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Neuropharmacology Jan 2014The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA... (Review)
Review
The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Topics: Animals; Dopamine; Humans; Nerve Net; Reward; Ventral Tegmental Area
PubMed: 23578393
DOI: 10.1016/j.neuropharm.2013.03.019 -
Nature Neuroscience Oct 2023Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been...
Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine neuron subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1 subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine neuron subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.
Topics: Dopaminergic Neurons; Substantia Nigra; Signal Transduction; Axons
PubMed: 37537242
DOI: 10.1038/s41593-023-01401-9 -
Neuron Aug 2022The serotonin system modulates a wide variety of emotional behaviors and states, including reward processing, anxiety, and social interaction. To reveal the underlying...
The serotonin system modulates a wide variety of emotional behaviors and states, including reward processing, anxiety, and social interaction. To reveal the underlying patterns of neural activity, we visualized serotonergic neurons in the dorsal raphe nucleus (DRN) of mice using miniaturized microscopy during diverse emotional behaviors. We discovered ensembles of cells with highly correlated activity and found that DRN neurons are preferentially recruited by emotionally salient stimuli as opposed to neutral stimuli. Individual DRN neurons responded to diverse combinations of salient stimuli, with some preference for valence and sensory modality. Anatomically defined subpopulations projecting to either a reward-related structure (the ventral tegmental area) or an anxiety-related structure (the bed nucleus of the stria terminalis) contained all response types but were enriched in reward- and anxiety-responsive cells, respectively. Our results suggest that the DRN serotonin system responds to emotional salience using ensembles with mixed selectivity and biases in downstream connectivity.
Topics: Animals; Dorsal Raphe Nucleus; Mice; Reward; Serotonergic Neurons; Serotonin; Ventral Tegmental Area
PubMed: 35700737
DOI: 10.1016/j.neuron.2022.05.015 -
Nature Communications Aug 2023Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these...
Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3→DA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3 → DA glutamatergic transmission and DA neural excitability. VGluT3 → DA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3 → DA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3 → DA → D2/D1 pathway in establishing and modulating chronic pain and CAB.
Topics: Humans; Ventral Tegmental Area; Chronic Pain; Dorsal Raphe Nucleus; Neuralgia; Anhedonia; Dopaminergic Neurons; Glutamic Acid
PubMed: 37612268
DOI: 10.1038/s41467-023-40860-3 -
Nature Biotechnology Feb 2021Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the...
Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.
Topics: Animals; Brain; Light; Male; Mice, Inbred C57BL; Neurons; Optogenetics; Rats; Ventral Tegmental Area; Mice
PubMed: 33020604
DOI: 10.1038/s41587-020-0679-9 -
The Journal of Physiology Jul 2017
Topics: Humans; Pain; Periaqueductal Gray
PubMed: 28664606
DOI: 10.1113/JP273361 -
Neurobiology of Disease Jun 2024
Topics: Humans; Animals; Substantia Nigra; Corpus Striatum; Neural Pathways
PubMed: 38614276
DOI: 10.1016/j.nbd.2024.106503 -
Neuroscience and Biobehavioral Reviews May 2021A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to... (Review)
Review
A major goal in psychology is to understand how environmental stimuli associated with primary rewards come to function as conditioned stimuli, acquiring the capacity to elicit similar responses to those elicited by primary rewards. Our neurobiological model is predicated on the Hebbian idea that concurrent synaptic activity on the primary reward neural substrate-proposed to be ventral tegmental area (VTA) dopamine (DA) neurons-strengthens the synapses involved. We propose that VTA DA neurons receive both a strong unconditioned stimulus signal (acetylcholine stimulation of DA cells) from the primary reward capable of unconditionally activating DA cells and a weak stimulus signal (glutamate stimulation of DA cells) from the neutral stimulus. Through joint stimulation the weak signal is potentiated and capable of activating the VTA DA cells, eliciting a conditioned response. The learning occurs when this joint stimulation initiates intracellular second-messenger cascades resulting in enhanced glutamate-DA synapses. In this review we present evidence that led us to propose this model and the most recent evidence supporting it.
Topics: Conditioning, Classical; Dopaminergic Neurons; Learning; Reward; Ventral Tegmental Area
PubMed: 33581225
DOI: 10.1016/j.neubiorev.2021.02.007 -
The Journal of Neuroscience : the... Apr 2022The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of the following two major pathways: the striatopallidal (indirect)...
The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of the following two major pathways: the striatopallidal (indirect) pathway or the striatonigral (direct) pathway. Striatonigral axons project long distances and encounter ascending tracts (thalamocortical) while coursing alongside descending tracts (corticofugal) as they extend through the internal capsule and cerebral peduncle. These observations suggest that striatal circuitry may help to guide their trajectories. To investigate the developmental contributions of striatonigral axons to internal capsule formation, we have made use of (striatal direct pathway) and (corticofugal pathway) BAC transgenic reporter mice in combination with immunohistochemical markers to trace these axonal pathways throughout development. We show that striatonigral axons pioneer the internal capsule and cerebral peduncle and are temporally and spatially well positioned to provide guidance for corticofugal and thalamocortical axons. Using conditional knock-out (cKO) mice, which exhibit disrupted striatonigral axon outgrowth, we observe both corticofugal and thalamocortical axon defects with either ventral forebrain- or telencephalon-specific inactivation, despite Isl1 not being expressed in either cortical or thalamic projection neurons. Striatonigral axon defects can thus disrupt internal capsule formation. Our genome-wide transcriptomic analysis in cKOs reveals changes in gene expression relevant to cell adhesion, growth cone dynamics, and extracellular matrix composition, suggesting potential mechanisms by which the striatonigral pathway exerts this guidance role. Together, our data support a novel pioneering role for the striatal direct pathway in the correct assembly of the ascending and descending axon tracts within the internal capsule and cerebral peduncle. The basal ganglia are a group of subcortical nuclei with established roles in the coordination of voluntary motor programs, aspects of cognition, and the selection of appropriate social behaviors. Hence, disruptions in basal ganglia connectivity have been implicated in the motor, cognitive, and social dysfunction characterizing common neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, and tic disorder. Here, we identified a novel role for the striatonigral (direct) pathway in pioneering the internal capsule and cerebral peduncle, and in guiding axons extending to and from the cortex. Our findings suggest that the abnormal development of basal ganglia circuits can drive secondary internal capsule defects and thereby may contribute to the pathology of these disorders.
Topics: Animals; Autism Spectrum Disorder; Axons; Cerebral Cortex; Cerebral Peduncle; Internal Capsule; Mice; Mice, Knockout; Mice, Transgenic; Neural Pathways; Thalamus
PubMed: 35273083
DOI: 10.1523/JNEUROSCI.2291-21.2022 -
Experimental Neurology Dec 2023Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia... (Review)
Review
Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia circuits. Research over the past twenty-five years has identified that midbrain dopamine neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) co-release multiple other transmitters including glutamate and GABA, in addition to their canonical transmitter, dopamine. This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.
Topics: Animals; Parkinson Disease; Substantia Nigra; Ventral Tegmental Area; Synaptic Transmission; Dopaminergic Neurons; Neurotransmitter Agents
PubMed: 37802381
DOI: 10.1016/j.expneurol.2023.114562