Feeding-Related Roles for Calcitonin Receptor Neurons in the Area Postrema

Abstract

Signals from the gut act in the dorsal vagal complex (DVC) to slow the flow of food from the stomach into the intestine, promote meal termination, and mediate aversive responses to gastrointestinal malaise. The DVC consists of the area postrema (AP), which lies outside of the blood-brain barrier, the adjacent nucleus tractus solitarius (NTS), and the dorsal motor nucleus of the vagus (DMV). While AP neurons are postulated to play crucial roles in appetite suppression and aversive responses (e.g., nausea) by anti-obesity peptides, individual populations of AP neurons remain relatively unstudied due to the difficulty of stereotaxically targeting them in mice. Because calcitonin receptor (Calcr)-expressing AP neurons specifically may be targets for anti-obesity treatments, but mice respond poorly to these compounds, we generated and validated a CalcrCre rat model to target AP Calcr neurons and understand their circuitry and function. Intra-AP injection of viruses to Cre-dependently express synaptic tracers in these animals revealed major projections to the NTS and DMV. AP Calcr neurons also sent sparse projections to the lateral parabrachial nucleus (lPBN). We injected a Cre-dependent AAV virus into the AP to express activating (hM3Dq) Designer Receptor Exclusively Activated by Designer Drugs (DREADD) in CalcrCre rats (CalcrAP-hM3Dq-mCherry rats) to permit the activation of AP Calcr neurons in response to CNO. CNO-dependent activation of AP Calcr neurons in these rats delayed gastric emptying and decreased food intake over 24 hours but did not provoke a conditioned taste avoidance (CTA) response. Interestingly, prolonged (multi-day) CNO-dependent activation of AP Calcr neurons in CalcrAP-hM3Dq-mCherry rats did not promote the prolonged suppression of food intake and failed to reduce body weight. Hence, non-aversive AP Calcr neurons delay gastric emptying and inhibit food intake over the short term but do not mediate the long-term suppression of food intake and body weight, suggesting that they may not represent useful targets for treating obesity.