Differential Regulation of Alcohol Consumption and Reward by the Transcription Cofactor LMO4
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141312 | GEO | 2020/02/29
REPOSITORIES: GEO
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Project description:The basolateral amygdala (BLA) contains discrete neuronal circuits that integrate positive or negative emotional information and drive the appropriate innate and learned behaviors. Whether how these circuits consist of genetically-identifiable and anatomically segregated neuron types, is currently poorly understood. Also, our understanding of the response patterns and behavioral spectra of genetically-identifiable BLA neurons is limited. Here, we classified 11 glutamatergic BLA cell types having topography in BLA. Several clusters were enriched in lateral versus basal amygdala, others were enriched in either anterior or posterior regions of the BLA. Two of these BLA subpopulations innately responded to valence-specific stimuli, whereas one represented to both aversive and social cues. Positive-valence BLA neurons promoted normal feeding, while mixed selectivity neurons promoted fear learning and social interactions. These findings enhance our understanding of cell type diversity and spatial organization of the BLA and the role of distinct BLA populations in representing valence-specific and mixed stimuli.
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Project description:Differential Regulation of Alcohol Consumption and Reward by the Transcription Cofactor LMO4
| PRJNA593033 | ENA
Project description:Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are integrated into a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24 h intermittent access drinking procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens enhanced alcohol consumption, whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference for alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of norbinaltorphimine, a selective kappa opioid receptor antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.
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Project description:The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Different neuronal populations of the basolateral amygdala complex (BLA) encode fearful or rewarding associations, but the molecular identity of these functionally distinct populations of BLA neurons remained unknown. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc-projectors) or the centromedial amygdala (CeM-projectors) underwent opposing synaptic changes following fear or reward conditioning. The photostimulation of NAc projectors supported positive reinforcement while photostimulation of CeM projectors mediated negative reinforcement. In search of defining molecular characteristics of these functionally-distinct BLA neuronal populations, we compared gene expression profiles of NAc- and CeM-projectors.
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Project description:This project examined if sex differences in K48 polyubiquitination in the amygdala were developmentally regulated. This used basolateral amygdala (BLA) samples collected from 4 and 9 week old male and female Sprague-Dawley rats.
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Project description:Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood, making it challenging to develop treatment strategies. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. RNA-seq was used to investigate the molecular landscape of the basolateral amygdala (BLA), a region previously implicated in loss, in adult male Sprague-Dawley rats following ER. Rats were subjected to standard housing (SH) for 6 weeks, environmental enrichment (EE) for 6 weeks, or enrichment removal (ER), consisting of 4 weeks of EE followed by 2 weeks of removal into impoverished conditions (n=10/pool/group). Rats were then perfused and micropunches were collected from the basolateral amygdala (BLA) for bulk RNA-seq.
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Project description:Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood, making it challenging to develop treatment strategies. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. RNA-seq was used to investigate the molecular landscape of the basolateral amygdala (BLA), a region previously implicated in loss, in adult male Sprague-Dawley rats following ER. Rats were subjected to standard housing (SH) for 6 weeks, environmental enrichment (EE) for 6 weeks, or enrichment removal (ER), consisting of 4 weeks of EE followed by 2 weeks of removal into impoverished conditions (n=6/group). Rats were then perfused and micropunches were collected from the basolateral amygdala (BLA) for bulk RNA-seq.
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Project description:The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Different neuronal populations of the basolateral amygdala complex (BLA) encode fearful or rewarding associations, but the molecular identity of these functionally distinct populations of BLA neurons remained unknown. Here, we show that BLA neurons projecting to the nucleus accumbens (NAc-projectors) or the centromedial amygdala (CeM-projectors) underwent opposing synaptic changes following fear or reward conditioning. The photostimulation of NAc projectors supported positive reinforcement while photostimulation of CeM projectors mediated negative reinforcement. In search of defining molecular characteristics of these functionally-distinct BLA neuronal populations, we compared gene expression profiles of NAc- and CeM-projectors. For comparison of gene expression profiles of NAc- and CeM-projectors, we conducted two independent RNA sequencing experiments. In experiment-1, a total of n=9 samples (n=4 NAc- and n=5 CeM-projectors) are analyzed. In experiment-2, a total of n=8 samples (n=4 NAc- and n=4 CeM-projectors) are analyzed.
2015-02-27 | E-GEOD-66345 | biostudies-arrayexpress
Project description:The amygdala is known to modulate hippocampal synaptic plasticity. One role could be an immediate effect of basolateral amygdala (BLA) in priming synaptic plasticity in the hippocampus. Another role could be through associative synaptic co-operation and competition that triggers events involved in the maintenance of synaptic potentiation. We present evidence that the timing and activity level of BLA stimulation are important factors for the induction and maintenance of long-term potentiation (LTP) in ventral hippocampal area CA1. A 100 Hz BLA co-stimulation facilitated the induction of LTP, whereas 200 Hz co-stimulation attenuated induction. A 100 Hz BLA co-stimulation also caused enhanced persistence, sufficient to prevent synaptic competition. This maintenance effect is likely through translational mechanisms, as mRNA expression of primary response genes was unaffected, whereas protein level of plasticity-related products was increased. Further understanding of the neural mechanisms of amygdala modulation on hippocampus could provide insights into the mechanisms of emotional disorders.
2022-03-03 | GSE197708 | GEO
Project description:We performed single cell transcriptomics analyses in medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). Ketamine induced changes in inflammatory pathways reversing corticosterone effects. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling is decreased after corticosterone but increased following ketamine administration in excitatory neurons. Single cell transcriptomics analyses in dorsolateral prefrontal cortical (dl-PFC) neurons of depressed patients also showed decreased PCP signaling in excitatory neurons. Using chemogenetics, we found that the BLA-projecting infra limbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Using RNAScope, we found, in the excitatory neurons in mPFC, Celsrs and Prickle2 were reduced by corticosterone but increased by ketamine. Using CRISPR-Cas9, we conditionally knocked out Celsrs and Prickle2 in the BLA-projecting IL-PFC neurons and found that ketamine-induced synapse restoration and behavioral remission were abolished. Ketamine affects gene expression and PCP proteins underly long-lasting effects of low-dose ketamine.
2024-06-20 | GSE191016 | GEO