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Cross-neuronal Structural Plasticity in Drosophila Motor Circuits

Award Number: R01NS142268
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Cross-neuronal Structural Plasticity in Drosophila Motor Circuits - Project Summary Damage to the nervous system results in the death of many neurons, leading to adverse outcomes such as locomotor and cognitive defects. Neural injuries may induce neuroplasticity responses in surviving neurons, where they extend their axons and dendrites and form new connections (undergo rewiring) to cope with the loss of their neighboring neurons. Neural circuits are composed of different neuronal types, each with unique intrinsic properties such as neural firing patterns, neurotransmitter identity, and synapses of different types and sizes. Whether different neuron and synapse types are equally capable of undergoing structural plasticity remains unclear. Furthermore, the role of non-neuronal cells (such as glia and muscles), intercellular signaling pathways, and cross-talk between neurons, glia, and muscles during the plasticity response are still under investigation. Addressing these knowledge gaps will help optimize therapeutic strategies, thereby maximizing the chance of the restoration of circuit function after neural injury. The objective of this proposal is to address these problems using the motor circuits underlying locomotion in Drosophila larvae. Two types of motor neurons (MNs) form neuromuscular junctions (NMJs) with larval body wall muscles: tonic-firing MNs with large NMJs and phasic firing MNs with small NMJs. These MNs receive input from excitatory and inhibitory premotor neurons (PMNs). In addition, different subtypes of glial cells in Drosophila are functionally and morphologically comparable to those found in vertebrates. The rich genetic toolkits in larvae provide an unprecedented opportunity to determine how PMN-MN-muscle circuits rewire in response to the death (or inactivation) of PMN and MN subsets and determine the role of glial and denervated muscles in mediating proper circuit rewiring. For the first time, strong preliminary data provided in this proposal demonstrate that in response to the death of MN subsets, the motor axon of a single surviving MN extensively sprouts and forms new NMJs on denervated muscles, recovering their contractility. Expanding on this experimental setup, Aim-1 will test the hypothesis that tonic-firing MNs and excitatory PMNs are more potent than phasic MNs and inhibitory PMNs to rewire and form new synapses upon loss of their neighboring neurons. Aim-2 will determine whether debris clearance and path formation by glial cells are prerequisites for sprouting and rewiring of PMN-MN-muscle circuits that survive post-injury. In parallel, Aim-2 will experimentally test a model based on which glial cells and denervated muscles release neurotrophic factors that instruct surviving MNs to form new synapses (i.e., new PMN-MN and MN-muscle connections) in proper locations. It is expected that this research will provide a deeper understanding of motor circuit recovery mechanisms mediated by synaptic plasticity that are conserved in mammals, and generate hypotheses to be tested in vertebrate locomotion.


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 = $500,307 )
2026	2026	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/26/2026	NEW	$500,307
														Subtotal = $500,307

Grand Total All Awards = $500,307

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Cross-neuronal Structural Plasticity in Drosophila Motor Circuits

Award Number: R01NS142268

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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