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NRSA application: Characterizing acetylcholine, noradrenaline, and dopamine diffusion through the extracellular space in three subregions of macaque neocortex

Award Number: F32NS129585
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: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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NRSA application: Characterizing acetylcholine, noradrenaline, and dopamine diffusion through the extracellular space in three subregions of macaque neocortex - PROJECT SUMMARY Much work has been done to characterize the structural underpinnings of neuromodulatory systems and how these architectural features shape neuromodulator action. Yet, although, neuromodulators primarily signal through volume transmission which requires them to traverse the extracellular space (ECS) from release site to target receptor, neuromodulatory diffusion through the ECS has received little attention. We know from computational models that ECS diffusion is dependent on factors such as volume fraction, tissue tortuosity and ECS geometry. Simulations so far have mainly focused on synaptic diffusion and synaptic spillover mechanisms whereas neuromodulation functions at much larger spatiotemporal scales than that: even neuromodulator diffusion through just layer IV in macaque cortex, for example, requires molecules to travel distances up to 0.5 mm from release site to target receptor. Factors related to tissue porosity become increasingly more important at such distances but current computer models like the common simulation engine MCell are only equipped to study molecular diffusion at the nanometer scale. Consequently, we need updated computational models capable of simulating the diffusion of neuromodulators across greater spatial and temporal ranges capable of incorporating measures that become relevant at that macroscale. For this, I propose to develop a hybrid model which will achieve this critical functionality by combining existing MCell capabilities with large-scale algorithms from models of bulk diffusion. Because ECS diffusion is thought to vary with brain regions which to date has not been systematically evaluated, I will then, with this multiscale model, simulate diffusion of acetylcholine, noradrenaline, and dopamine across different regions of macaque cortex to test how factors such as tissue granularity or tissue anisotropy affect common diffusion metrics (e.g., concentrations, diffusion rates, effective diffusion coefficients, and diffusion tensor). Since neuromodulatory networks have been linked to virtually every brain function, understanding the dynamics of neuromodulator diffusion across the brain is an important step in understanding normal brain function. Furthermore, because changes in ECS dynamics and in neuromodulatory systems have been observed throughout development and normal aging or with neuropathology like stroke-related ischemia and dementia, identifying key parameters that determine signaling outcomes, but also the active processes by which they can be modified, may be key for the advancement in diagnostics and therapeutics.


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 = $87,964 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2024	NON-COMPETING CONTINUATION	$86,488
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/23/2025	NON-COMPETING CONTINUATION	$1,476
														Subtotal = $87,964

Issue Date FY: 2024 ( Subtotal = $86,488 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/9/2024	NON-COMPETING CONTINUATION	$5,684
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/10/2023	NON-COMPETING CONTINUATION	$80,804
														Subtotal = $86,488

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/1/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $76,246 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/28/2022	NEW	$76,246
														Subtotal = $76,246

Grand Total All Awards = $250,698

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NRSA application: Characterizing acetylcholine, noradrenaline, and dopamine diffusion through the extracellular space in three subregions of macaque neocortex

Award Number: F32NS129585

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: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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