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Neuroinflammatory and cognitive consequences of losing cholinergic anti-inflammatory tone in the forebrain

Award Number: R01AG050626
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Neuroinflammatory and cognitive consequences of losing cholinergic anti-inflammatory tone in the forebrain - Project Summary (complete rewrite) Acute cognitive dysfunction (including delirium) is a highly prevalent neuropsychiatric complication of systemic inflammation in the elderly and, in particular, in those with dementia. As well as extending hospital stays, acute systemic inflammatory episodes also increase the risk for subsequent dementia and accelerate existing dementia. Despite these economic and public health imperatives, the pathophysiological mechanisms of systemic inflammation- induced acute cognitive dysfunction and lasting brain injury are poorly understood. We have previously demonstrated that systemic inflammation, when superimposed on existing neurodegenerative pathology, produces acute, fluctuating and reversible impairments in cognitive domains relevant to delirium (Davis et al., 2015) and accelerates the trajectory of long-term decline (Cunningham et al, 2009). Acetylcholine (ACh) is a neuromodulator with important roles in attention and cognitive function and the cholinergic neurons of the basal forebrain degenerate significantly in Alzheimer's disease. We have recently demonstrated that existing neurodegeneration in the basal forebrain cholinergic system leads to more severe acute cognitive dysfunction after systemic administration of bacterial endotoxin (LPS; Field et al., 2012). Macrophage lineage cells can also be modulated by ACh and here we highlight that loss of cholinergic forebrain ennervation leads to a priming of the forebrain microglial population to show exaggerated IL-1β responses to subsequent inflammatory stimulation. We propose that this cholinergic and consequent inflammatory predisposition significantly impacts on the short-term cognitive/neurophysiological, and long-term cognitive and neuropathological, outcomes of systemic inflammation. We will address this hypothesis directly by administering LPS or poly-microbial sepsis (cecal ligation and puncture; CLP) to mice with immunotargeted degeneration of the basal forebrain cholinergic system. In AIM1 we will demonstrate exaggered microglia, astroglial and neuronal responses to systemic inflammation and probe the role of nicotinic receptors in these effects. In AIM 2 we will use both LPS and CLP coupled with unique real-time in vivo brain monitoring of acetylcholine and of key determinants of neuronal function: oxygen, glucose, lactate, time-synced to behavioral testing to interrogate the neurophysiological underpinning of acute cognitive changes and the mechanisms of brain injury leading to long-term cognitive impairment. In AIM3 we will examine differential effects (on hypocholinergic versus normal mice) of some pharmacological interventions typical of the acute medical setting. Together we believe that these studies will significantly contribute to our understanding of acute cognitive dysfunction occurring during systemic inflammation and the exacerbation of ongoing cognitive decline relevant to aging and dementia.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$12,993 )
2025	2020	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN				IRL	Aging Research	000	5	10/1/2024	NON-COMPETING CONTINUATION	-$12,993
														Subtotal = -$12,993

Issue Date FY: 2024 ( Subtotal = -$756 )
2024	2020	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN				IRL	Aging Research	000	5	1/10/2024	NON-COMPETING CONTINUATION	-$756
														Subtotal = -$756

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN	CO DUBLIN			IRL	Aging Research	000	5	3/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $153,231 )
2020	2020	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN		2		IRL	Aging Research	000	5	5/20/2020	NON-COMPETING CONTINUATION	$153,231
														Subtotal = $153,231

Issue Date FY: 2019 ( Subtotal = $247,166 )
2019	2019	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN		2		IRL	Aging Research	000	4	5/23/2019	NON-COMPETING CONTINUATION	$247,166
														Subtotal = $247,166

Issue Date FY: 2018 ( Subtotal = $254,171 )
2018	2018	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN		2		IRL	Aging Research	000	3	5/21/2018	NON-COMPETING CONTINUATION	$254,171
														Subtotal = $254,171

Issue Date FY: 2017 ( Subtotal = $249,958 )
2017	2017	TRINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN		2		IRL	Aging Research	000	2	6/22/2017	NON-COMPETING CONTINUATION	$249,958
														Subtotal = $249,958

Issue Date FY: 2016 ( Subtotal = $275,284 )
2016	2016	RINITY COLLEGE DUBLIN	COLLEGE GREEN	DUBLIN				IRL	Aging Research	000	1	9/2/2016	NEW	$275,284
														Subtotal = $275,284

Grand Total All Awards = $1,166,061

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Neuroinflammatory and cognitive consequences of losing cholinergic anti-inflammatory tone in the forebrain

Award Number: R01AG050626

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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