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Genomic Mechanisms of BDNF Signaling in the Brain

Award Number: F32NS134623
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Genomic Mechanisms of BDNF Signaling in the Brain - PROJECT SUMMARY/ABSTRACT Sensory experience shapes the maturation of neural circuits during critical periods of development. How early- life experience modifies synaptic connectivity to refine sensory information processing remains a central question in neurobiology. Neurons respond to external sensory experience through the rapid, activity-dependent transcription of immediate early gene (IEG) transcription factors (TFs), such as Fos, Npas4, and Egr1. Once expressed, IEGs regulate a wave of late-response genes (LRGs) that mediate the influence of activity on synaptic remodeling in a cell type-specific manner. In particular, activity-dependent transcription of the neurotrophin Bdnf/BDNF within excitatory neurons establishes the critical period for ocular dominance plasticity in the visual cortex by promoting the formation of inhibitory synapses onto excitatory neuron cell bodies. However, specific mechanisms by which BDNF mediates this unique form of synaptic plasticity, known as somatic inhibition, remain poorly understood. Although BDNF influences gene transcription, whether BDNF regulates transcription within specific neuron types to direct inhibitory synapses onto neuronal soma is not yet known. This project seeks to identify and characterize the genomic mechanisms by which BDNF regulates somatic inhibition in the mouse visual cortex. Aim 1 of this proposal uses a transgenic mouse line that lacks activity-dependent Bdnf transcription to identify BDNF-regulated genes and gene regulatory elements during visual cortex development. The experiments in Aim 1 test the hypothesis that BDNF regulates the transcription of key synaptic organizer genes in a cell type-specific manner to drive the formation of somatic inhibitory synapses. Aim 2 of this proposal seeks to identify specific IEG TFs that mediate the effects of BDNF on transcriptional activation. Recently, I discovered that the neuron-specific IEG TF, Egr4/EGR4, preferentially responds to BDNF in primary cortical neurons and binds the NuA4/TIP60 histone acetyltransferase complex in vitro. In this aim, I will use immunoprecipitation mass spectrometry and CUT&RUN to determine the interaction partners and genomic binding sites of EGR4 in mouse visual cortex. Given that NuA4/TIP60 both activates transcription and repairs transcription-coupled DNA double- strand breaks (DSBs), I will further test the hypothesis that EGR4 mediates BDNF-dependent DSB repair. Collectively, the proposed studies will provide novel insights into how BDNF regulates the maturation of cortical circuits and, more broadly, how neurons achieve stimulus-specific transcriptional regulation and genomic maintenance. Improved understanding of these processes will inform the study of neurological disorders that display a loss of BDNF production, including Alzheimer’s and Huntingtin’s disease.


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: 2026 ( Subtotal = $70,050 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/19/2025	NON-COMPETING CONTINUATION	$68,920
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/1/2026	NON-COMPETING CONTINUATION	$1,130
														Subtotal = $70,050

Issue Date FY: 2025 ( Subtotal = $78,040 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2024	NON-COMPETING CONTINUATION	$76,756
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/22/2025	NON-COMPETING CONTINUATION	$1,284
														Subtotal = $78,040

Issue Date FY: 2024 ( Subtotal = $74,284 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/27/2023	NEW	$0
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/27/2023	NEW	$69,500
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/7/2024	NEW	$4,784
														Subtotal = $74,284

Grand Total All Awards = $222,374

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Genomic Mechanisms of BDNF Signaling in the Brain

Award Number: F32NS134623

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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