Impulsivity, acting without appropriate forethought and/or choosing small, immediate rewards over a larger, delayed reward, is a component of numerous mental health disorders, including attention-deficit hyperactivity disorder, substance abuse, and bipolar and antisocial personality disorders. Additionally, impulsivity increases the likelihood of making poor health choices, and has been linked to both smoking [1] and obesity [2], which are leading causes of mortality in the US [3]. These are preventable deaths, which could be reduced by changing behavior. Given the broad negative impact of impulsive behavior, a better understanding of the underlying molecular mechanisms is critical. There is currently a need for better animal models in which to study the neural circuitry that drives impulsive behavior. Current animal models to study impulsivity primarily involve the study of natural genetic variation (e.g. high versus low impulsivity in behavioral tasks), as well as a handful of (mono)genic mutations. Neurobiological information has been gained through the use of lesion studies, bearing in mind the associated limitations of this approach, as well as through the study of drugs which induce impulsive behavior. Because the etiologies of impulsivity are likely diverse, work in animal models that test the importance of specific environmental antecedents is needed. We propose that offspring born to dams fed a high fat diet during pregnancy represent a novel animal model in which to study the neurobiology of impulsivity in a model that has construct and face validity. Excessive gestational weight gain and maternal obesity, which affect over half of US pregnancies, significantly increase the risk for a baby to be large for gestational age (LGA). In our model, dams are fed a high fat (HF) diet during pregnancy and lactation, and the offspring are born LGA. These LGA offspring display an increase in impulsivity. Gene expression profiling of the prefrontal cortex reveals a relationship between impulsivity and changes in the and ?- opioid receptors (MOR and DOR). LGA animals have an increase in microglial activation within the PFC, which may contribute to executive function deficits like impulsivity. The goal of the present proposal is to test specific molecular mediators driving impulsivity in LGA mice. The overarching strategy is to use sophisticated operant behavioral testing to examine the role of opioids and microglial activation in a novel model of impulsivity (LGA mice). These two mediators are interconnected and experiments will test not only direct effects on impulsivity, but interactions between the mediators as well. In both aims, two behavioral tasks, the 5 choice serial reaction time task (5CSRTT) and delay discounting (DD), will be used to determine impulsive action and impulsive choice, respectively.
Impulsivity is a component of many mental health disorders, and contributes to poor health-related behaviors (e.g., smoking, drug use, overeating). Maternal consumption of a high fat diet can affect the development of the infant brain, and increase the risk for neurobehavioral disabilities, such as increased impulsivity. Experiments in this application will use an animal model to examine the mechanisms that increase impulsivity.
| McKee, Sarah E; Zhang, Sisi; Chen, Li et al. (2018) Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain. J Neurochem 145:362-373 |
| Lloyd, Kelsey R; Yaghoubi, Sarah K; Makinson, Ryan A et al. (2018) Housing and testing in mixed-sex rooms increases motivation and accuracy during operant testing in both male and female mice. Neurobiol Learn Mem 150:20-24 |
| Smith, B L; Reyes, T M (2017) Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders. Front Neuroendocrinol 47:109-122 |
