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BNST_AV ^GABA-PVN^CRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice.

ABSTRACT: Visceral hypersensitivity as a common clinical manifestation of irritable bowel syndrome (IBS) may contribute to the development of chronic visceral pain. Our prior studies authenticated that the activation of the corticotropin-releasing factor (CRF) neurons in paraventricular nucleus (PVN) contributed to visceral hypersensitivity in mice, but puzzles still remain with respect to the underlying hyperactivation of corticotropin-releasing factor neurons. Herein, we employed maternal separation (MS) to establish mouse model of visceral hypersensitivity. The neuronal circuits associated with nociceptive hypersensitivity involved paraventricular nucleus CRF neurons by means of techniques such as behavioral test, pharmacology, molecular biology, retrograde neuronal circuit tracers, electrophysiology, chemogenetics and optogenetics. MS could predispose the elevated firing frequency of CRF neurons in PVN in murine adulthood, which could be annulled via the injection of exogenous GABA (0.3mM, 0.2µl) into PVN. The PVN-projecting GABAergic neurons were mainly distributed in the anterior ventral (AV) region in the bed nucleus of stria terminalis (BNST), wherein the excitability of these GABAergic neurons was reduced. Casp3 virus was utilized to induce apoptosis of GABA neurons in BNST-AV region, resulting in the activation of CRF neurons in PVN and visceral hyperalgesia. In parallel, chemogenetic and optogenetic approaches to activate GABAergic BNST_AV-PVN circuit in MS mice abated the spontaneous firing frequency of PVN CRF neurons and prevented the development of visceral hypersensitivity. A priori, PVN^CRF-projecting GABAergic neurons in BNST-AV region participated in the occurrence of visceral hypersensitivity induced by MS. Our research may provide a new insight into the neural circuit mechanism of chronic visceral pain.

SUBMITTER: Huang ST

PROVIDER: S-EPMC8017215 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.Methods: We performed 18F-flortaucipir imaging in patients with the FTD syndromes (n?=?45): nonfluent variant primary progressive aphasia (nfvPPA) (n?=?11), corticobasal syndrome (CBS) (n?=?10), behavioral variant frontotemporal dementia (bvFTD) (n?=?10), semantic variant primary progressive aphasia (svPPA) (n?=?2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n?=?6), chromosome 9 open reading frame 72 (C9ORF72) (n?=?5), and progranulin (GRN) (n?=?1). All patients underwent MRI and ?-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 ?-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.Results: On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of ?-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions: 18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

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BNST_AV ^GABA-PVN^CRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice.

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BNSTAV GABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice.

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OmicsDI is part of the ELIXIR infrastructure

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BNST_AV ^GABA-PVN^CRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice.