Gestational programming of ingestive behavior via effects on the mesolimbic dopaminergic reward pathway.
Authors: Rhinehart Erin , Waldron Madison 
Published: April 2020

Obesity is a worldwide health issue that has reached epidemic proportions. While much of the research to this point has focused on discerning the role of hypothalamic feeding peptides in energy balance, this line of research has yielded little insight into how to resolve the obesity crisis. Therefore, it may be more productive to investigate other central neural systems that affect ingestive behavior, such as the mseolimbic dopaminergic reward system comprised of the ventral tegmental area (VTA) and nucleus accumbens (NAc). Recent research regarding the impact of gestational environment on energy balance indicates that gestational under‐ or over‐nutrition causes perturbations in hypothalamic neuropeptides responsible for regulating ingestive behavior and metabolism. This type of gestational programming may also affect the mesolimbic reward pathway, which serves to reinforce natural behaviors such as eating, drinking, and sexual activity. Because some research indicates that low birth weight (LBW) humans tend to exhibit both obesity and a propensity toward addiction, we hypothesized that maternal undernutrition during pregnancy may affect dopaminergic neuron function, which would impact the regulation of ingestive behavior. To test this hypothesis, we utilized a traditional rat model of intrauterine growth restriction by placing dams on a 50% food‐restricted diet during the second half of pregnancy. At PND1, litters were culled to 8 animals (4 male and 4 female) and cross‐fostered to control dams. At PND60 offspring were sacrificed by overdose of pentobarbital and perfused with saline followed by 4% paraformaldehyde. Afterward, brains were removed, post‐fixed in 4% paraformaldehyde for 48 hours, followed by a 30% sucrose sink. Brains were then sectioned at 35 microns and processed for immunohistochemical staining of tyrosine hydroxylase (TH), the rate‐limiting enzyme for dopamine production. Offspring of food restricted dams had significantly lower birth weights (5.6±0.08 g vs. 6.5±0.06 g, p<0.01) and significantly higher TH immunoreactivity in the VTA than controls (159±19 A.U. vs. 454±88 A.U., p<0.05). In a separate set of male and female PND90 offspring, we examined 24‐hour sucrose consumption as well as sucrose consumption in a limited access paradigm where animals received 10% sucrose for 90 minute intervals every 48 hours for one week. LBW offspring consumed significantly more sucrose during the limited access test (29±2 ml vs. 23±1 ml, p<0.05), but not when sucrose was provided with unlimited access over 24 hours. This suggests that LBW offspring exhibit enhanced ingestive behaviors when given limited access to rewarding substances. Consequently, the dopaminergic reward system appears to be a significant player in the underlying mechanism responsible for gestational programming related perturbations in ingestive behavior and energy balance. Further investigation into the contribution of reward pathway alterations that occur as a result of gestational programming could provide novel insight into potential ways to combat the obesity epidemic.

Support or Funding Information

NSF CAREER 1350448