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Disruption of Pre-Bötzinger Complex neuropeptidergic tonality controls fear and metabolic response

ABSTRACT: Stress profoundly impacts systemic metabolism, yet the central circuits linking stress responses to peripheral metabolic regulation remain poorly defined. Here, we identify the preBötzinger complex (preBötC), a brainstem breathing rhythm generator, as a key stress-responsive hub coordinating metabolic adaptations. Using viral tracing, we show that preBötC neurons project to brown adipose tissue and liver, and that a subset of these projection neurons expresses the pituitary adenylate cyclase–activating polypeptide (PACAP) receptor PAC1R, positioning PACAP signaling as a critical modulator of this circuit. Whole-brain c-Fos mapping revealed robust preBötC activation under stress, while spatial transcriptomics demonstrated altered neuronal metabolic circuitry in preBötC following PAC1R ablation. PAC1R knockdown in preBötC combined with stress resulted in blunted respiratory rhythmicity, reduced sympathetic innervation, and suppression of energy expenditure and lipid metabolic pathways in brown fat, while reprogramming hepatic transcriptional networks toward amino acid metabolism and gluconeogenesis. These findings define a unique neuropeptidergic brainstem–periphery circuit integrating stress, respiration, and metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE307852 | GEO | 2025/09/16

REPOSITORIES: GEO

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Project description:We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c.v. one hour after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 hours later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice. A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at one hour post-MCAO (acute response transcripts), 142 were up-regulated only at 24 hours post-MCAO (delayed response transcripts) and 37 transcripts were up-regulated at both times (sustained response transcripts). More than 50% of these are transcripts not previously reported to be associated with brain ischemia responses. Many of the acutely regulated neurotrauma-associated transcripts, but a larger percentage of the delayed ones, require endogenous PACAP for up-regulation by ischemia, suggesting a more prominent role for PACAP in later response to injury than in the initial response, and consistent with a neuroprotective role for PACAP in late response to injury and neuroprotective efficacy when given post-MCAO. Putative injury effector transcripts regulated by PACAP include ãÑ-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these were transcripts encoding the PACAP-regulated gene Ier3, and the neuropeptides enkephalin, substance P (tachykinin 1), and neurotensin. Keywords: transcript identification design

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Disruption of Pre-Bötzinger Complex neuropeptidergic tonality controls fear and metabolic response

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