Activity In Ventral Tegmental Area Research Articles

Hippocampus and Prefrontal Cortex Predict Distinct Timescales of Activation in the Human Ventral Tegmental Area

The mesolimbic dopamine system contributes to a remarkable variety of behaviors at multiple timescales. Midbrain neurons have fast and slow signaling components, and specific afferent systems, such as the hippocampus (HPC) and prefrontal cortex (PFC), have been demonstrated to drive these components in anesthetized animals. Whether these interactions exist during behavior, however, is unknown. To address this question, we developed a novel analysis of human functional magnetic resonance imaging data that fits models of network excitation and inhibition on ventral tegmental area (VTA) activation. We show that specific afferent systems predict distinct temporal components of midbrain VTA signal. We found that PFC, but not HPC, positively predicted transient, event-evoked VTA activation. In contrast, HPC, but not PFC, positively predicted slow shifts in VTA baseline variability. Thus, unique functional contributions of afferent systems to VTA physiology are detectable at the network level in behaving humans. The findings support models of dopamine function in which dissociable neural circuits support different aspects of motivated behavior via active regulation of tonic and phasic signals.

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons.

Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.

Corticosterone enhances N-methyl-D-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway.

Elevations in circulating corticosteroids during periods of stress may influence activity of the mesolimbic dopamine reward pathway by increasing glutamatergic N-methyl-D-aspartate (NMDA) receptor expression and/or function in a glucocorticoid receptor-dependent manner. The current study employed organotypic co-cultures of the ventral tegmental area (VTA) and nucleus accumbens (NAcc) to examine the effects of corticosterone exposure on NMDA receptor-mediated neuronal viability. Co-cultures were pre-exposed to vehicle or corticosterone (CORT; 1 μM) for 5 days prior to a 24 h co-exposure to NMDA (200 μM). Co-cultures pre-exposed to a non-toxic concentration of corticosterone and subsequently NMDA showed significant neurotoxicity in the VTA only. This was evidenced by increases in propidium iodide uptake as well as decreases in immunoreactivity of the neuronal nuclear protein (NeuN). Co-exposure to the NMDA receptor antagonist 2-amino-7-phosphonovaleric acid (APV; 50 μM) or the glucocorticoid receptor (GR) antagonist mifepristone (10 μM) attenuated neurotoxicity. In contrast, the combination of corticosterone and NMDA did not produce any significant effects on either measure within the NAcc. Cultures of the VTA and NAcc maintained without synaptic contact showed no response to CORT or NMDA. These results demonstrate the ability to functionally reconstitute key regions of the mesolimbic reward pathway ex vivo and to reveal a GR-dependent enhancement of NMDA receptor-dependent signaling in the VTA.

Prenatal ethanol exposure alters ethanol-induced Fos immunoreactivity and dopaminergic activity in the mesocorticolimbic pathway of the adolescent brain

Prenatal ethanol exposure (PEE) promotes alcohol intake during adolescence, as shown in clinical and pre-clinical animal models. The mechanisms underlying this effect of prenatal ethanol exposure on postnatal ethanol intake remain, however, mostly unknown. Few studies assessed the effects of moderate doses of prenatal ethanol on spontaneous and ethanol-induced brain activity on adolescence. This study measured, in adolescent (female) Wistar rats prenatally exposed to ethanol (0.0 or 2.0g/kg/day, gestational days 17–20) or non-manipulated (NM group) throughout pregnancy, baseline and ethanol-induced cathecolaminergic activity (i.e., colocalization of c-Fos and tyrosine hydroxylase) in ventral tegmental area (VTA), and baseline and ethanol-induced Fos immunoreactivity (ir) in nucleus accumbens shell and core (AcbSh and AcbC, respectively) and prelimbic (PrL) and infralimbic (IL) prefrontal cortex. The rats were challenged with ethanol (dose: 0.0, 1.25, 2.5 or 3.25g/kg, i.p.) at postnatal day 37. Rats exposed to vehicle prenatally (VE group) exhibited reduced baseline dopaminergic tone in VTA; an effect that was inhibited by prenatal ethanol exposure (PEE group). Dopaminergic activity in VTA after the postnatal ethanol challenge was greater in PEE than in VE or NM animals. Ethanol-induced Fos-ir at AcbSh was found after 1.25g/kg and 2.5g/kg ethanol, in VE and PEE rats, respectively. PEE did not alter ethanol-induced Fos-ir at IL but reduced ethanol-induced Fos-ir at PrL. These results suggest that prenatal ethanol exposure heightens dopaminergic activity in the VTA and alters the response of the mesocorticolimbic pathway to postnatal ethanol exposure. These effects may underlie the enhanced vulnerability to develop alcohol-use disorders of adolescents with a history of in utero ethanol exposure.

Brain activity classifies adolescents with and without a familial history of substance use disorders.

We aimed to uncover differences in brain circuits of adolescents with parental positive or negative histories of substance use disorders (SUD), when performing a task that elicits emotional conflict, testing whether the brain circuits could serve as endophenotype markers to distinguish these adolescents. We acquired functional magnetic resonance imaging data from 11 adolescents with a positive familial history of SUD (FH+ group) and seven adolescents with a negative familial history of SUD (FH− group) when performing an emotional stroop task. We extracted brain features from the conflict-related contrast images in group level analyses and granger causality indices (GCIs) that measure the causal interactions among regions. Support vector machine (SVM) was applied to classify the FH+ and FH− adolescents. Adolescents with FH+ showed greater activity and weaker connectivity related to emotional conflict, decision making and reward system including anterior cingulate cortex (ACC), prefrontal cortex (PFC), and ventral tegmental area (VTA). High classification accuracies were achieved with leave-one-out cross validation (89.75% for the maximum conflict, 96.71% when combining maximum conflict and general conflict contrast, 97.28% when combining activity of the two contrasts and GCIs). Individual contributions of the brain features to the classification were further investigated, indicating that activation in PFC, ACC, VTA and effective connectivity from PFC to ACC play the most important roles. We concluded that fundamental differences of neural substrates underlying cognitive behaviors of adolescents with parental positive or negative histories of SUD provide new insight into potential neurobiological mechanisms contributing to the elevated risk of FH+ individuals for developing SUD.

Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women

After giving birth, women typically experience decreased sexual desire and increased responsiveness to infant stimuli. These postpartum changes may be viewed as a trade-off in reproductive interests, which could be due to alterations in brain activity including areas associated with reward. The goal of this study was to describe the roles of oxytocin and parity on reward area activation in response to reproductive stimuli, specifically infant and sexual images. Because they have been shown to be associated with reward, the ventral tegmental area (VTA) and nucleus accumbens (NAc) were targeted as areas of expected alterations in activity. Oxytocin was chosen as a potential mediator of reproductive trade-offs because of its relationship to both mother–infant interactions, including breastfeeding and bonding, and sexual responses. We predicted that postpartum women would show higher reward area activation to infant stimuli and nulliparous women would show higher activation to sexual stimuli and that oxytocin would increase activation to infant stimuli in nulliparous women. To test this, we measured VTA and NAc activation using fMRI in response to infant photos, sexual photos, and neutral photos in 29 postpartum and 30 nulliparous women. Participants completed the Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales and the Brief Index of Sexual Function for Women (BISF-W), which includes a sexual desire dimension, and received either oxytocin or placebo nasal spray before viewing crying and smiling infant and sexual images in an fMRI scanner. For both groups of women, intranasal oxytocin administration increased VTA activation to both crying infant and sexual images but not to smiling infant images. We found that postpartum women showed lower SES, higher SIS, and lower sexual desire compared to nulliparous women. Across parity groups, SES scores were correlated with VTA activation and subjective arousal ratings to sexual images. In postpartum women, sexual desire was positively correlated with VTA activation to sexual images and with SES. Our findings show that postpartum decreases in sexual desire may in part be mediated by VTA activation, and oxytocin increased activation of the VTA but not NAc in response to sexual and infant stimuli. Oxytocin may contribute to the altered reproductive priorities in postpartum women by increasing VTA activation to salient infant stimuli.

Serotonin-2C receptor agonists decrease potassium-stimulated GABA release in the nucleus accumbens.

The serotonin 5-HT2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4-phenyl-2-N,N-dimethylaminotetralin (PAT) drug candidate, that demonstrates 5-HT2C receptor agonist activity together with 5-HT2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5-HT2C receptor is found throughout the mesoaccumbens pathway and that 5-HT2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons. It is unknown what effect 5-HT2C receptor modulation has on GABA release in the nucleus accumbens core (NAcc). To this end, microdialysis coupled to capillary electrophoresis with laser-induced fluorescence was used to quantify extracellular neurotransmitter concentrations in the NAcc under basal and after potassium stimulation conditions, in response to PAT analogs and other 5-HT2C receptor modulators administered by reverse dialysis to rats. 5-HT2C receptor agonists specifically attenuated stimulated GABA release in the NAcc while 5-HT2C antagonists or inverse agonists had no effect. Agents with activity at 5-HT2A receptors had no effect on GABA release. Thus, in contrast to results reported for the VTA, current results suggest 5-HT2C receptor agonists decrease stimulated GABA release in the NAcc, and provide a possible mechanism of action for 5HT2C -mediated negative modulation of ethanol self-administration.

A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons.

Electrical stimulation of the dorsal raphe (DR) and ventral tegmental area (VTA) activates the fibers of the same reward pathway but the phenotype of this pathway and the direction of the reward-relevant fibers have not been determined. Here we report rewarding effects following activation of a DR-originating pathway consisting of vesicular glutamate transporter 3 (VGluT3) containing neurons that form asymmetric synapses onto VTA dopamine neurons that project to nucleus accumbens. Optogenetic VTA activation of this projection elicits AMPA-mediated synaptic excitatory currents in VTA mesoaccumbens dopaminergic neurons and causes dopamine release innucleus accumbens. Activation also reinforces instrumental behavior and establishes conditioned place preferences. These findings indicate that the DR-VGluT3 pathway to VTA utilizes glutamate as a neurotransmitter and is a substrate linking the DR—one of the most sensitive reward sites in the brain—to VTA dopaminergic neurons.

Voltage-sensitive dye imaging of primary motor cortex activity produced by ventral tegmental area stimulation.

The primary motor cortex (M1) receives dopaminergic projections from the ventral tegmental area (VTA) through the mesocortical dopamine pathway. However, few studies have focused on changes in M1 neuronal activity caused by VTA activation. To address this issue, we used voltage-sensitive dye imaging (VSD) to reveal the spatiotemporal dynamics of M1 activity induced by single-pulse stimulation of VTA in anesthetized rats. VSD imaging showed that brief electrical stimulation of unilateral VTA elicited a short-latency excitatory-inhibitory sequence of neuronal activity not only in the ipsilateral but also in the contralateral M1. The contralateral M1 response was not affected by pharmacological blockade of ipsilateral M1 activity, but it was completely abolished by corpus callosum transection. Although the VTA-evoked neuronal activity extended throughout the entire M1, we found the most prominent activity in the forelimb area of M1. The 6-OHDA-lesioned VTA failed to evoke M1 activity. Furthermore, both excitatory and inhibitory intact VTA-induced activity was entirely extinguished by blocking glutamate receptors in the target M1. When intracortical microstimulation of M1 was paired with VTA stimulation, the evoked forelimb muscle activity was facilitated or inhibited, depending on the interval between the two stimuli. These findings suggest that VTA neurons directly modulate the excitability of M1 neurons via fast glutamate signaling and, consequently, may control the last cortical stage of motor command processing.

Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

Ventral tegmental area activation promotes firing precision and strength through circuit inhibition in the primary auditory cortex.

The activation of the ventral tegmental area (VTA) can rebuild the tonotopic representation in the primary auditory cortex (A1), but the cellular mechanisms remain largely unknown. Here, we investigated the firing patterns and membrane potential dynamics of neurons in A1 under the influence of VTA activation using in vivo intracellular recording. We found that VTA activation can significantly reduce the variability of sound evoked responses and promote the firing precision and strength of A1 neurons. Furthermore, the compressed response window was caused by an early hyperpolarization as a result of enhanced circuit inhibition. Our study suggested a possible mechanism of how the reward system affects information processing in sensory cortex: VTA activation strengthens cortical inhibition, which shortens the response window of post-synaptic cortical neurons and further promotes the precision and strength of neuronal activity.

Optogenetic Activation of the Excitatory Neurons Expressing CaMKIIαin the Ventral Tegmental Area Upregulates the Locomotor Activity of Free Behaving Rats

The ventral tegmental area (VTA) plays an important role in motivation and motor activity of mammals. Previous studies have reported that electrical stimulations of the VTA's neuronal projections were able to upregulate the locomotor activity of behaving rats. However, which types of neurons in the VTA that take part in the activation remain elusive. In this paper we employed optogenetic technique to selectively activate the excitatory neurons expressing CaMKIIα in the VTA region and induced a higher locomotor activity for free behaving rats. Further behavioral studies indicated that reward learning mediated in the enhancement of the rat locomotor activity. Finally the immunohistochemistry studies explored that the excitatory neurons under the optogenetic activation in VTA were partly dopaminergic that may participate as a vital role in the optogenetic activation of the locomotor activity. In total, our study provided an optogenetic approach to selectively upregulate the locomotor activity of free behaving rats, thus facilitating both neuroscience researches and neural engineering such as animal robotics in the future.

English

English

The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways.

The ventral tegmental area (VTA) has been implicated in a number of psychiatric disorders, including schizophrenia, depression, and bipolar disorder. One major regulator of the mesolimbic dopaminergic system is the medial prefrontal cortex (mPFC), which makes direct and indirect connections to the hippocampus and amygdala, as well as directly to the VTA. The mPFC is comprised of two subregions: the infralimbic and prelimbic cortices (ilPFC and plPFC). However, the specific roles of these subregions in regulating VTA dopamine activity have remained unclear. In this study, we aim to clarify this role and to examine the divergent neuranatomical circuits by which the mPFC regulates VTA activity. Using in vivo extracellular recordings in rats, we tested the effects of pharmacological activation (with NMDA) and inactivation (with TTX) of the ilPFC and plPFC on dopamine neuron activity, and tested the roles of the ventral subiculum (vSub) and basolateral amygdala in this process. We found that the ilPFC exerts a bidirectional control of VTA dopamine neurons, which are differentially modulated through the vSub and the basolateral amygdala. Specifically, activation or inactivation of the ilPFC attenuated or activated dopamine neuron population activity, respectively. Furthermore, dopamine activation depended on the ventral hippocampus and inactivation on the amygdala. In contrast, only inactivation of the plPFC altered dopamine neuron activity. These data indicate that the mPFC has the ability to uniquely fine-tune dopaminergic activity in the VTA. Furthermore, the data presented here suggest that the ilPFC may have a role in the pathophysiology of psychiatric disorders.

Oxytocin activation of neurons in ventral tegmental area and interfascicular nucleus of mouse midbrain

Oxytocin (OT) was reported to affect cognitive and emotional behavior by action in ventral tegmental area (VTA) and other brain areas. However, it is still unclear how OT activates VTA and related midline nucleus. Here, using patch-clamp recording, we studied the effects of OT on neuron activity in VTA and interfascicular nucleus (IF). OT dose-dependently and selectively excited small neurons located in medial VTA and the majority of IF neurons but not large neurons in lateral VTA. We found the hyperpolarization-activated current (Ih) and the membrane capacitance of OT-sensitive neuron were significantly smaller than those of OT-insensitive neurons. The action potential width of OT-sensitive neurons was about half that of OT-insensitive neurons. The OT effect was blocked by the OT receptor antagonist atosiban and WAY-267464 but not by tetrodotoxin, suggesting a direct postsynaptic activation of OT receptors. In addition, the phospholipase C (PLC) inhibitor U73122 antagonized the depolarization by OT. Both the nonselective cation channel (NSCC) antagonist SKF96365 and the Na+–Ca2+ exchanger (NCX) blocker SN-6 attenuated OT effects. These results suggested that the PLC signaling pathway coupling to NSCC and NCX contributes to the OT-mediated activation of neurons in medial VTA and IF. Taken together, our results indicate OT directly acted on medial VTA and especially IF neurons to activate NSCC and NCX via PLC. The direct activation by OT of midbrain neurons may be one mechanism underlying OT effects on social behavior.

Nucleus accumbens high-frequency stimulation selectively impacts nigrostriatal dopaminergic neurons

High-frequency stimulation of the nucleus accumbens, also known as deep brain stimulation (DBS), is currently used to alleviate obsessive compulsive symptoms when pharmacotherapy is ineffective. However, the mechanism by which DBS achieves its therapeutic actions is not understood. Imaging studies and the actions of dopaminergic drugs in untreated patients suggest that the dopamine (DA) system likely plays a role in the pathophysiology of obsessive compulsive disorder. Therefore, we examined whether DBS would impact the DA system as a potential component of its therapeutic actions. The activity of DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were recorded in anesthetized rats under high-frequency stimulation. DA neuron activity was measured in terms of number of neurons firing, average firing rate and firing pattern. DBS of the nucleus accumbens core did not significantly affect VTA activity or discharge pattern. On the other hand, DBS caused a potent decrease in the number of SNc DA neurons firing spontaneously. Such an effect could contribute to the disruption of pathological habit formation in the SNc-dorsal striatal projection system that may have therapeutic implications for the treatment of obsessive compulsive disorder.

Nicotinic acetylcholine receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons

Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild-type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the α6 nAChR subunit (α6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre-application of the α6 subtype-selective nAChR antagonist, α-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices. Finally, pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse

Inhibition of VTA neurons activates the centrally projecting Edinger–Westphal nucleus: Evidence of a stress–reward link?

The primary site of urocortin 1 (Ucn1) expression in the brain is the centrally projecting Edinger–Westphal nucleus. The EWcp is innervated by dopaminergic neurons of the ventral tegmental area (VTA). To investigate whether activity of EWcp is regulated by the VTA, we investigated the effects of local pharmacological inhibition of VTA activity on the induction of Fos immunoreactivity in the EWcp of male C57BL/6J mice. A unilateral intracranial administration of the GABA agonist muscimol aimed at the VTA resulted in increased number of Fos-positive cells in the EWcp. This induction was lower than that produced by an intraperitoneal injection of 2.5g/kg of ethanol. To investigate whether inhibition of dopaminergic neurons was responsible for induction of Fos, a second experiment was performed where the dopamine agonist quinpirole was unilaterally injected targeting the VTA. Injections of quinpirole also significantly induced Fos in the EWcp neurons. The induction occurred only on the side of the EWcp ipsilateral to the VTA injection. These results indicate that activity of EWcp is inhibited by tonic activity of dopaminergic VTA neurons, and that unilateral projections of VTA onto Ucn1-containing EWcp neurons provide a link between systems regulating approach and avoidance behaviors.

Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection

Dopamine neurons of the ventral tegmental area (VTA) signal the occurrence of a reward-predicting conditioned stimulus (CS) with a subsecond duration increase in post-CS firing rate. Important theories about reward-prediction error and reward expectancy have been informed by the substantial number of studies that have examined post-CS phasic VTA neuron activity. On the other hand, the role of VTA neurons in anticipation of a reward-predicting CS and analysis of prestimulus spike rate rarely has been studied. We recorded from the VTA in rats during the 3-choice reaction time task, which has a fixed-duration prestimulus period and a difficult-to-detect stimulus. Use of a stimulus that was difficult to detect led to behavioral errors, which allowed us to compare VTA activity between trials with correct and incorrect stimulus-guided choices. We found a sustained increase in firing rate of both putative dopamine and GABA neurons during the pre-CS period of correct and incorrect trials. The poststimulus phasic response, however, was absent on incorrect trials, suggesting that the stimulus-evoked phasic response of dopamine neurons may relate to stimulus detection. The prestimulus activation of VTA neurons may modulate cortical systems that represent internal states of stimulus expectation and provide a mechanism for dopamine neurotransmission to influence preparatory attention to an expected stimulus.