Biology subjects

Griffin, E. W.

Publications and source records attributed to Griffin, E. W..

4 recordsLinked to original sources

bioRxiv2021

Cholinergic signalling in the forebrain controls microglial phenotype and responses to systemic inflammation

Abstract(250)Loss of basal forebrain cholinergic projections occurs in Alzheimers disease, frontotemporal dementia and in aging. Moreover, nicotinic stimulation is anti-inflammatory in macrophages and microglia but how loss of basal forebrain acetylcholine impacts on microglial phenotype is poorly understood. Here we hypothesized that endogenous ACh maintains homeostatic microglial phenotype and that neurodegeneration-evoked loss of ACh tone, triggers microglial activation. Using the specific immunotoxin, mu-p75NTR-saporin, we performed partial lesions of the basal forebrain cholinergic nuclei, medial septum and ventral diagonal band. We examined microglial phenotype in the hippocampus, the major projection area for these nuclei, using bulk RNA preparations, Flow cytometry-sorted microglial cells, immunohistochemistry and ELISA to examine responses to cholinergic withdrawal and acute responses to subsequent systemic inflammation with LPS. Basal forebrain cholinergic degeneration elicited lasting activation of microglia in the hippocampus, showing suppression of Sall1 and persistent elevation of Trem2, Clec7a, Itgax and complement genes proportionate to Chat loss. These primed microglia showed exaggerated IL-1{beta} responses to systemic LPS challenge. In normal animals LPS evoked acute increases in extracellular choline, a proxy for ACh release, and this response was lost in lesioned animals. Restoration of basal cholinergic signalling via serial treatments with the nicotinic agonist PNU282,987 resulted in reversion to the homeostatic microglial phenotype and prevented exaggerated responses to acute systemic inflammation. The data indicate that neurodegeneration-evoked loss of cholinergic tone, triggers microglial activation via impaired microglial nicotinic signalling and leaves these microglia more vulnerable to secondary inflammatory insults. The data have implications for neuroinflammation during aging and neurodegeneration and for responses to sepsis and systemic inflammation.

neuroscience↗

bioRxiv2021

Double stranded RNA drives innate immune responses, sickness behavior and cognitive impairment dependent on dsRNA length, IFNAR1 expression and age

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinsons disease and Alzheimers disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF responses than poly I:C of <500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFN{beta} nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFN{beta} binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1{beta} and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

neuroscience↗

bioRxiv2019

Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, that while adaptive for the organism, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here we used bacterial lipopolysaccharide (LPS) in C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 g/kg) induced hypoglycemia, which was mimicked by IL-1{beta} (25 g/kg) but not prevented in IL-1RI-/- mice, nor by IL-1RA (10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentration, was mitigated by exogenous glucose (2 g/kg) and was exacerbated by 2-deoxyglucose glycolytic inhibition, which prevented IL-1{beta} synthesis. Using the ME7 model of chronic neurodegeneration, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 g/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in cerebrospinal fluid (CSF) in humans during delirium, triggered by acute inflammatory trauma. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with altered brain energy metabolism. Collectively the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.

neuroscience↗

bioRxiv2017

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Acute episodes of delirium also contribute significantly to rates of long-term cognitive decline, implying that de novo pathology occurs during these acute episodes. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms has not been investigated. Here we show that systemic inflammation, induced by bacterial LPS, produces both working memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100g/kg) did not affect working memory but robustly impaired contextual fear conditioning (CFC). However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1{beta} replicated, these working memory deficits. Although LPS-induced deficits still occured in IL-1RI-/- mice, systemic TNF- was sufficient to induce similar deficits, indicating redundancy among these cytokines. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits despite failing to block brain IL-1{beta} synthesis. Direct application of IL-1{beta} to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/- dependent-fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1{beta} but dysfunction leading to neuronal death is mediated by hippocampal IL-1{beta}. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury that may lead to long-term cognitive impairment but that these events are mechanistically dissociable. This would have significant implications for management of cognitive dysfunction and decline during acute illness.

neuroscience↗