State-Dependent Plasticity of the Anterior Piriform Cortex Regulates Food Foraging Behavior and Novel Food Learning

Abstract

Hunger is a robust physiological state that motivates foraging and feeding in times of caloric insufficiency. Decades of research have uncovered the network of central appetitive neurons in the hypothalamus, as well as the hormones secreted by the peripheral organs that control food intake and metabolism. However, the role of sensory information that signals food cues, the potential risks in foraging, and how they integrate into the subsequent decision-making of food consumption are less studied.

Olfaction is an important sensory modality in foraging as it integrates chemosensory signals from afar to inform the risks and rewards in the environment. In the olfactory system, the anterior piriform cortex (APC) receives direct input from the olfactory bulb (OB) for odor coding, discrimination, and perception. It is also highly modulated by sensory experience and serves as an important hub for odor learning. However, its role in mediating foraging and feeding remains unknown. This thesis is undertaken to examine the circuit mechanism of the APC in foraging and learning of novel food odors under fasted conditions.

Firstly, I investigated how acute fasting in mice changes their foraging behavior, the population activities of the principal neurons in the APC, and the expression of structural excitatory/inhibitory synapses. I found that acute fasting enhanced the exploration time and consumption of the familiar laboratory chow pellet. The discrimination of the chow pellet from almond also enhanced under acute fasting. Foraging activated the excitatory and inhibitory neurons in different layers of the APC in fasted mice, as revealed by c-Fos immunostaining coupled with markers for excitatory neuron (CaMKII) and inhibitory neuron (GAD67). Foraging also enhanced excitation-inhibition ratio of synaptic density in the APC of the acutely fasted mice. Chemogenetic inhibition of the APC decreased the sniffing time and discrimination of chow, but the intake of chow was not affected. This suggests APC plays a role in foraging, notably the discrimination of familiar food when mice are fasted.

Next, I asked whether the APC takes part in learning different food choices with different valences other than the standard laboratory chow, which is the only type of food that the mice are exposed to in laboratory settings. I developed a new food learning paradigm that introduced lab mice to peanut butter (PB) as a more caloric, rewarding substance than laboratory chow, and examined their foraging and intake preference. At naïve condition, fasted mice preferred the chow. After feeding PB for three days, the fasted mice showed enhanced foraging preference and intake preference for PB. The population response towards PB in the APC principal neurons increased substantially after learning. On the other hand, chemogenetic inhibition of the APC prevented the mice from acquiring olfactory cues of PB, but the response to innate odor such as pheromone were retained. Furthermore, the aversion towards butyric acid, an unpleasant odor emanating from spoiled food, was attenuated as it was mixed with PB. The results suggest that the APC takes part in experience-dependent learning of food substances, ultimately governing the choice of food.

Having established the role of the APC in foraging, I further investigated the molecular mechanism underlying the enhanced foraging and the enhanced APC responsiveness upon fasting. Adiponectin is an abundant circulating adipokine secreted by adipocytes to enhance food intake and decrease energy expenditure. It has been shown to act on the hypothalamus to promote feeding. Emerging evidence also suggests its effect on the olfactory system such as the OB, but its effect on the APC remains elusive. Here, I found that adiponectin receptor 1 (AdipoR1) was expressed in the APC and colocalized with both excitatory and inhibitory neurons. Acute fasting enhanced the phosphorylation of AMP-activated protein kinase (AMPK) in the APC, which is a biochemical energy sensor and a downstream signal transducer of AdipoR1. Systemic administration of high dose of AdipoRon, a small molecule agonist of adiponectin receptors, enhanced the sniffing time for chow among sated mice and was comparable to the acutely fasted mice. The phosphorylation of AMPK in the APC increased following AdipoRon treatment, whereas knockdown of AdipoR1 gene expression decreased foraging for chow at fasted condition. The results suggest that foraging is mediated by AdipoR1 signaling in the APC.

To conclude, this thesis illuminates the role of higher olfactory region, the APC, in food foraging and learning of novel food substances. The results also uncover the orchestration between olfactory region and energy homeostasis through metabolic hormones. The current study paves the way for discovering neural circuits that ultimately link sensory information to central and peripheral pathways of feeding regulation.

Date of Award	23 Apr 2025
Original language	English
Awarding Institution	City University of Hong Kong
Supervisor	Chun Yue Geoffrey LAU (Supervisor)