Following a lipid rich meal, circulating triglyceride levels increase and some level of reward is experienced. We suspect that a dietary triglyceride processing enzyme known as lipoprotein lipase (LPL) is the sensor involved in triglyceride sensing in the mesolimbic brain. We also believe that circulating triglycerides in the brain increase activity of the reward circuit, signaling positive reinforcement and in cases of overexposure, promoting neuroadaptations similar to those seen in individuals addicted to substances of abuse. Using fluorescent in-situ hybridization we found that LPL’s expression was specific to specific cell types within mesolimbic circuitry, namely dopaminergic and medium spiny neurons. By chronically catheterizing the carotid artery of mice, we were able to directly infuse triglycerides to the brain via catheter in order to emulate post-meal neurophysiology. We performed lipid profile analyses of mice that had received brain triglyceride delivery (BTGD) and found significant changes in striatal glycerolipid, free fatty acid, and eicosanoid species, validating our approach to examining post-meal neurophysiology and pointing to activation of the pro-inflammatory lipoxygenase (LOX) pathway. Using immunohistochemistry following BTGD, we found that circulating triglycerides may upregulate markers of neural activity in mesolimbic and basal ganglia circuitry. Lastly, we assayed the effects that circulating triglycerides may have on anxiety, and found mice that received BTGD exhibited a more anxious behavioral phenotype. We therefore have further reason to believe in the ability of palatable foods to act as an addictive substance, and in the role of LPL as a lipid sensor in the mesolimbic brain.

The subthalamic nucleus (STN) is a small excitatory nucleus with a significant role in response inhibition. STN activity has been previously shown to be correlated with behavioral stopping or switching, but no studies have yet shown a causal role. This dissertation provides the first evidence that STN activation interrupts behavior, and blocking the STN blunts the interruptive effect of surprise. Thus, the STN is both necessary and sufficient for such forms of behavioral response suppression. Further, STN activation also is sufficient to interrupt cognition, decreasing performance on a working memory task. Finally, viral tracing evidence demonstrates a topological organization of cortical “hyperdirect pathway” inputs onto STN, with motor cortex projecting dominantly to lateral STN and limbic and associative-related cortical regions projecting dominantly to medial STN.

The mesolimbic dopaminergic system consists of interconnected brain regions that include the nucleus accumbens (NAc), ventral tegmental area (VTA), ventral pallidum (VP) and lateral habenula (LHb). These circuits have each been implicated in processes that underlie reward and motivation. The VP is a highly heterogeneous structure with varying cell types, projection targets, and functional roles that are only recently being appreciated. Indeed, recent work has revealed a possible opponent role of VP GABA and glutamate neurons in motivated behavior. Specifically, activation of VP GABA neurons, mainly through their projections to the VTA, induced positive reinforcement; while stimulation of VP glutamate neurons, particularly their projection to the LHb, triggered avoidance. In this work, I further elucidated the mechanism by which VP GABA neurons elicit reward. Particularly, I studied the VP to VTA pathway and assessed the potential for VP GABA terminal stimulation in VTA to trigger dopamine release in the NAc. I showed that stimulation of VP GABA terminals elicits an increase in dopamine release upon both behavior-contingent and non-contingent stimulation. However, both amplitude and duration of dopamine release appeared to be modulated by whether stimulation was contingent on behavior, suggesting a role for motivational or other components in gating the ability of VP GABA inputs to VTA to influence dopamine signaling. These studies provide a foundation for further testing of associated pathways that correlate with reward, learning, and ultimately addiction.