Prefrontal D2- dopamine receptor deactivates top-down inhibitory control by regulating striatal cholinergic interneurons
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ABSTRACT:
PROVIDER: PRJNA983850 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24922018.fastq.gz | Fastqsanger.gz | |||
| SRR24922018_1.fastq.gz | Fastqsanger.gz | |||
| SRR24922018_2.fastq.gz | Fastqsanger.gz | |||
| SRR24922019.fastq.gz | Fastqsanger.gz | |||
| SRR24922019_1.fastq.gz | Fastqsanger.gz |
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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:Chronic stress is a major triggering factor for neuropsychiatric disorders including obsessive-compulsive disorder (OCD), a mental health condition characterized by motor stereotypies and striatal overactivation. However, the mechanisms at the cell- and microcircuit-level through which stress triggers motor symptoms is currently unknown. Here, we report that chronic stress (CS) in mice alters dorsomedial striatum (DMS) function, by affecting GABAergic interneuron populations and somatostatin-positive (SOM) interneurons in particular. Specifically, we show that CS impairs communication between SOM interneurons and medium spiny neurons, promoting striatal overactivation / disinhibition and increased motor output. Using probabilistic machine learning for analyzing animal behavior we further demonstrate that in vivo chemogenetic manipulation of SOM interneurons in DMS modulates motor phenotypes in stressed mice. Altogether, we propose a causal link between dysfunction of striatal SOM interneurons and motor symptoms in stress-related neuropsychiatric disorders.
2022-12-13 | PXD031193 | Pride
Project description:BackgroundDYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.Methods and resultsWe characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-?-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.ConclusionsThese results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.
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Project description:Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons. However, broader taxonomic and developmental characterization is required to address novelty in cell type evolution. Here, we examine gene expression in inhibitory neurons across 11 mammalian species, spanning 160 million years divergence from primates. We find that the initial class of newborn TAC3 interneurons specified during development represents an ancestral, MGE-derived striatal population also present in pig and ferret cortex. This discovery prompted a reexamination of the Glire clade, including mice which are thought to lack the TAC3 type. Targeted enrichment of MGE precursors in mice reveals conservation of the TAC3 initial class, camouflaged by reduced expression of Tac2 (the mouse ortholog of TAC3) and a gain of Th expression. Extending our analysis to the adult striatum further supports the homology of primate TAC3 and mouse Th striatal interneurons, while uncovering a rare Tac2 subpopulation in mouse ventromedial striatum. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.
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Project description:Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D2 dopamine receptor modulation of Na+ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D2 receptor activation led to a reduction in Na+ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na+ channels into the slow-inactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.
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Project description:Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.
2023-01-12 | GSE222383 | GEO
Project description:Conservation and alteration of mammalian striatal interneurons
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Project description:Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.
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Project description:The dopamine D1R is Gs coupled GPCR which is expressed in striatal neurons and stimulates gene expression upon activation by dopamine or other agonists. In this work we investigated the role of the BET protein bromodomain containing protein 4 (Brd4) in mediating D1R-dependent gene expression in rat striatal neurons. Here we report the results of 3 RNA sequencing experiments. In Experiment 1 we treated primary striatal neurons with the D1R-selective agonist SKF-81297 alone or in combination with the non-selective BET inhibitor JQ1 for 60 minutes to assess the effect of BET inhibition on acute D1R-dependent gene expression. In Experiment 2, we treated primary striatal neurons with the D1R-selective agonist SKF-81297 alone or in combination with the BET bromodomain 2 selective inhibitor iBD2 for 60 minutes to determine the contribution of BD2 specifically to D1R-dependent gene expression. In Experiment 3 we treated primary striatal neurons with the D1R-selective agonist SKF-81297 alone or in combination with the non-selective BET inhibitor JQ1 for 24 hours to assess the effect of prolonged BET inhibition on basal gene expression and D1R-dependent gene expression.
2021-07-05 | GSE179370 | GEO
Project description:The widely held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre-dependent channelrhodopsin-2 (ChR2) the PfN of Vglut2-Cre mice that were dopamine-depleted with 6-hydroxydopamine (6-OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6-OHDA-treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6-OHDA lesions failed to affect short-term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA-to-AMPA ratios at PfN synapses-that were significantly larger than NMDA-to-AMPA ratios at cortical synapses-were reduced by 6-OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short-term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de-potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.
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