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Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment

Award Number: F30AG082448
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/03/2023
PERIOD OF PERFORMANCE END DATE: 05/02/2028

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Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment - PROJECT ABSTRACT Chemotherapy-induced cognitive impairment (CICI) is a condition commonly reported in cancer patients, where learning, memory, attention, and executive functions are impaired following cancer chemotherapy treatment. To date, the most common genetic risk factor associated with CICI is the APOE4 gene, which is also the strongest genetic risk factor for Alzheimer’s Disease. Little is known about how APOE4 affects excitatory and inhibitory neurons in the entorhinal cortex (a region of the brain critical for information gating between the cerebral cortex and the hippocampus) and how those differences may make APOE4 neurons more susceptible to environmental stress. Using our novel mouse model of CICI that combines the effects of a chemotherapeutic challenge (doxorubicin) and genetic susceptibility (APOE4 genotype), I hypothesize that APOE4-TR mice have a deficit in inhibitory neuron function which prevents them from responding to chemotherapy in a protective manner. I will test two specific hypotheses in this proposal: 1) APOE4-TR mice are vulnerable to the effects of chemotherapy due to an inability to preserve parvalbumin interneuron dendritic complexity in the entorhinal cortex, leading to synaptic excitation-inhibition (E/I) imbalance and 2) apoE isoform levels drive the difference in circuit dysfunction in APOE4-TR mice treated with chemotherapy. The following aims will investigate how APOE genotype and chemotherapy affect entorhinal cortex circuitry: Aim 1: Examine mechanisms underlying entorhinal cortex circuit dysfunction in CICI. I will use a combination of electrophysiology, confocal microscopy, and transgenic mice to measure changes in E/I balance and interrogate underlying causes of E/I dysregulation in the presence and absence of chemotherapy. Aim 2: Test whether increasing apoE levels protects against entorhinal cortex circuit dysfunction in CICI. I will use an AAV construct to introduce astrocytic-apoE3 into APOE3 and APOE4 mice treated with chemotherapy. Changes to E/I balance will be measured to assess if apoE levels minimize vulnerability to CICI. These aims will collectively identify circuit-based mechanisms underlying CICI. Outcomes of this proposal can provide clinical guidance on 1) identifying at-risk patients prior to chemotherapy treatment and 2) reducing the likelihood of CICI by altering apoE levels.


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 = $65,038 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	002	3	6/23/2025	NON-COMPETING CONTINUATION	$564
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	001	3	5/16/2025	SUPPLEMENT FOR EXPANSION	$10,500
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	3	4/18/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $65,038

Issue Date FY: 2024 ( Subtotal = $36,274 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	2	5/13/2024	NON-COMPETING CONTINUATION	$36,274
														Subtotal = $36,274

Issue Date FY: 2023 ( Subtotal = $34,994 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	001	1	5/3/2023	NEW	$0
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	1	5/3/2023	NEW	$34,994
														Subtotal = $34,994

Grand Total All Awards = $136,306

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Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment

Award Number: F30AG082448

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/03/2023

PERIOD OF PERFORMANCE END DATE: 05/02/2028

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