Overlapping representations of food and social stimuli in VTA dopamine neurons
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ABSTRACT:
PROVIDER: PRJNA984670 | ENA |
REPOSITORIES: ENA
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Project description:We used 2-photon calcium imaging to determine whether the same or different dopamine neurons of the ventral tegmental area (VTADA) encode food and social stimuli, and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience increased the proportion of neurons that respond to both stimuli, implying that increasing motivation for one stimulus further increases overlap. We used single-nucleus RNA sequencing (snRNA-seq) to examine cell type-specific gene expression changes across different hunger states and the level of co-expression of feeding- and social-hormone related genes in individual VTADA neurons.
2023-08-21 | GSE235149 | GEO
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Project description:While stressful life events are an important cause of psychopathology such as Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD), most individuals exposed to chronic stress remain psychologically unperturbed. The molecular mechanisms such variations in stress resilience remain to be explored. Utilizing a mouse social defeat paradigm as a model for chronic social stress exposure, we segregated socially defeated c57bl/6J mice into Susceptible and Unsusceptible groups based on scores of social avoidance, and these groups differ along multiple behavioral and physiological domains. To explore neuroplastic changes within the mesolimbic dopamine circuit that may explain variations in susceptibility, we examined global patterns of gene expression within the VTA (ventral tegmental area) and the NAc (nucleus accumbens). Tissue punches of NAc and VTA were obtained from either non-defeated control, Susceptible and Unsusceptible mice approximately 48 hours after the cessation of social defeat stress. Data from Illumina sentrix gene expression microarrays revealed three main findings: (1) the total number of genes significantly up or downregulated was considerably higher within the NAc, (2) the Unsusceptible phenotype was associated with the regulation of a much higher number of genes, and (3) as compared to the NAc, the VTA displayed far fewer genes that were identically regulated in both Susceptible and Unsusceptible groups. Taken together, these data strongly suggest that the VTA is an important substrate for transcriptional changes that can be correlated with variations in Susceptibility. In addition, they suggest that changes in anxiety (found in both Susceptible and Unsusceptible groups) versus changes in reward behavior (found only in Susceptilbe mice) can be explained by gene expression changes within the mesolimbic dopamine circuit. Keywords: neural stress response
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Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP. Transgenic hTH-GFP mice were treated with MPTP (4mg/kg) for either 2 or 10 days. Control mice were given an equal volume of saline for 10 days. Dopamine neurons from the substantia nigra and ventral tegmental areas of control and MPTP treated animals were laser captured. The RNA was isolated and processed for microarray hybridization. Each group had three biological replicates, for a total of 18 samples. Three each in the following: Control SN, Control VTA, 2 day MPTP SN, 2 day MPTP VTA, 10 day MPTP SN, 10 day MPTP VTA. Samples were log2 transformed and RMA normalized using Agilent Genespring 10.0 GX.
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Project description:Alzheimer's disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2). Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings shed light on a complex interplay between neuropsychiatric symptoms and subcortical circuits in AD, paving the way for novel treatment strategies.
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Project description:Implications for neuroprotection in Parkinson's disease Parkinson’s disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. This pattern of cell loss is mimicked in humans, primates, and certain rodents by the neurotoxin MPTP. In this study, we aimed to test the hypothesis that there are factors in the VTA that are potentially neuroprotective against MPTP and that these factors change over time. We have found a differential transcriptional response within the cells of the SN and VTA to sustained exposure to a low dose of MPTP. Specifically, the VTA has increased expression of 148 genes as an early response to MPTP and 113 genes as a late response to MPTP toxicity. This response encompasses many areas of cellular function, including protein regulation (Phf6) and ion/metal regulation (PANK2, Car4). Notably, these responses were largely absent from the cells of the SN. Our data show a clear dynamic response in maintaining the homeostasis and viability of the neurons in the VTA that is lacking in the SN after neurotoxin challenge. We used microarrays to analyze the differential response of the substantia nigra (SN) and ventral tegmental area (VTA) to a chronic low dose of the neurotoxin MPTP.
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