scholarly journals Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

2016 ◽  
Vol 113 (3) ◽  
pp. 757-762 ◽  
Author(s):  
Matthew C. Hearing ◽  
Jakub Jedynak ◽  
Stephanie R. Ebner ◽  
Anna Ingebretson ◽  
Anders J. Asp ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Cell Type ◽  
Nucleus Accumbens Shell ◽  
Glutamate Signaling ◽  
Excitatory Transmission ◽  
Cell Type Specific ◽  
Abused Drugs

Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type–specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10–14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine

2021 ◽  
Author(s):  
David A Gallegos ◽  
Melyssa Minto ◽  
Fang Liu ◽  
Mariah F Hazlett ◽  
S Aryana Yousefzadeh ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Mutant Mouse ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Cell Type ◽  
Transcriptional Program ◽  
Behavioral Sensitivity ◽  
Cell Type Specific ◽  
Insight Into

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we observed dysregulation of multiple PV-specific, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants, suggesting the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Guangwei Liu ◽  
Xuelian Hu ◽  
Bo Sun ◽  
Tao Yang ◽  
Jianfeng Shi ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Neutrophil Differentiation ◽  
Deficient Mice

Abstract Neutrophils are critically involved in host defense and tissue damage. Intrinsic molecular mechanisms controlling neutrophil differentiation and activities are poorly defined. Herein we found that p53-induced phosphatase 1(Wip1) is preferentially expressed in neutrophils among immune cells. The Wip1 expression is gradually up-regulated during the differentiation of myeloid precursors into mature neutrophils. Wip1-deficient mice and chimera mice with Wip1−/− hematopoietic cells had an expanded pool of neutrophils with hypermature phenotypes in the periphery. The in vivo and in vitro studies showed that Wip1 deficiency mainly impaired the developing process of myeloid progenitors to neutrophils in an intrinsic manner. Mechanism studies showed that the enhanced development and maturation of neutrophils caused by Wip1 deficiency were mediated by p38 MAPK-STAT1 but not p53-dependent pathways. Thus, our findings identify a previously unrecognized p53-independent function of Wip1 as a cell type-specific negative regulator of neutrophil generation and homeostasis through limiting the p38 MAPK-STAT1 pathway.

scholarly journals Multiomics analysis reveals extensive epigenome remodeling during cortical development

2020 ◽  
Author(s):  
Florian Noack ◽  
Silvia Vangelisti ◽  
Madalena Carido ◽  
Faye Chong ◽  
Boyan Bonev
Keyword(s):  
Single Cell ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Lineage Specification ◽  
3D Genome ◽  
Epigenetic Remodeling ◽  
Cell Type Specific

AbstractDespite huge advances in stem-cell, single-cell and epigenetic technologies, the precise molecular mechanisms that determine lineage specification remain largely unknown. Applying an integrative multiomics approach, e.g. combining single-cell RNA-seq, single-cell ATAC-seq together with cell-type-specific DNA methylation and 3D genome measurements, we systematically map the regulatory landscape in the mouse neocortex in vivo. Our analysis identifies thousands of novel enhancer-gene pairs associated with dynamic changes in chromatin accessibility and gene expression along the differentiation trajectory. Crucially, we provide evidence that epigenetic remodeling generally precedes transcriptional activation, yet true priming appears limited to a subset of lineage-determining enhancers. Notably, we reveal considerable heterogeneity in both contact strength and dynamics of the generally cell-type-specific enhancer-promoter contacts. Finally, our work suggests a so far unrecognized function of several key transcription factors which act as putative “molecular bridges” and facilitate the dynamic reorganization of the chromatin landscape accompanying lineage specification in the brain.

scholarly journals Biology and Bias in Cell Type-Specific RNAseq of Nucleus Accumbens Medium Spiny Neurons

2018 ◽  
Author(s):  
Hope Kronman ◽  
Felix Richter ◽  
Benoit Labonté ◽  
Ramesh Chandra ◽  
Shan Zhao ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Affinity Purification ◽  
Cell Types ◽  
Medium Spiny Neuron ◽  
The Other ◽  
Biological Interactions ◽  
Cell Type ◽  
Genome Wide ◽  
Cell Type Specific

AbstractIsolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.

ITag-RNA Allows in Vivo Cell-Type Specific Transcriptional Characterization and Tracking of Circulating Transcripts

2018 ◽  
Author(s):  
J. Darr ◽  
M. Lassi ◽  
R. Gerlini ◽  
F. Scheid ◽  
M. Hrabě de Angelis ◽  
...  
Keyword(s):  
Cell Type ◽  
Cell Type Specific

Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons

2021 ◽  
pp. 0271678X2110103
Author(s):  
Nao Hatakeyama ◽  
Miyuki Unekawa ◽  
Juri Murata ◽  
Yutaka Tomita ◽  
Norihiro Suzuki ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Acetylcholine Receptors ◽  
Step Function ◽  
Muscarinic Acetylcholine Receptors ◽  
Cell Type ◽  
Function Type ◽  
Neuron Activation ◽  
Cell Type Specific ◽  
Arterial Responses

A variety of brain cells participates in neurovascular coupling by transmitting and modulating vasoactive signals. The present study aimed to probe cell type-dependent cerebrovascular (i.e., pial and penetrating arterial) responses with optogenetics in the cortex of anesthetized mice. Two lines of the transgenic mice expressing a step function type of light-gated cation channel (channelrhodopsine-2; ChR2) in either cortical neurons (muscarinic acetylcholine receptors) or astrocytes (Mlc1-positive) were used in the experiments. Photo-activation of ChR2-expressing astrocytes resulted in a widespread increase in cerebral blood flow (CBF), extending to the nonstimulated periphery. In contrast, photo-activation of ChR2-expressing neurons led to a relatively localized increase in CBF. The differences in the spatial extent of the CBF responses are potentially explained by differences in the involvement of the vascular compartments. In vivo imaging of the cerebrovascular responses revealed that ChR2-expressing astrocyte activation led to the dilation of both pial and penetrating arteries, whereas ChR2-expressing neuron activation predominantly caused dilation of the penetrating arterioles. Pharmacological studies showed that cell type-specific signaling mechanisms participate in the optogenetically induced cerebrovascular responses. In conclusion, pial and penetrating arterial vasodilation were differentially evoked by ChR2-expressing astrocytes and neurons.

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