Dynorphin Modulates Reward-Seeking Actions Through a Pallido-Amygdala Cholinergic Circuit

Neurology Psychiatry Life Sciences Medicine
Dynorphin Reward-Seeking Cholinergic Circuit Ventral Pallidum Amygdala Neuromodulation Learning

Dynorphin is an endogenous opioid peptide that primarily acts through κ-opioid receptors (KOR) and is widely involved in the regulation of various behaviors, including reward and aversive responses. However, the specific mechanisms of Dynorphin/KOR signaling in reward-seeking behaviors remain unclear. Previous research has predominantly focused on the “anti-reward” effects of Dynorphin/KOR signaling, particularly its role in inhibiting dopamine release and inducing aversive responses. However, recent studies suggest that Dynorphin/KOR signaling may also promote reward-seeking behaviors in certain brain regions. To better understand the complex role of Dynorphin in reward-seeking behaviors, Sun et al. conducted an in-depth study, revealing the mechanism by which Dynorphin modulates reward-seeking actions through a pallido-amygdala cholinergic circuit.

Source of the Paper

This paper was co-authored by Qingtao Sun, Mingzhe Liu, Wuqiang Guan, and others, who are affiliated with multiple research institutions, including Cold Spring Harbor Laboratory, University of California, Davis, and University of Washington. The paper was published on June 4, 2025, in the journal Neuron, titled “Dynorphin modulates reward-seeking actions through a pallido-amygdala cholinergic circuit.”

Research Process and Results

1. Research Objectives and Design

The study aimed to elucidate the specific mechanisms of Dynorphin in reward-seeking behaviors, particularly its regulatory role through the pallido-amygdala cholinergic circuit. The research team systematically investigated the release of Dynorphin from nucleus accumbens (NAc) Dynorphinergic neurons (NAcPDyn neurons) and its impact on ventral pallidum (VP) cholinergic neurons and basolateral amygdala (BLA) cholinergic transmission using molecular, genetic, and optogenetic manipulations, combined with electrophysiology, behavioral experiments, and real-time dynamic monitoring techniques.

2. Experimental Process and Results

a) Disinhibition of VP Cholinergic Neurons by NAcPDyn Neurons

The research team first activated the axonal terminals of NAcPDyn neurons using optogenetics and recorded inhibitory postsynaptic currents (IPSCs) in VP cholinergic neurons. The results showed that NAcPDyn neurons disinhibit VP cholinergic neurons by inhibiting GABAergic neurons in the VP. This disinhibition depends on Dynorphin/KOR signaling, as the KOR antagonist Norbinaltorphimine (Norbni) blocked this effect.

b) Dynorphin Release in the VP and Its Impact on BLA Cholinergic Transmission

To study Dynorphin release in the VP, the research team developed a novel Dynorphin sensor, Klight1.3, and monitored Dynorphin release in real-time using optogenetics. The results showed that rewarding stimuli (e.g., water) triggered Dynorphin release from NAcPDyn neurons into the VP, while aversive stimuli (e.g., air puff) did not. This finding indicates that Dynorphin release in the VP is reward-related.

c) Regulation of Reward-Seeking Behavior by the NAcPDyn/VP Pathway

The research team further validated the role of the NAcPDyn/VP pathway in reward-seeking behavior through behavioral experiments. In a “Go/No-Go” task, inhibiting the axonal terminals of NAcPDyn neurons significantly reduced reward-seeking behavior in mice, while activating this pathway enhanced it. Additionally, in a progressive ratio (PR) task, inhibiting NAcPDyn neurons reduced the motivation level of mice, indicating that Dynorphin plays a crucial role in regulating reward-seeking behavior.

d) Role of KOR in VP GABAergic Neurons and NAcPDyn Neurons

Using CRISPR-Cas9 technology, the research team specifically knocked out the KOR gene (Oprk1) in VP GABAergic neurons and found that this significantly reduced acetylcholine (ACh) release in the BLA and weakened reward-seeking behavior in mice. Furthermore, knocking out KOR in NAcPDyn neurons prolonged the duration of ACh release, suggesting that KOR exerts an autoinhibitory function in NAcPDyn neurons, preventing excessive activation of cholinergic neurons.

3. Conclusions and Significance

This study reveals the mechanism by which Dynorphin modulates reward-seeking behavior through the NAcPDyn/VP GABA/VP cholinergic/BLA cholinergic circuit. Dynorphin promotes the disinhibition of VP cholinergic neurons by mediating inhibition through KOR in VP GABAergic neurons, thereby enhancing ACh release in the BLA and promoting reward-seeking behavior. Simultaneously, the autoinhibitory function of Dynorphin in NAcPDyn neurons fine-tunes this process, preventing excessive activation of reward-seeking behavior.

This research not only deepens our understanding of the role of Dynorphin/KOR signaling in reward-seeking behavior but also provides new insights for treating motivation-related psychiatric disorders such as depression and addiction.

Research Highlights

  1. Novel Dynorphin Sensor: The research team developed the Klight1.3 sensor, enabling real-time monitoring of Dynorphin release in live animals for the first time.
  2. Interdisciplinary Research: This study integrated molecular biology, genetics, optogenetics, electrophysiology, and behavioral science to systematically uncover the regulatory mechanisms of Dynorphin.
  3. Fine-Tuning Mechanism: The study found that Dynorphin has dual roles in VP GABAergic neurons and NAcPDyn neurons, both promoting reward-seeking behavior and preventing its excessive activation.

Other Valuable Information

The study also found that the projection of VP cholinergic neurons to the BLA plays a crucial role in regulating reward-seeking behavior. Activating this projection enhances motivation levels in mice, while inhibiting it weakens motivation. This discovery provides a new perspective on the role of the cholinergic system in reward-seeking behavior.

Summary

Through an interdisciplinary approach, Sun et al. systematically revealed the mechanism by which Dynorphin modulates reward-seeking behavior through the pallido-amygdala cholinergic circuit. This research not only deepens our understanding of Dynorphin/KOR signaling but also offers new avenues for treating motivation-related psychiatric disorders.