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Nature Neuroscience Jan 2022Social interactions are motivated behaviors that, in many species, facilitate learning. However, how the brain encodes the reinforcing properties of social interactions...
Social interactions are motivated behaviors that, in many species, facilitate learning. However, how the brain encodes the reinforcing properties of social interactions remains unclear. In this study, using in vivo recording in freely moving mice, we show that dopamine (DA) neurons of the ventral tegmental area (VTA) increase their activity during interactions with an unfamiliar conspecific and display heterogeneous responses. Using a social instrumental task, we then show that VTA DA neuron activity encodes social prediction error and drives social reinforcement learning. Thus, our findings suggest that VTA DA neurons are a neural substrate for a social learning signal that drives motivated behavior.
Topics: Animals; Dopaminergic Neurons; Mice; Reinforcement, Psychology; Reward; Social Interaction; Ventral Tegmental Area
PubMed: 34857949
DOI: 10.1038/s41593-021-00972-9 -
Nature Communications Feb 2019Midbrain dopamine (mDA) neurons constitute a heterogenous group of cells that have been intensely studied, not least because their degeneration causes major symptoms in...
Midbrain dopamine (mDA) neurons constitute a heterogenous group of cells that have been intensely studied, not least because their degeneration causes major symptoms in Parkinson's disease. Understanding the diversity of mDA neurons - previously well characterized anatomically - requires a systematic molecular classification at the genome-wide gene expression level. Here, we use single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3, a marker for mDA neurons. Analyses include cells isolated during development up until adulthood and the results are validated by histological characterization of newly identified markers. This identifies seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons. Five of them express dopaminergic markers, while two express glutamatergic and GABAergic markers, respectively. Analysis also indicate evolutionary conservation of diversity in humans. This comprehensive molecular characterization will provide a valuable resource for elucidating mDA neuron subgroup development and function in the mammalian brain.
Topics: Animals; Brain; Dopaminergic Neurons; Gene Expression Regulation, Developmental; Homeodomain Proteins; Mice; Sequence Analysis, RNA; Transcription Factors
PubMed: 30718509
DOI: 10.1038/s41467-019-08453-1 -
Nature Apr 2023The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by...
The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by either aversive or appetitive stimuli. How it participates in these divergent functions remains elusive. Here we show that somatostatin-expressing (Sst) CeA neurons, which mediate much of CeA functions, generate experience-dependent and stimulus-specific evaluative signals essential for learning. The population responses of these neurons in mice encode the identities of a wide range of salient stimuli, with the responses of separate subpopulations selectively representing the stimuli that have contrasting valences, sensory modalities or physical properties (for example, shock and water reward). These signals scale with stimulus intensity, undergo pronounced amplification and transformation during learning, and are required for both reward and aversive learning. Notably, these signals contribute to the responses of dopamine neurons to reward and reward prediction error, but not to their responses to aversive stimuli. In line with this, Sst CeA neuron outputs to dopamine areas are required for reward learning, but are dispensable for aversive learning. Our results suggest that Sst CeA neurons selectively process information about differing salient events for evaluation during learning, supporting the diverse roles of the CeA. In particular, the information for dopamine neurons facilitates reward evaluation.
Topics: Animals; Mice; Avoidance Learning; Central Amygdaloid Nucleus; Dopaminergic Neurons; Motivation; Reward; Neuronal Plasticity; Somatostatin; Electroshock
PubMed: 37020025
DOI: 10.1038/s41586-023-05910-2 -
ELife Jun 2022New findings cast doubt on whether suppressing the RNA-binding protein PTBP1 can force astrocytes to become dopaminergic neurons.
New findings cast doubt on whether suppressing the RNA-binding protein PTBP1 can force astrocytes to become dopaminergic neurons.
Topics: Astrocytes; Cells, Cultured; Dopaminergic Neurons; Gatekeeping
PubMed: 35723428
DOI: 10.7554/eLife.80232 -
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 -
Molecular Neurodegeneration Jun 2022A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson's disease (PD),... (Review)
Review
A constant metabolism and energy supply are crucial to all organs, particularly the brain. Age-dependent neurodegenerative diseases, such as Parkinson's disease (PD), are associated with alterations in cellular metabolism. These changes have been recognized as a novel hot topic that may provide new insights to help identify risk in the pre-symptomatic phase of the disease, understand disease pathogenesis, track disease progression, and determine critical endpoints. Nuclear receptor-related factor 1 (NURR1), an orphan member of the nuclear receptor superfamily of transcription factors, is a major risk factor in the pathogenesis of PD, and changes in NURR1 expression can have a detrimental effect on cellular metabolism. In this review, we discuss recent evidence that suggests a vital role of NURR1 in dopaminergic (DAergic) neuron development and the pathogenesis of PD. The association between NURR1 and cellular metabolic abnormalities and its implications for PD therapy have been further highlighted.
Topics: Dopamine; Dopaminergic Neurons; Humans; Nuclear Receptor Subfamily 4, Group A, Member 2; Parkinson Disease; Transcription Factors
PubMed: 35761385
DOI: 10.1186/s13024-022-00544-w -
Neuron Jan 2018Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent...
Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics, and behavioral assays, we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.
Topics: Afferent Pathways; Animals; Behavior, Animal; Channelrhodopsins; Conditioning, Operant; Dopamine; Dopaminergic Neurons; Exploratory Behavior; Female; GABAergic Neurons; Male; Maze Learning; Mice; Mice, Inbred C57BL; Motivation; Nucleus Accumbens; Optogenetics; Reward; Ventral Tegmental Area
PubMed: 29307710
DOI: 10.1016/j.neuron.2017.12.022 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
The Journal of Comparative Neurology May 2019The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of... (Review)
Review
The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others.
Topics: Age of Onset; Brain; Dopaminergic Neurons; Forecasting; Gene Expression Regulation; Gene Ontology; Humans; Loss of Function Mutation; Nerve Tissue Proteins; Neural Pathways; Parkinson Disease
PubMed: 30680728
DOI: 10.1002/cne.24642 -
Journal of Visualized Experiments : JoVE Nov 2021Dopamine neuron loss is involved in the pathology of Parkinson's Disease (PD), a highly prevalent neurodegenerative disorder affecting over 10 million people worldwide....
Dopamine neuron loss is involved in the pathology of Parkinson's Disease (PD), a highly prevalent neurodegenerative disorder affecting over 10 million people worldwide. Since many details about PD etiology remain unknown, studies investigating genetic and environmental contributors to PD are needed to discover methods of prevention, management, and treatment. Proper characterization of dopaminergic neuronal loss may be relevant not only to PD research, but to other increasingly prevalent neurodegenerative disorders. There are established genetic and chemical models of dopaminergic neurodegeneration in the Caenorhabditis elegans model system, with easy visualization of neurobiology supported by the nematodes' transparency and invariant neuronal architecture. In particular, hermaphroditic C. elegans' dopaminergic neuron morphological changes can be visualized using strains with fluorescent reporters driven by cell-specific promotors such as the dat-1 dopamine transporter gene, which is expressed exclusively in their eight dopaminergic neurons. With the capabilities of this model system and the appropriate technology, many laboratories have studied dopaminergic neurodegeneration. However, there is little consistency in the way the data is analyzed and much of the present literature uses binary scoring analyses that capture the presence of degeneration but not the full details of the progression of neuron loss. Here, we introduce a universal scoring system to assess morphological changes and degeneration in C. elegans' cephalic neuron dendrites. This seven-point scale allows for analysis across a full range of dendrite morphology, ranging from healthy neurons to complete dendrite loss, and considering morphological details including kinks, branching, blebs, and breaks. With this scoring system, researchers can quantify subtle age-related changes as well as more dramatic chemical-induced changes. Finally, we provide a practice set of images with commentary that can be used to train, calibrate, and assess the scoring consistency of researchers new to this method. This should improve within- and between- laboratory consistency, increasing rigor and reproducibility.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Disease Models, Animal; Dopaminergic Neurons; Humans; Reproducibility of Results
PubMed: 34866619
DOI: 10.3791/62894