SEX-specific effects and the role of ovarian hormones in striatal-mediated food-seeking

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the Regents of the University of Michigan $230,388 on December 11, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to support research on sex-specific effects and the role of ovarian hormones in striatal-mediated food-seeking behavior.

The research examines how excitatory neurotransmission, particularly glutamate signaling through calcium-permeable AMPA receptors in the nucleus accumbens, is regulated by diet and ovarian hormones to influence cue-triggered food-seeking urges. The work uses selectively bred obesity-prone and obesity-resistant rats to investigate mechanisms underlying sex differences in feeding behavior and striatal function. The studies aim to provide insight into the neurobiological basis for the higher prevalence of severe obesity in women compared to men and how individual differences in susceptibility to weight gain correlate with enhanced Pavlovian motivation for food.

The work is performed at the University of Michigan in Ann Arbor, Michigan, with a period of performance through August 14, 2028. This is a Project Grant, an assistance type supporting investigator-initiated research.

Abstract

In the united states, women experience a significantly higher prevalence of severe obesity (BMI ≥40 KG/M2) than men. Among these women, individual differences in susceptibility to weight gain positively correlate with an underlying predisposition for enhanced pavlovian motivation for food. In addition, the magnitude of striatal activation to food cues positively correlates with subsequent weight gain. However, directly examining relationships between striatal function and propensity for weight gain in humans is difficult. To address this GAP, our laboratory uses selectively bred rats that are obesity-prone (OP) and obesity-resistant (or). The proposed studies will provide significant insight into how excitatory neurotransmission is regulated in response to diet and ovarian hormones to influence CUE-triggered urges to seek food. Glutamate is the primary excitatory neurotransmitter within the central nervous system (CNS) and exerts its actions through binding of ionotropic (i.e., nmda, ampa, kainate) and metabotropic (e.g., mglurs) receptors. Glutamate receptors within the striatum, and in particular the nucleus accumbens (NAC), are important for both natural reward processing and addiction. Thus, differences in excitatory neurotransmission within the NAC may contribute to a vulnerability for enhanced food-CUE motivation and propensity for weight gain. Furthermore, there is abundant and compelling evidence of SEX differences in both feeding behavior and NAC function. Work from our laboratory has demonstrated SEX differences in excitatory neurotransmission mediated by calcium-permeable ampa receptors (CP-ampars) within the NAC. Specifically, we have shown that NAC CP-ampars are upregulated by brief exposure to moderately fatty, junk-food (JF) diets in obesity-prone (OP) rats, and that the persistence of this effect differs in males and females. This plasticity is critical because NAC CP-ampars also underlie CUE- triggered food-seeking in OP males. However, very little is known about these behaviors and their underlying mechanisms in females, or how they may be influenced by ovarian hormones including estrogens. To address these gaps in knowledge, studies in this proposal will characterize pavlovian motivation across the cycle in OP and or females, as well as identify a potential role for NAC CP-ampars in CUE-induced food-seeking (aim 1). In addition, this proposal will directly examine the influence of estrogen on excitatory neurotransmission in the NAC (aim 2). This work will provide significant insight into the neurobiology food motivation and glutamatergic plasticity in females.