Investigating The Neural Mechanisms of Motivational Responses to Food Cues in Female Rats

Abstract

Obesity is a complex and multifactorial disease in which an individual’s genetic background can interact with environmental factors in ways that promote unhealthy feeding behaviors. The nutrients found in the food that we consume, as well as the amount of food consumed are important for healthy energy balance and proper development of the body. Importantly, overconsumption of sugary-fatty diets can lead to neuroadaptations that promote weight gain, although knowledge in this area is still developing.

The mesocorticolimbic system regulates the appetitive and consummatory aspects of feeding. Activity in this network in anticipation of food is enhanced in obese compared to lean people. Specifically, overweight and obese individuals have greater activation in these brain areas in response to the smells or sights of food. Interestingly, in women, neural activations in response to these cues, and cue-triggered food cravings fluctuate across the menstrual cycle. However, few preclinical studies have examined pre-existing differences in motivational responses to food cues (conditioned approach) and the neural mechanisms involved in female rats. In addition, little is known about the role and effects of the cycle in conditioned approach or in the brain areas involved.

In Chapter 2, I examined differences in food intake, motivation to work for food and conditioned approach between obesity-prone and obesity-resistant female rats. Additionally, I determined the effects of the estrous cycle and ovarian hormones on these behaviors. Here, I measured daily food intake, used progressive ratio testing to measure motivation to work for food and Pavlovian conditioning to measure conditioned approach. I found that obesity-prone females eat more and have enhanced conditioned approach compared to obesity-resistant. Moreover, the cycle modulates food intake and motivation to work for food in both groups, but only affected conditioned approach in obesity-prone females. Next, I determined the role of estradiol and progesterone in conditioned approach. I found that estradiol and progesterone synergistically decreased conditioned approach in ovariectomized obesity-prone and outbred rats. Furthermore, I determined effects of cycle in intrinsic excitability of medium spiny neurons (MSN) in the nucleus accumbens (NAc) core of obesity-prone and obesity-resistant females. I found that excitability is enhanced in obesity-prone compared to obesity-resistant only during metestrus/diestrus.

In Chapter 3, I determined how sugary, fatty “junk-food” diet (JF) affect calcium-permeable AMPA receptor (CP-AMPAR) expression and function in obesity-prone and obesity-resistant male and female rats. I used BS3-crosslink to examine the effects of JF and JF-deprivation in GluA1 surface expression in the NAc of obesity-prone and obesity-resistant male and female rats. I found that JF increased GluA1 surface expression only in obesity-prone males. Next, patch clamp electrophysiology was used to determine JF-deprivation effects on CP-AMPAR function and silent synapses generation in the NAc core of obesity-prone males. I found that JF generates silent synapses, but JF-deprivation decreased silent synapses and increased CP-AMPAR function. Together, this suggest synaptic insertion of CP-AMPARs, and possible maturation of silent synapses. Surprisingly, no effects of JF on CP-AMPAR function were found in obesity-prone females.

Together, these data suggest that the mechanisms by which ovarian hormones influence motivational responses to food cues differs from those that influence motivation for food itself and that there are sex differences in diet-induced glutamatergic plasticity within the NAc. Thus, to properly address the obesity epidemic, studies of the neurobiology of motivation and feeding in females (both lean and obese models) are needed.