Biology subjects

Walsh, A. E.

Publications and source records attributed to Walsh, A. E..

3 recordsLinked to original sources

bioRxiv2025

Peripheral Inflammation Limits Serotonin Neuron Signaling Capacity via Serotonergic IL-1R1 to Reduce Neuronal Excitability and Enhance Serotonin Clearance

Neurobehavioral disorders, ranging from depression to schizophrenia, have been found to display immune system alterations. The high incidence of comorbidity of these disorders, particularly depression, with chronic inflammatory conditions suggests shared mechanisms contributing to the manifestation of these conditions. We have previously shown that peripheral modulation of the innate immune system in mice rapidly triggers enhanced serotonin (5-HT) clearance in vivo associated with increased anxiety- and despair-like behaviors that can be suppressed by serotonergic elimination of p38 MAPK. Forebrain-projecting 5-HT synthesizing neurons of the dorsal raphe nucleus (DRN5-HT) play a key role in regulating behaviors related to mood and anxiety and whose perturbations are observed in multiple affective disorders. Here we identify molecular and circuit-level mechanisms that can translate peripheral innate immune system activation into changes in 5-HT signaling capacity. Using whole cell patch clamp recordings from acute midbrain slices, we demonstrate that the proinflammatory cytokine, IL-1{beta}, acts cell autonomously through its receptor, IL-1R1, via the p38 MAPK signaling pathway to rapidly inhibit firing of DRN5-HT neurons. In the dorsal hippocampus, we found that as with acute, peripheral lipopolysaccharide (LPS) administration, local injections of IL-1{beta} rapidly enhance 5-HT clearance as assessed by in vivo chronoamperometry. Like IL-1{beta}, TNF also acts via a serotonergic p38 MAPK dependent pathway to reduce excitability of DRN5-HT neurons. Immunocytochemical studies reveal that, IL-1R1, is nonuniformly expressed by DRN5-HT neurons and is required for LPS-induced inhibition of these cells as detected by cFos activation, with sex-dependent patterns evident. Moreover, we detected both DRN5-HT IL-1R1-dependent and -independent LPS-mediated changes in cFos changes in forbrain projection areas. Our findings support a growing appreciation that serotoninergic neurons contribute to changes in CNS physiology and behavior following peripheral immune activation. More specifically, our studies attest to a functional role of serotonergic IL-1R1 in mediating IL-1{beta} following peripheral innate immune activation, effects likely to arise both from changes in diminished 5-HT neuron excitability and elevated 5-HT clearance.

neuroscience↗

bioRxiv2023

ApoE4 drives maladaptive heterogeneity and immunometabolic responses of astrocytes

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimers disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

neuroscience↗

bioRxiv2022

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response - two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1 expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

neuroscience↗