Sheridan Balthazar
Research Mentor(s): Paula Goforth
Department or Program: Pharmacology
Authors: Sheridan Balthazar, Ainsley Caldwell, Paula Goforth
Session: Session 1: 12:00pm-12:50pm
Poster: 11
Abstract
Obesity and diabetes are closely linked, influenced by how our brains control food intake. Restraint of food intake occurs by both aversive and non aversive mechanisms within the brain. New treatments targeting the brain show promise in fighting obesity, but they often cause nausea, raising concerns about their side effects. Although there is still more to discover about the mechanisms by which central neural circuits regulate food intake in response to gut inputs, the area postrema (AP) is known to play a role (Browning, 2021). The AP is a small chemoreceptor trigger zone in the hindbrain that responds to gut peptides in order to modulate food intake through both non-aversive satiety, and aversive mechanisms, such as nausea (Browning, 2021). The AP exists beyond the blood-brain barrier, making it sensitive to systemic circulating factors and pharmacological agents in a way that is distinct from other brain regions that regulate consumption (Browning, 2021). By utilizing calcium imaging, we can examine the activity of distinct neurons in the AP in genetic mouse models to understand the underlying cellular mechanisms. This was done by exposing the AP and its receptors to drugs which increase and decrease calcium response. We completed a series of experiments to measure changes in the fluorescence of the calcium indicator, GCaMP, to observe the overall activity from neurons that express Glucagon-like-1 receptors (GLP1R) in the AP. Increased action potential firing increases intracellular calcium, which in turn increases GCaMP fluorescence, and vice versa. To replicate biological conditions we used a solution of artificial cerebrospinal fluid to maximize overall activity of the mouse brain while we conducted experiments. To gain insight into the agents that affect these neural circuits involved in aversion we administered drugs such as ethanol or cisplatin, a chemotherapeutic known to induce nausea. We hypothesize that ethanol and cisplatin act directly on neurons in the area postrema that regulate food intake and aversion. To assess whether the effects are direct, we conducted experiments in the presence of synaptic blockade consisting of toxins that effectively cut off communication between cells. If neuronal activity (either basal or drug-induced) is intrinsic, the neuron will continue fluorescing when the synaptic blockade is introduced. If the signaling is the result of intercellular communication, the downstream cells will decrease fluorescence when the synaptic blockade is introduced. By manipulating inputs to neurons and measuring their activity in the AP before, during, and after the administration of various drugs, we can study the neural mechanisms of aversion and identify potential therapeutic targets we can use for mitigating the aversive responses in the future.
