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Neural and pituitary mechanisms linking epilepsy to co-morbid reproductive endocrine dysfunction

Award Number: R01NS105825
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Both men and women with temporal lobe epilepsy (TLE), the most common partial epilepsy in adults, exhibit higher rates of reproductive endocrine disorders compared to the general population. Reproductive endocrine disorders significantly impact quality of life and, if untreated, can result in elevated risks for other central nervous system, metabolic, and cardiovascular disorders, and cancer. Seizures appear to be major drivers of reproductive endocrine co-morbidities, but the neural mechanisms underlying this relationship have not been described. In the proposed work, we will elucidate neural mechanisms that link epilepsy to reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons form the final common pathway in the brain's control of reproduction and thus likely play critical roles in the pathophysiology of epilepsy-associated reproductive endocrine disorders. Proper GnRH release patterns are necessary to drive pulsatile luteinizing hormone (LH) release from the pituitary gland in both males and females. Clinical studies have reported disrupted patterns of LH release in men and women with epilepsy, but the mechanistic underpinnings have yet to be elucidated. A major gap in knowledge thus exists about the effects of epilepsy on GnRH neurons, their synaptic afferents, and downstream impacts on pituitary function. Our overall objectives in the proposed studies are to determine key functional changes in hypothalamic-pituitary cells and circuits in a mouse model of TLE. We recently reported that female estrous cyclicity is disrupted in most epileptic female mice in this model, indicating that it is appropriate for these studies. Our central hypothesis is that seizure activity drives changes in the activity of GnRH neurons and their synaptic inputs, thereby impacting downstream pituitary LH release. We will test this hypothesis using an innovative combination of patch clamp electrophysiology, electroencephalography (EEG), optogenetics, pituitary gene expression analysis, and a cutting-edge ultrasensitive assay for determining mouse LH release patterns in vivo. In Aim 1 we will perform the first direct investigations of epilepsy-associated changes in GnRH neuron firing activity, intrinsic excitability, and fast synaptic inputs. In Aim 2 we will determine the functional relationships between hippocampal seizure activity, hypothalamic GnRH release, and pituitary response to GnRH. Successful completion of these Aims will have positive translational impact and further the goals of the NINDS Epilepsy Research Benchmarks by providing key mechanistic insights into the underlying neural and pituitary substrates of reproductive endocrine disorders that commonly arise with epilepsy.


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 = -$105 )
2025	2022	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/9/2024	NON-COMPETING CONTINUATION	-$105
														Subtotal = -$105

Issue Date FY: 2022 ( Subtotal = $329,319 )
2022	2022	UNIVERSITY OF ILLINOIS	352 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/10/2022	NON-COMPETING CONTINUATION	$296,387
2022	2022	UNIVERSITY OF ILLINOIS	352 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/8/2022	NON-COMPETING CONTINUATION	$32,932
														Subtotal = $329,319

Issue Date FY: 2021 ( Subtotal = $390,230 )
2021	2021	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/16/2021	NON-COMPETING CONTINUATION	$390,230
														Subtotal = $390,230

Issue Date FY: 2020 ( Subtotal = $390,590 )
2020	2020	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/16/2020	NON-COMPETING CONTINUATION	$390,590
														Subtotal = $390,590

Issue Date FY: 2019 ( Subtotal = $391,090 )
2019	2019	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/21/2019	NON-COMPETING CONTINUATION	$330,269
2019	2019	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/25/2019	SUPPLEMENT FOR EXPANSION	$60,821
														Subtotal = $391,090

Issue Date FY: 2018 ( Subtotal = $334,111 )
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/12/2018	NEW	$334,111
														Subtotal = $334,111

Grand Total All Awards = $1,835,235

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Neural and pituitary mechanisms linking epilepsy to co-morbid reproductive endocrine dysfunction

Award Number: R01NS105825

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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