Prefrontal cortex glutamatergic neurons as a target for metabolic and cognitive symptoms in a mouse model of PWS (Year 2)

Funding Summary

Dr. Ross has been investigating a particular region of the brain (medial prefrontal cortex) and class of neurons in PWS mice, to understand their link to cognitive and metabolic changes in PWS. They will determine whether stimulating these neural circuits in the brains of PWS mice reduces food intake and improves learning, potentially identifying a subset of cells that need to be targeted for therapeutics. 

Lay Abstract

Prader–Willi Syndrome (PWS) is a genetic disorder characterized by insatiable appetite which, if left unchecked, can lead to morbid obesity later in childhood. Individuals with PWS also exhibit other challenging behavioral features, including impulsivity, compulsive behavior, and impaired social cognition. However, the neural mechanisms underlying this complex behavioral phenotype in PWS, which rely on development of intact cognitive function and persist into adulthood, are not well understood. Using behavioral neuroscience methods, we recently discovered that the Magel2 mouse model for PWS displays learning deficits related to cue-associated feeding, and unexpectedly impaired motivation in the context of chronic hunger. In a recent paper we showed that a specific population of neurons in the medial prefrontal cortex (mPFC), a region responsible for cognitive function regulation, receives satiety signals from hypothalamic neurons involved in feeding behavior and metabolism. When we inhibit this broad population of mPFC neurons, we see cognitive function impairments. This suggests that the region is an important integrator of hunger signals and cognitive function in mice, which we aim to investigate further in the Magel2 mouse model. 
In this proposal we will use cutting-edge techniques to further molecularly define the identity of the relevant neurons within this region, testing specifically for receptors to pharmacologic agents that show promise in clinical trials for PWS, such as oxytocin and melanin-concentrating hormone.  We will use genetically modified mouse models and a combination of innovative approaches, including chemogenetics (drug-assisted remote stimulation), fiber photometry (neural population activity monitoring) and in situ hybridization (a method to quantify RNA expression) to test the hypothesis that molecularly-defined subset of metabolic-signal responsive neurons in the mPFC are involved in cognitive function related to food intake, such as cue-associated feeding and food-related impulsivity. We hypothesize that maladaptive behaviors that result from impaired cortical response to appetite-suppression signals can be reversed by stimulating a specific population of neurons in the medial prefrontal cortex. 
Completing the work of this proposal will allow us to identify the impaired brain systems linking the hypothalamus to the mPFC that may explain why individuals with PWS response to satiety signals is compromised, and why hyperphagia and maladaptive behavior are seen together in PWS. The next steps forward for this project will be to target the newly defined subpopulation of medial prefrontal cortex neurons in the Magel2 mouse model. This will suggest novel druggable targets for the development of therapeutic approaches or interventions to treat insatiable appetite and maladaptive cognitive function for individuals with PWS.