Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation (original) (raw)
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The Journal of Neuroscience, 2004
Reward-predictive cues exert powerful control over behavioral choice and may be a critical factor in drug addiction. Reward-seeking elicited by predictive cues is facilitated by the release of dopamine in the nucleus accumbens (NAc), yet the contribution of dopamine to the specific NAc firing patterns that underlie goal-directed behavior has remained elusive. We present evidence that subpopulations of NAc neurons that respond to predictive cues require the dopaminergic projection from the ventral tegmental area (VTA) to promote reward-seeking behavior. Rats trained to perform an operant response to a cue to obtain a sucrose reward were implanted with both multiunit recording electrodes in the NAc and microinjection cannulas in the VTA. Both the behavioral response to cues and the cue-evoked firing of NAc neurons were blocked by injection of the GABA B agonist baclofen into the VTA. An additional group of rats was trained on the same task and then implanted with microinjection cannulas in the NAc. Like VTA baclofen injection, injection of dopamine receptor antagonists into the NAc profoundly reduced cue-elicited reward seeking. Together, these results support the conclusion that both the behavioral response to the cue and the specific NAc neuronal firing that promotes the response depend on dopamine release within the NAc. Our findings suggest a neural mechanism by which the dopamine-dependent firing of NAc neurons mediates goaldirected behavior.
Current biology : CB, 2017
Eating is a learned process. Our desires for specific foods arise through experience. Both electrical stimulation and optogenetic studies have shown that increased activity in the lateral hypothalamus (LH) promotes feeding. Current dogma is that these effects reflect a role for LH neurons in the control of the core motivation to feed, and their activity comes under control of forebrain regions to elicit learned food-motivated behaviors. However, these effects could also reflect the storage of associative information about the cues leading to food in LH itself. Here, we present data from several studies that are consistent with a role for LH in learning. In the first experiment, we use a novel GAD-Cre rat to show that optogenetic inhibition of LH γ-aminobutyric acid (GABA) neurons restricted to cue presentation disrupts the rats' ability to learn that a cue predicts food without affecting subsequent food consumption. In the second experiment, we show that this manipulation also d...
Nature Neuroscience, 2021
The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction.
Ventral Tegmental Area Neurons in Learned Appetitive Behavior and Positive Reinforcement
Annual Review of Neuroscience, 2007
Ventral tegmental area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection t...
Journal of Comparative Neurology
The ventral tegmental area (VTA) is a heterogeneous midbrain structure that contains dopamine (DA), GABA and glutamate neurons that project to many different brain regions. Here we combined retrograde tracing with immunocytochemistry against tyrosine hydroxylase (TH) or glutamate decarboxylase (GAD) to systematically compare the proportion of dopaminergic and GABAergic VTA projections to ten target nuclei; anterior cingulate, prelimbic, and infralimbic cortex; nucleus accumbens core, medial shell, and lateral shell; anterior and posterior basolateral amygdala; ventral pallidum; and periaqueductal gray. Overall, the non-dopaminergic component predominated VTA efferents, accounting for more than 50% of all projecting neurons to each region except the nucleus accumbens core. Additionally, GABA neurons contributed no more than 20% to each projection, with the exception of the projection to the ventrolateral periaqueductal gray, where the GABAergic contribution approached 50%. Therefore, there is likely a significant glutamatergic component to many of the VTA's projections. We also found that VTA cell bodies retrogradely labeled from the various target brain regions had distinct distribution patterns within the VTA, including in the locations of DA and GABA neurons. Despite this patterned organization, VTA neurons comprising these different projections were intermingled and never limited to any one sub-region. These anatomical results are consistent with the idea that VTA neurons participate in multiple distinct, parallel circuits that differentially contribute to motivation and reward. While attention has largely focused on VTA DA neurons, a better understanding of VTA sub-populations, especially the contribution of non-DA neurons to projections, will be critical for future work.
European Journal of Neuroscience, 2004
Discriminative stimuli (DSs) inform animals that reward can be obtained contingent on the performance of a specific behavior. Such stimuli reinstate drug-seeking behavior, evoke dopamine release in the nucleus accumbens (NAc) and excite and inhibit specific subpopulations of NAc neurons. Here we show in rats 2 that DSs can reinstate food-seeking behavior. In addition, we compare the effects of injecting dopamine receptor antagonists into the NAc with those of general NAc inactivation on the performance of a DS task. Selective antagonism of D1 receptors reduced responding to the DS and increased the latency to respond, whereas general inactivation of NAc neuronal activity increased the latency to respond to the DS and increased behaviors extraneous to the task, such as responding in the absence of cues and responding on the inactive lever. Based on these results and our previous findings that NAc neuronal responses to DSs are dependent on the ventral tegmental area, we propose a model for the functional role of NAc neurons in controlling behavioral responses to reward-predictive stimuli.
Dopamine-glutamate neuron projections to the nucleus accumbens medial shell and behavioral switching
Neurochemistry International, 2019
Dopamine (DA) neuron projections to the striatum are functionally heterogeneous with diverse behavioral roles. We focus here on DA neuron projections to the nucleus accumbens (NAc) medial Shell, their distinct anatomical and functional connections, and discuss their role in motivated behavior. We first review rodent studies showing that a subpopulation of DA neurons in the medial ventral tegmental area (VTA) project to the NAc medial Shell. Using a combinatoric strategy, we show that the majority of DA neurons projecting to the NAc Shell express vesicular glutamate transporter 2 (VGLUT2) making them capable of glutamate co-transmission (DA-GLU neurons). In the NAc dorsal medial Shell, all of the DA neuron terminals arise from DA-GLU neurons, while in the lateral NAc Shell, DA neuron terminals arise from both DA-GLU neurons and DA-only neurons, without VGLUT2. DA-GLU neurons make excitatory connections to the three major cells types, spiny projection neurons, fast-spiking interneuron and cholinergic interneurons (ChIs). The strongest DA-GLU neuron excitatory connections are to ChIs. Photostimulation of DA-GLU neuron terminals in the slice drive ChIs to fire in a burst. Finally, we review studies that address specially the behavioral function of this subpopulation of DA neurons in extinction learning and latent inhibition. Taking into account findings from anatomical and functional connectome studies, we propose that DA-GLU neuron connections to ChIs in the medial Shell play a crucial role in switching behavioral responses under circumstances of altered cue-reinforcer contingencies.
Nature Communications
The ability to learn Pavlovian associations from environmental cues predicting positive outcomes is critical for survival, motivating adaptive behaviours. This cued-motivated behaviour depends on the nucleus accumbens (NAc). NAc output activity mediated by spiny projecting neurons (SPNs) is regulated by dopamine, but also by cholinergic interneurons (CINs), which can release acetylcholine and glutamate via the activity of the vesicular acetylcholine transporter (VAChT) or the vesicular glutamate transporter (VGLUT3), respectively. Here we investigated behavioural and neurochemical changes in mice performing a touchscreen Pavlovian approach task by recording dopamine, acetylcholine, and calcium dynamics from D1- and D2-SPNs using fibre photometry in control, VAChT or VGLUT3 mutant mice to understand how these signals cooperate in the service of approach behaviours toward reward-predicting cues. We reveal that NAc acetylcholine-dopaminergic signalling is continuously updated to regula...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016
Although the release of mesoaccumbal dopamine is certainly involved in rewarding responses, recent studies point to the importance of the interaction between it and glutamate. One important component of this network is the anterior nucleus accumbens shell (aNAcSh), which sends GABAergic projections into the lateral hypothalamus (LH) and receives extensive glutamatergic inputs from, among others, the medial prefrontal cortex (mPFC). The effects of glutamatergic activation of aNAcSh on the ingestion of rewarding stimuli as well as its effect in the LH and mPFC are not well understood. Therefore, we studied behaving mice that express a light-gated channel (ChR2) in glutamatergic fibers in their aNAcSh while recording from neurons in the aNAcSh, or mPFC or LH. In Thy1-ChR2, but not wild-type, mice activation of aNAcSh fibers transiently stopped the mice licking for sucrose or an empty sipper. Stimulation of aNAcSh fibers both activated and inhibited single-unit responses aNAcSh, mPFC, a...