HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease
NIA - National Institute on Aging
About This Grant
Project Summary/Abstract Olfaction frequently declines during aging and in neurological diseases including Alzheimer’s disease. Hyperpolarization- activated cyclic nucleotide-gated cation (HCN) channels (isoforms 1-4) generate the Ih conductance, playing controlling roles in neuronal excitability and rhythmic firing activity in individual and networks of neurons. HCN channel dysfunction is commonly observed in aging and almost all neurological diseases. This proposal uncovers a novel mechanism of olfactory bulb function and dysfunction in which there is aging/disease related decline in HCN channel regulation of excitatory neuron output from mitral/tufted cells (M/TCs) in olfactory bulb. Large Ih currents are present in external tufted cells (eTCs, a class of M/TCs), acting as a pacemaker current generating spontaneous intrinsic bursts, which drive long-last depolarizations and cluster firing of deeper output neurons. Our overarching hypothesis is downregulation of HCN channels during aging and Alzheimer’s disease disrupts output neuron firing leading to diminished performance on olfactory mediated behavioral tasks. Across four aims we will undertake a project spanning from the gene to cells, to circuits, and to behavior, linking HCN channel expression to olfactory bulb output neural activity, to olfactory performance in health and aged/disease. We will show that there is a significant and selective reduction in HCN4 channel expression and Ih conductance during aging and in an animal model that recapitulates some elements of familial Alzheimer’s disease (the 5xFAD mice, Aim 1). Furthermore, we will demonstrate that expression decline correlates with impaired Ih mediated activity of olfactory bulb output neurons in aging/disease and that pharmacological suppression of Ih in young mice recapitulates aspects of aging/disease olfactory network activity disruption (Aim 2). In Aim 3, we will show pharmacological manipulation of HCN channel function in the olfactory bulb causes diminished behavioral performance in young animals on olfactory mediated tasks, similar to aging/disease related performance decline. Finally, in Aim 4 we will manipulate HCN4 expression selectively in olfactory bulb output neurons (using a vGlut2-cre line of mice with viral knockdown construct) to show that downregulation of HCN4 in young olfactory bulbs ‘ages/diseases’ the network, causing output neuron activity and behavior to diminish to that of an aged/diseased olfactory bulb. Furthermore, we will show that olfactory decline in aging/disease can be ‘rescued’ by HCN4 upregulation selectively in olfactory bulb output neurons (vGlut2-cre line of mice with a viral overexpression construct). Upregulated HCN4 restores Ih currents, increases M/TC neural activity, and ameliorates olfactory behavior deficits. What we show in robust preliminary data is that pharmacological and genetic manipulation of olfactory bulb output neuron HCN4 expression can artificially ‘age’ younger animals or ‘rejuvenate’ an aged/diseased mouse to rescue performance. Taken together, these aims are a coordinated investigation of HCN channel function/dysfunction in the excitatory cell network of the olfactory bulb in adult, normal aging, and an animal model of neurodegenerative disease. The results of this study highlight new circuit mechanisms and potential therapeutic targets for mitigating olfactory deficits.
Grant Summary
HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease is a NIA - National Institute on Aging grant providing up to $650K for university, nonprofit, healthcare org. Applications are due 2031-01-31 (open). Check eligibility and apply with FindGrants.
Focus Areas
Eligibility
How to Apply
Up to $650K
2031-01-31
- 1Confirm your organization is eligible for HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease from NIA - National Institute on Aging, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NIA - National Institute on Aging before the deadline.
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HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease: Frequently Asked Questions
Who is eligible for the HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease?
HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease is offered by NIA - National Institute on Aging and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease provide?
HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease provides up to $650K per award from NIA - National Institute on Aging. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease deadline?
Applications for HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease are due 2031-01-31 (open). Because deadlines can change, verify the date with the funder, NIA - National Institute on Aging, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease?
To apply for HCN Channels Mediate Olfactory Dysfunction in Aging and Neurological Disease, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIA - National Institute on Aging.