Involvement of the nucleus accumbens 𝛍Opioid system in palatability perception and the development of overeating

• Applicant: Dr. Julian Hinz
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572335749

This project investigates how the µ-opioid system in the nucleus accumbens (NAc) influences hedonic feeding and contributes to the development of overeating. While traditional models of feeding emphasize homeostatic regulation via the hypothalamic arcuate nucleus (ARC), recent evidence shows that hedonic pathways, particularly those involving µ-opioid receptors (MORs), play a dominant role in driving overconsumption of highly palatable foods. This dysregulation can initiate and sustain obesity, often overriding physiological satiety signals. Feeding behavior results from interactions between two neural systems: (1) homeostatic circuits, which maintain energy balance through AgRP and POMC neurons in the ARC, and (2) hedonic circuits, which include the ventral tegmental area (VTA), lateral hypothalamus (LH), and the NAc, and respond to the sensory and rewarding aspects of food. Crucially, β-endorphins released by POMC neurons activate MORs in downstream regions like the NAc. These receptors are highly enriched in D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), which are known to inhibit feeding-promoting neurons in the LH. The central hypothesis is that MOR activation in the NAc inhibits D1-MSNs, disinhibiting LH output and promoting palatable food consumption. Repeated activation of this circuit could form a positive feedback loop that fosters compulsive overeating. This view challenges traditional assumptions about the anorexigenic role of POMC neurons and repositions β-endorphin-MOR signaling as a driver of hedonic intake. To test this, the project employs a novel naturalistic feeding paradigm where mice live in enriched operant chambers with unrestricted access to chow and palatable foods. Using dual-site or multi-color fiber photometry, neural activity in homeostatic and hedonic circuits is recorded in real time. This approach avoids motivational artifacts introduced by caloric restriction and better models human overeating, which often occurs in the absence of metabolic need. The project is structured into three aims: Identify MOR-expressing neurons in the NAc and determine how exogenous and endogenous opioids modulate their excitability and synaptic input using patch-clamp recordings in MOR-Cre mice. Measure in vivo interactions between ARC and NAc activity during naturalistic feeding and overeating, linking neuronal activity to escalating intake. Establish causal links between MOR signaling and overeating by manipulating MOR+ neuron activity via genetic knockout or chemogenetics and assessing behavioral outcomes. Together, these studies aim to define how MOR-mediated signaling in the NAc contributes to the transition from need-driven to reward-driven feeding. By revealing mechanisms underlying hedonic overconsumption, this research has the potential to inform more targeted interventions for obesity especially as current treatments like GLP-1 receptor agonists are ineffective for long-term treatment.

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Dr. Christian Lüscher