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Metabolic hormones and their involvement in the positive and negative effects of maternal exercise and obesity on synaptic development

Award Number: R01HD111948
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Metabolic hormones and their involvement in the positive and negative effects of maternal exercise and obesity on synaptic development - PROJECT SUMMARY Mental health disorders are the leading cause of disability in the U.S., affecting approximately 1 in 5 people. While the causes are likely multifactorial, hippocampal glutamatergic synapse formation and number are strongly correlated with mental health outcomes. In utero environmental cues critically alter development of hippocampal synapses. Over 30% of people in the US are obese and maternal obesity now affects more than 1 million developing babies in the US annually. Children of obese mothers have a higher risk of anxiety, autism spectrum disorder (ASD) and reduced cognition. In contrast, maternal exercise (ME) is associated with increased cognition, emotional resilience, and reduced risk of ASD. The mechanisms underlying both the positive and negative effects of maternal metabolic state on development are largely unknown. Insulin is a key metabolic hormone that is upregulated with maternal obesity (MO); however, MO is associated with insulin resistance. Interestingly, insulin sensitivity is restored by exercise in both MO mothers and offspring. However, critically we do not know how MO, ME, and insulin affect hippocampal synapse formation. Our preliminary data show that insulin increases glutamatergic synapse formation through induction of a novel factor called apelin. Moreover, both insulin and apelin require FNDC5/irisin to promote the effects of BDNF on glutamate synapse formation. BDNF is a classic neurotrophic factor whose levels rise during development at a critical time for glutamatergic synaptogenesis. Disruptions in BDNF or its receptor, TrkB, in humans lead to impairments in both cognition and emotionality. Here, our preliminary data shows that maternal obesity leads to a decrease in hippocampal synapse formation in vivo. However, a critical gap in our knowledge is how maternal obesity causes this effect. In contrast, we have found that maternal exercise increases hippocampal synapse formation. Our collaborators showed that apelin is required for the beneficial effects of maternal exercise on metabolic function in their offspring. However, while we have found apelin increases synapse formation in vivo, it is not known if it is required to mediate the effects of exercise, or how this links to the effects of insulin. Our central hypothesis is that insulin increases synapse formation in the developing hippocampus through the actions of apelin and irisin to increase BDNF, and that this pathway is blunted by maternal obesity and increased by maternal exercise. We will test this with the following Specific Aims: 1. Determine if insulin’s neurotrophic actions are mediated by apelin, irisin and BDNF. 2. Determine if maternal obesity alters synaptic development by miss-regulating insulin, apelin, irisin and BDNF signaling. 3. Determine if maternal exercise stimulates synaptic development and plasticity via insulin and apelin regulating the expression of hippocampal BDNF. The rationale for the proposed research is that understanding how insulin, MO and ME impact BDNF and glutamatergic synapse development, will allow us to better predict the long-term consequences of different maternal environments and help direct behavioral and therapeutic strategies to alleviate cognitive and emotional disorders.


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 = $534,602 )
2026	2026	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	3	5/15/2026	NON-COMPETING CONTINUATION	$534,602
														Subtotal = $534,602

Issue Date FY: 2025 ( Subtotal = $537,296 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	2	4/29/2025	NON-COMPETING CONTINUATION	$537,296
														Subtotal = $537,296

Issue Date FY: 2024 ( Subtotal = $565,246 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	1	7/19/2024	NEW	$565,246
														Subtotal = $565,246

Grand Total All Awards = $1,637,144

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Metabolic hormones and their involvement in the positive and negative effects of maternal exercise and obesity on synaptic development

Award Number: R01HD111948

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/22/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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