scholarly journals SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

2021 ◽  
Author(s):  
Abdallah Zayed ◽  
Camille Baranowski ◽  
Anne Claire Compagnion ◽  
Cecile Vernochet ◽  
Samah Karaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Social Defeat ◽  
Global Scale ◽  
Chromatin Accessibility ◽  
Dopamine Neurons ◽  
Behavioral Adaptations ◽  
Atpase Subunits ◽  
Reward Pathway ◽  
Midbrain Dopamine ◽  
Preclinical And Clinical Studies

Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

scholarly journals Purity and Enrichment of Laser-Microdissected Midbrain Dopamine Neurons

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Amanda L. Brown ◽  
Trevor A. Day ◽  
Christopher V. Dayas ◽  
Doug W. Smith
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Acid Decarboxylase ◽  
Cell Groups ◽  
Midbrain Dopamine ◽  
High Degree ◽  
Midbrain Dopamine Neurons

The ability to microdissect individual cells from the nervous system has enormous potential, as it can allow for the study of gene expression in phenotypically identified cells. However, if the resultant gene expression profiles are to be accurately ascribed, it is necessary to determine the extent of contamination by nontarget cells in the microdissected sample. Here, we show that midbrain dopamine neurons can be laser-microdissected to a high degree of enrichment and purity. The average enrichment for tyrosine hydroxylase (TH) gene expression in the microdissected sample relative to midbrain sections was approximately 200-fold. For the dopamine transporter (DAT) and the vesicular monoamine transporter type 2 (Vmat2), average enrichments were approximately 100- and 60-fold, respectively. Glutamic acid decarboxylase (Gad65) expression, a marker for GABAergic neurons, was several hundredfold lower than dopamine neuron-specific genes. Glial cell and glutamatergic neuron gene expression were not detected in microdissected samples. Additionally, SN and VTA dopamine neurons had significantly different expression levels of dopamine neuron-specific genes, which likely reflects functional differences between the two cell groups. This study demonstrates that it is possible to laser-microdissect dopamine neurons to a high degree of cell purity. Therefore gene expression profiles can be precisely attributed to the targeted microdissected cells.

scholarly journals Classification of Midbrain Dopamine Neurons Using Single-Cell Gene Expression Profiling Approaches

2020 ◽  
Vol 43 (3) ◽  
pp. 155-169 ◽  
Author(s):  
Jean-Francois Poulin ◽  
Zachary Gaertner ◽  
Oscar Andrés Moreno-Ramos ◽  
Rajeshwar Awatramani
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Dopamine Neurons ◽  
Cell Gene Expression ◽  
Midbrain Dopamine ◽  
Cell Gene ◽  
Midbrain Dopamine Neurons

scholarly journals Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients

2021 ◽  
Vol 14 ◽  
Author(s):  
Katarína Tiklová ◽  
Linda Gillberg ◽  
Nikolaos Volakakis ◽  
Hilda Lundén-Miguel ◽  
Lina Dahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Lewy Body Disease ◽  
Dopamine Neurons ◽  
Differentially Expressed ◽  
Incidental Lewy Body Disease ◽  
Advanced Stages ◽  
Midbrain Dopamine

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.

scholarly journals Histone Glutamine Modification by Neurotransmitters: Paradigm Shift in the Epigenetics of Neuronal Gene Activation and Dopaminergic VTA Reward Pathway

2020 ◽  
Author(s):  
Samir PATRA
Keyword(s):  
Gene Expression ◽  
Neuronal Development ◽  
Tissue Transglutaminase ◽  
Gene Activation ◽  
Central Element ◽  
Dopamine Neurons ◽  
Normal Brain ◽  
Reward Pathway ◽  
Neuronal Functions ◽  
The Brain

Normal brain function means fine-tuned neuronal circuitry with optimum neurotransmitter signaling. The classical views and experimental demonstrations established neurotransmitters release-uptake through synaptic vesicles. Current research highlighted that neurotransmitters not merely influence electrical impulses; however, contribute to gene expression, now we know, by posttranslational modifications of chromatinised histones. Epigenetic modifications of chromatin, like DNA methylation, histone methylation, acetylation, ubiquitilation etc., influence gene expression during neuronal development, differentiation and functions. Protein glutamine (Q) modification by tissue transglutaminase (TGM2) controls a wide array of metabolic and signaling activities, including neuronal functions. Dopamine neurons are central element in the brain reward system that controls the learning of numerous behaviours. The ventral tegmental area (VTA) consists of dopamine, GABA, or glutamate neurons. The VTA and adjacent substantia nigra are the two major dopaminergic areas in the brain. In view of this, and to focus insight into the neuronal functions caused by TGM2 mediated histone modifications at the Q residues, either serotonylation (for example, H3K4me3Q5 to H3K4me3Q5ser) in the context of cellular differentiation and signaling, or dopaminylation (for example, H3Q5 to H3Q5dop) in the dopaminergic VTA reward pathway and the precise role of cocaine withdrawal in this scenario are summarized and discussed in this contribution.

scholarly journals Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

Science ◽  
2020 ◽  
Vol 368 (6487) ◽  
pp. 197-201 ◽  
Author(s):  
Ashley E. Lepack ◽  
Craig T. Werner ◽  
Andrew F. Stewart ◽  
Sasha L. Fulton ◽  
Ping Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Critical Role ◽  
Histone H3 ◽  
Dopamine Neurons ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Transcriptional Plasticity

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

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