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Mechanisms and Function of Firing Rate Homeostasis in Cortical Circuits

Award Number: R35NS111562
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: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Mechanisms and Function of Firing Rate Homeostasis in Cortical Circuits - The overall goal of my NS-supported research program is to understand the mechanisms that stabilize the function of central nervous system (CNS) microcircuits during experience- dependent plasticity and learning. Over the past ~20 years of NS support we discovered and characterized several forms of homeostatic plasticity, including synaptic scaling and intrinsic homeostatic plasticity, that are postulated to sense perturbations in mean neuronal activity, then bidirectionally adjust synaptic and cellular properties to keep activity within a set point range. Our recent work has focused on a) identifying the cellular and molecular mechanisms of these homeostatic forms of plasticity in order to bolster our mechanistic and functional understanding, and to generate tools that allow us to selectively block homeostatic plasticity in vivo; and b) to determine what aspect of neuronal activity is under homeostatic control in intact CNS circuits in vivo. We recently showed that the mean firing rates of neocortical pyramidal neurons in freely behaving animals return back to an individual baseline following prolonged perturbations to sensory drive, strongly supporting the idea that neocortical neurons homeostatically regulate their mean firing around an individual 'firing rate set point'. Such a process is theoretically important for preventing circuit hypo- or hyperexcitability during experience-dependent development, as well as to short-circuit the positive feedback nature of Hebbian plasticity rules that can degrade memory fidelity. We now have (or are developing) the tools to disrupt homeostatic plasticity and firing rate set points in vivo, allowing us to assess the impact of this disruption on network function and memory storage. The major goals of my NS- supported research program going forward are: 1) to determine how activity set points are built, and how individual neurons can have set points that are orders of magnitude different from each other; 2) to understand how multiple homeostatic mechanisms cooperate with each other to stabilize network activity in the face of profound perturbations; and 3) to test the role of synaptic scaling and intrinsic homeostatic plasticity in memory encoding and generalization. These studies will have important implications for our understanding of neurological disorders that arise from aberrant circuit excitability (epilepsy, autism-spectrum disorders). They may also provide a new avenue into understanding disorders such as PTSD that are likely to arise from excessive generalization during aversive learning.


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 = $1,056,987 )
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	5/23/2025	NON-COMPETING CONTINUATION	$1,056,987
2025	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,056,987

Issue Date FY: 2024 ( Subtotal = $1,083,356 )
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	8/12/2024	SUPPLEMENT FOR EXPANSION	$239,125
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/29/2024	NON-COMPETING CONTINUATION	$844,231
														Subtotal = $1,083,356

Issue Date FY: 2023 ( Subtotal = $922,675 )
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/19/2023	NON-COMPETING CONTINUATION	$817,737
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/26/2023	NON-COMPETING CONTINUATION	$0
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	8/23/2023	SUPPLEMENT FOR EXPANSION	$104,938
														Subtotal = $922,675

Issue Date FY: 2022 ( Subtotal = $817,737 )
2022	2022	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/6/2022	NON-COMPETING CONTINUATION	$817,737
														Subtotal = $817,737

Issue Date FY: 2021 ( Subtotal = $817,737 )
2021	2021	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/12/2021	NON-COMPETING CONTINUATION	$817,737
														Subtotal = $817,737

Issue Date FY: 2020 ( Subtotal = $817,737 )
2020	2020	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/15/2020	NON-COMPETING CONTINUATION	$817,737
														Subtotal = $817,737

Issue Date FY: 2019 ( Subtotal = $749,970 )
2019	2019	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/30/2019	NEW	$749,970
														Subtotal = $749,970

Grand Total All Awards = $6,266,199

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Mechanisms and Function of Firing Rate Homeostasis in Cortical Circuits

Award Number: R35NS111562

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: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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