmission in the mesolimbic pathway.

Activity changes in a large subset of midbrain dopamine neurons fulfill numerous assumptions of learning theory by encoding a prediction error between actual and predicted reward. This computational interpretation of dopaminergic spike activity invites the important question of how changes in spike rate are translated into changes in dopamine delivery at target neural structures. Using electrochemical detection of rapid dopamine release in the striatum of freely moving rats, we established that a single dynamic model can capture all the measured fluctuations in dopamine delivery. This model revealed three independent short-term adaptive processes acting to control dopamine release. These short-term components generalized well across animals and stimulation patterns and were preserved under anesthesia. The model has implications for the dynamic filtering interposed between changes in spike production and forebrain dopamine release.

No abstract

Transient (200--900 ms), high concentrations (200--500 nM) of dopamine, measured using fast-scan cyclic voltammetry, occurred in the nucleus accumbens core of male rats at the presentation of a receptive female. Additional dopamine signals were observed during subsequent approach behavior. Background-subtracted cyclic voltammograms of the naturally-evoked signals matched those of electrically-evoked dopamine measured at the same recording sites. Administration of nomifensine amplified natural and evoked dopamine release, and increased the frequency of detectable signals. While gradual changes in dopamine concentration during sexual behavior have been well established, these findings dramatically improve the time resolution. The observed dopamine transients, probably resulting from neuronal burst firing, represent the first direct correlation of dopamine with sexual behavior on a sub-second time scale.