CRISPR/Cas9 mediated intersectional knockout of GSK3b in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139564 | GEO | 2020/08/14
REPOSITORIES: GEO
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Project description:CRISPR/Cas9 mediated intersectional knockout of GSK3b in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation
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Project description:The heterogeneity of cortical dopamine D2 receptor expressing cells is not well characterized We performed microarrays to study expression of all the transcriprts specifically from Drd2+ neurons of mouse mPFC. For this we immunoprecipitated ribosomes from mPFC of D2Cre::RiboTag mouse, where ribosomal subunit Rpl22 is tagged with HA epitope specifically in Drd2+ neurons
2018-06-16 | GSE115887 | GEO
Project description:Glycogen synthase kinase 3β (GSK3β) activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor-dependent manner. However, GSK3β is ubiquitously expressed in the brain, and D2 receptor-expressing cells are distributed as a mosaic in multiple cortical regions. This complicates the interrogation of GSK3β functions in cortical D2 cells in a circuit-defined manner using conventional animal models. We used a CRISPR-Cas9-mediated intersectional approach to achieve targeted deletion of GSK3β in D2-expressing neurons of the adult medial prefrontal cortex (mPFC). Isolation and analysis of ribosome-associated RNA specifically from mPFC D2 neurons lacking GSK3β demonstrated large-scale translatome alterations. Deletion of GSK3β in mPFC D2 neurons revealed its contribution to anxiety-related, cognitive, and social behaviors. Our results underscore the viability of an intersectional knockout approach to study functions of a ubiquitous gene in a network-defined fashion while uncovering the contribution of GSK3β expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3β action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics.
| S-EPMC7307679 | biostudies-literature
Project description:Inhibitory control is a core cognitive function preventing the expression of maladaptive behaviors. This function is overridden in mental illnesses including bipolar disorder, autism spectrum disorders and schizophrenia, causing maladaptive psychomotor agitation. We developed intersectional CRISPR/Cas9 targeting approaches in adult mice to identify receptor/circuit selective mechanisms responsible for inactivation of inhibitory control in two models of amphetamine-induced psychomotor agitation. Inactivation of dopamine D2-receptors in the medial-prefrontal cortex (mPFC) abolished amphetamine-induced: psychomotor agitation, motor sensitization, and cAMP-associated transcriptome changes in the striatum. Further characterization using intersectional projection preparations indicate that these deficits implicate D2-receptors expressed on projection neurons innervating cholinergic interneurons of the dorsomedial striatum (DMS). Trans-synaptic targeting of acetylcholine production in DMS neurons receiving these projections restored psychomotor agitation in mice lacking mPFC D2- receptor expression. These findings identify a circuit by which activation of cortical D2-receptor circumvent an acetylcholine-mediated inhibition of DMS functions by the mPFC to promote psychomotor activation.
2023-06-17 | GSE234994 | GEO
Project description:Pseudoalteromonas tunicata D2 strain:D2 Genome sequencing
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Project description:Projection-dependent ribosome profling from mouse mPFC. Ribosome from NAC- and VTA- projecting mPFC cells were immunoprecipited using GFP-trap (Chromotech). Translating mRNA was isolated and analyzed
2017-09-15 | GSE101185 | GEO
Project description:Chronic pain is a major health care problem with great social and economic consequences. Although the medial prefrontal cortex (mPFC) and the thalamus have been implicated in regulating pain, whether and how these regions may involve in pain chronification process have remained largely unknown. Here, we show that Foxp2+ neurons in mPFC, which are corticothalamic (CT) neurons representing the major mPFC output to thalamus, are deactivated in chronic inflammatory pain. Interestingly, prolonged, but not short-term, inactivation of the Foxp2+ neurons in mPFC increases the sensitivity to noxious stimulations. Conversely, chemogenetic activation of this neuronal cluster induces robust antinociceptive effects in both naïve mice and mice with chronic inflammatory pain. Furthermore, we found that the mPFC Foxp2+ neurons project to several thalamic relay nuclei and that activation of the mPFC to the parataenial nucleus of thalamus (PTN) circuit relieves pain. Finally, RNA-seq of the mPFC Foxp2+ neurons revealed that many genes related to neuronal activity are dysregulated in mice with chronic inflammatory pain. Collectively, our studies revealed that Foxp2+ neurons in mPFC that project to thalamus play a critical role in somatosensory processing and pain chronification.
2023-09-16 | GSE243136 | GEO
Project description:Arthrobacter sp. D2 strain:D2 Genome sequencing and assembly
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Project description:Background: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena. Methods: Spontaneous recovery and fear renewal tests, assessed persistence and context-independence of treatments rescuing deficient fear extinction in 129S1/SvImJ mice. To reveal neurobiological mechanisms supporting long-lasting extinction rescue, whole-genome expression profiling, qRT-PCR, immunohistochemistry and chromatin immunoprecipitation were used. Results: Persistent and context-independent rescue of deficient fear extinction induced by dietary zinc-restriction was associated with enhanced expression of dopamine-related genes, such as genes encoding the dopamine- D1 (Drd1a) and -D2 (Drd2) receptor in the medial prefrontal cortex (mPFC) and amygdala. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a possibly involved gene regulatory mechanism. While enhancing histone acetylation, via administering the HDAC inhibitor MS275, does not induce successful fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated. This was associated with enhanced neuronal histone acetylation in the mPFC and amygdala. Finally, as a proof of principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. Conclusion: Current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear inhibitory memory.
2016-12-21 | GSE76103 | GEO
Project description:Kocuria rhizophila strain:D2 | isolate:D2 Genome sequencing and assembly
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