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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 -
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 -
Neuron Oct 2022The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive...
The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive behaviors affect anxiety regulation is unclear. Here, we identify that the excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPL neurons) in mice promote self-grooming and encode reward. MPL neurons display prominent grooming-related neuronal activity. Loss of function of MPL neurons impairs both self-grooming and post-stress anxiety alleviation. Activation of MPL neurons is rewarding and sufficient to drive reinforcement by activating dopamine (DA) neurons in the ventral tegmental area (VTA) and eliciting dopamine release. The neuropeptide SST facilitates the rewarding impact of MPL neurons. MPL neuron-mediated self-grooming is triggered by the input from the central amygdala (CeA). Our study reveals a dual role of CeA-MPL-VTA circuit in self-grooming and post-stress anxiety regulation and conceptualizes MPL neurons as an interface linking the stress and reward systems in mice.
Topics: Animals; Mice; Grooming; Dopamine; Reward; Ventral Tegmental Area; Dopaminergic Neurons; Pontine Tegmentum; Somatostatin
PubMed: 36070748
DOI: 10.1016/j.neuron.2022.08.010 -
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 -
Addiction Biology May 2019Glial cell line-derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system,... (Review)
Review
Glial cell line-derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system, although evidence suggests that GDNF also plays a role in drug and alcohol addiction. This review focuses on the unique actions of GDNF in the mechanisms that prevent the transition from recreational alcohol use to abuse. Specifically, we describe studies in rodents suggesting that alcohol acutely increases GDNF expression in the ventral tegmental area, which enables the activation of the mitogen-activated protein kinase signaling pathway and the gating of alcohol intake. We further provide evidence to suggest that GDNF acts in the ventral tegmental area via both nongenomic and genomic mechanisms to suppress alcohol consumption. In addition, we describe findings indicating that when this endogenous protective pathway becomes dysregulated, alcohol intake levels escalate. Finally, we describe the potential use of GDNF inducers as a novel therapeutic approach to treat alcohol use disorder.
Topics: Alcoholism; Central Nervous System Depressants; Dopaminergic Neurons; Ethanol; Glial Cell Line-Derived Neurotrophic Factor; Humans; Limbic System; Mental Disorders; Nucleus Accumbens; Signal Transduction; Tegmentum Mesencephali
PubMed: 29726054
DOI: 10.1111/adb.12628 -
Neurocritical Care Aug 2017Basilar artery occlusion can cause locked-in syndrome, which is characterized by quadriplegia, anarthria, and limited communication via eye movements. Here, we describe...
BACKGROUND
Basilar artery occlusion can cause locked-in syndrome, which is characterized by quadriplegia, anarthria, and limited communication via eye movements. Here, we describe an uncommon stroke syndrome associated with endovascular recanalization of the top of the basilar artery: "reverse locked-in syndrome."
METHODS
We report the case of a patient with atypical neurological deficits caused by acute ischemic stroke of the midbrain tegmentum. We perform neuroanatomic localization of the patient's infarcts by mapping the magnetic resonance imaging (MRI) data onto a brainstem atlas.
RESULTS
A 61-year-old man presented with acute coma and quadriplegia due to top of the basilar artery occlusion. He underwent emergent endovascular thrombectomy, with successful recanalization of the basilar artery at 4 h and 43 min post-ictus. The patient regained consciousness and purposeful movement in all four extremities, but the post-procedure neurological examination demonstrated bilateral ptosis with complete pupillary and oculomotor paralysis. MRI revealed infarction of the bilateral oculomotor nuclei in the midbrain tegmentum. At 9-month follow-up, he had anisocoria and dysconjugate gaze, but was living at home and required minimal assistance in performing all activities of daily living.
CONCLUSIONS
Since the patient's deficits were the exact opposite of those described in locked-in syndrome, we propose the term "reverse locked-in syndrome" to describe this neurological entity characterized by bilateral ptosis, non-reactive pupils, and ophthalmoplegia with preservation of consciousness and extremity motor function.
Topics: Basilar Artery; Blepharoptosis; Cerebral Infarction; Humans; Male; Middle Aged; Ophthalmoplegia; Tegmentum Mesencephali; Thrombectomy
PubMed: 28324264
DOI: 10.1007/s12028-017-0391-x -
Molecular Psychiatry Dec 2022Freezing is a conserved defensive behaviour that constitutes a major stress-coping mechanism. Decades of research have demonstrated a role of the amygdala,...
Freezing is a conserved defensive behaviour that constitutes a major stress-coping mechanism. Decades of research have demonstrated a role of the amygdala, periaqueductal grey and hypothalamus as core actuators of the control of fear responses, including freezing. However, the role that other modulatory sites provide to this hardwired scaffold is not known. Here, we show that freezing elicited by exposure to electrical foot shocks activates laterodorsal tegmentum (LDTg) GABAergic neurons projecting to the VTA, without altering the excitability of cholinergic and glutamatergic LDTg neurons. Selective chemogenetic silencing of this inhibitory projection, but not other LDTg neuronal subtypes, dampens freezing responses but does not prevent the formation of conditioned fear memories. Conversely, optogenetic-activation of LDTg GABA terminals within the VTA drives freezing responses and elicits bradycardia, a common hallmark of freezing. Notably, this aversive information is subsequently conveyed from the VTA to the amygdala via a discrete GABAergic pathway. Hence, we unveiled a circuit mechanism linking LDTg-VTA-amygdala regions, which holds potential translational relevance for pathological freezing states such as post-traumatic stress disorders, panic attacks and social phobias.
Topics: Freezing; Periaqueductal Gray; Amygdala; GABAergic Neurons
PubMed: 36127430
DOI: 10.1038/s41380-022-01765-7 -
Anesthesiology Jun 2022Increasing evidence supports a role for brain reward circuitry in modulating arousal along with emergence from anesthesia. Emergence remains an important frontier for... (Review)
Review
Increasing evidence supports a role for brain reward circuitry in modulating arousal along with emergence from anesthesia. Emergence remains an important frontier for investigation, since no drug exists in clinical practice to initiate rapid and smooth emergence. This review discusses clinical and preclinical evidence indicating a role for two brain regions classically considered integral components of the mesolimbic brain reward circuitry, the ventral tegmental area and the nucleus accumbens, in emergence from propofol and volatile anesthesia. Then there is a description of modern systems neuroscience approaches to neural circuit investigations that will help span the large gap between preclinical and clinical investigation with the shared aim of developing therapies to promote rapid emergence without agitation or delirium. This article proposes that neuroscientists include models of whole-brain network activity in future studies to inform the translational value of preclinical investigations and foster productive dialogues with clinician anesthesiologists.
Topics: Brain; Nucleus Accumbens; Reward; Ventral Tegmental Area
PubMed: 35362070
DOI: 10.1097/ALN.0000000000004148 -
Nature Neuroscience Sep 2023Arrest of ongoing movements is an integral part of executing motor programs. Behavioral arrest may happen upon termination of a variety of goal-directed movements or as...
Arrest of ongoing movements is an integral part of executing motor programs. Behavioral arrest may happen upon termination of a variety of goal-directed movements or as a global motor arrest either in the context of fear or in response to salient environmental cues. The neuronal circuits that bridge with the executive motor circuits to implement a global motor arrest are poorly understood. We report the discovery that the activation of glutamatergic Chx10-derived neurons in the pedunculopontine nucleus (PPN) in mice arrests all ongoing movements while simultaneously causing apnea and bradycardia. This global motor arrest has a pause-and-play pattern with an instantaneous interruption of movement followed by a short-latency continuation from where it was paused. Mice naturally perform arrest bouts with the same combination of motor and autonomic features. The Chx10-PPN-evoked arrest is different to ventrolateral periaqueductal gray-induced freezing. Our study defines a motor command that induces a global motor arrest, which may be recruited in response to salient environmental cues to allow for a preparatory or arousal state, and identifies a locomotor-opposing role for rostrally biased glutamatergic neurons in the PPN.
Topics: Mice; Animals; Neurons; Movement; Periaqueductal Gray; Pedunculopontine Tegmental Nucleus
PubMed: 37501003
DOI: 10.1038/s41593-023-01396-3 -
Brain Structure & Function Jan 2021The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal... (Review)
Review
The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal cord, during its phylogenesis the RN shows a progressive segregation between a magnocellular part, involved in the rubrospinal system, and a parvocellular part, involved in the olivocerebellar system. Despite exhibiting distinct evolutionary trajectories, these two regions are strictly tied together and play a prominent role in motor and non-motor behavior in different animal species. However, little is known about their function in the human brain. This lack of knowledge may have been conditioned both by the notable differences between human and non-human RN and by inherent difficulties in studying this structure directly in the human brain, leading to a general decrease of interest in the last decades. In the present review, we identify the crucial issues in the current knowledge and summarize the results of several decades of research about the RN, ranging from animal models to human diseases. Connecting the dots between morphology, experimental physiology and neuroimaging, we try to draw a comprehensive overview on RN functional anatomy and bridge the gap between basic and translational research.
Topics: Brain Mapping; Humans; Neuroimaging; Red Nucleus
PubMed: 33180142
DOI: 10.1007/s00429-020-02171-x