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Mapping genomic mechanisms underlying BDNF signaling in the visual cortex

Award Number: F31MH146015
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/05/2027
PERIOD OF PERFORMANCE END DATE: 02/04/2028

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Mapping genomic mechanisms underlying BDNF signaling in the visual cortex - Project Summary/Abstract Sensory experience shapes the maturation and stabilization of neural circuits during development and throughout life. How experience modifies synaptic connectivity to refine sensory information processing remains a central question in neurobiology. The neurotrophin Bdnf/BDNF is a secreted factor required for proper development of the nervous system, including the maturation of sensory cortical circuits like the primary visual cortex (V1) and cellular survival into adulthood. Experience-dependent expression and release of BDNF from excitatory neurons is a crucial step in establishing the visual critical period of circuit refinement by promoting the formation of inhibitory synapses onto excitatory neuron cell bodies, known as perisomatic inhibition, thereby enabling circuit plasticity needed for lifelong cognition. However, the gene regulatory mechanisms by which BDNF mediates this form of synaptic plasticity, along with its other roles as a neuroprotective agent, remain unknown. This project seeks to identify and characterize these mechanisms by focusing on the initial immediate- early gene (IEG) transcription factors (TFs) triggered by BDNF signaling and the resulting late-response gene (LRG) programs activated across cell types to mediate perisomatic inhibition in the mouse visual cortex. Aim 1 of this proposal seeks to characterize the initial wave of chromatin remodeling and TFs rapidly induced by BDNF signaling in the brain. My preliminary studies show BDNF rapidly induces the poorly characterized TF, EGR4, which can recruit the NuA4/TIP60 histone acetyltransferase complex to chromatin in vitro. I will validate this interaction and identify genomic binding sites of EGR4 following visual stimulation in vivo. Given the role of the NuA4/TIP60 complex in activating transcription and repairing transcription-induced DNA double-stranded breaks (DSBs), I will test the hypothesis that BDNF signaling recruits the EGR4-NuA4/TIP60 complex to chromatin after sensory experience in V1 to activate gene expression and repair DNA damage. Aim 2 of this proposal seeks to identify the BDNF-dependent downstream LRG programs promoting perisomatic inhibition. My preliminary work has discovered a small set of BDNF-dependent genes induced by light in either excitatory or inhibitory neurons in the visual cortex with strong potential to mediate synaptogenesis. In this aim, I will profile whether sparse knock-down of these genes blocks experience-dependent perisomatic recruitment. I will test the hypothesis that BDNF signaling mediates transcriptional programs in both excitatory and inhibitory neurons, ultimately promoting the recruitment of perisomatic synapses between them. Collectively, the proposed studies will provide novel insights into how BDNF regulates genomic mechanisms underlying the maturation, plasticity, and survival of neural circuits. Since neurodegenerative diseases like Alzheimer’s and Huntingtin’s disease involve diminished BDNF levels and evidence suggests the accumulation of DNA damage like DSBs may contribute to disease pathology, this project may uncover a role of BDNF in promoting neuroprotection by maintaining genome integrity through lifelong DNA damage repair.


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 = $38,280 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	8/6/2026	NEW	$38,280
														Subtotal = $38,280

Grand Total All Awards = $38,280

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Mapping genomic mechanisms underlying BDNF signaling in the visual cortex

Award Number: F31MH146015

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/05/2027

PERIOD OF PERFORMANCE END DATE: 02/04/2028

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