Orexin and CRF Receptors Form Heteromers
Gemma Navarro, César Quiroz, David Moreno-Delgado, Adam Sierakowiak, Kimberly McDowell, et al.
(see pages 6639–6653)
Orexin is best known for its roles in arousal and feeding. Hunger or the presence of food-related stimuli activates orexin neurons, and orexin motivates animals to obtain food. Cues associated with other rewards, including addictive drugs, also activate orexin neurons, leading animals to seek these rewards. Thus, for example, orexin infusion can reinstate cocaine seeking in rats after the behavior has been extinguished. This effect is mediated by OX1 receptors (OX1Rs) on dopaminergic neurons in the ventral tegmental area (VTA), which stimulate dopamine release.
Orexin also plays a role in stress-induced reward seeking. Psychological stressors and the stress-associated neuropeptide corticotropin-releasing factor (CRF) activate orexin neurons, and stress-induced cocaine seeking (which depends on CRF) is blocked by OX1R antagonists. Interestingly, orexin also stimulates CRF release, and orexin-triggered cocaine seeking is blocked by CRF1R antagonists, suggesting CRF and orexin signaling pathways interact to control motivated behaviors.
One site where this interaction occurs is in dopaminergic VTA neurons, which express the CRF receptor CRF1R as well as OX1Rs. In fact, Navarro et al. demonstrate that OX1Rs and CRF1Rs form heteromeric receptors that can be activated by either peptide. OX1R–CRF1R heteromers exhibited cross antagonism: both OX1R-specific and CRF1R-specific antagonists blocked the effects of both peptides. Furthermore, applying the two peptides together blunted downstream signaling, indicating negative crosstalk between the pathways. Indeed, OX1R is coupled to Gi proteins, which reduce cAMP levels, while CRF1R couples with Gs proteins, which increase cAMP.
Intriguingly, cocaine reduced negative crosstalk and cross antagonism between orexin and CRF pathways by binding to σ1 receptors (σ1Rs), which caused σ1Rs to disrupt OX1R–CRF1R heteromers. Consequently, CRF—which did not induce dopamine release initially—induced dopamine release after cocaine treatment, and co-application of orexin and CRF induced more dopamine release than either alone.
These results suggest that reward-seeking triggered by orexin in response to internal or external cues is inhibited by CRF during stress. Exposure to cocaine disrupts this regulation by binding to σ1Rs. This may explain stress-induced relapse in former cocaine users. Whether endogenous σ1R ligands contribute to stress-induced pursuit of natural rewards, such as food, is an enticing question for future research.
Dopamine Depletion Affects Subpopulation of GPe Neurons
Azzedine Abdi, Nicolas Mallet, Foad Y. Mohamed, Andrew Sharott, Paul D. Dodson, et al.
(see pages 6667–6688)
Loss of dopaminergic inputs to the basal ganglia (BG) alters activity in the globus pallidus external capsule (GPe)—a nucleus in the indirect pathway between BG input and output nuclei—and this contributes to motor deficits. The GPe contains a heterogeneous population of GABAergic neurons; however, how these populations contribute to motor deficits is unclear. Mallet et al. (2012, Neuron 74:1075) identified two neuronal populations distinguishable by their activity after dopamine depletion in rats. One population, called “prototypic” neurons, fired preferentially during the trough of slow cortical oscillations. These neurons expressed parvalbumin and projected to the subthalamic nucleus, striatum, and other BG nuclei. The second population, “arkypallidal” neurons, fired preferentially during the peak of slow oscillations, expressed preproenkephalin, and projected only to the striatum.
In normal rats (top two traces), prototypic GPe neurons (bottom trace in each pair) fire at high rates, are weakly phase-locked to SWA (top trace in each pair), and fire most strongly at the peak of the cortical oscillation. After dopamine depletion (bottom two traces), these neurons are more tightly phase-locked to SWA and fire preferentially during the trough of the oscillation. See the article by Abdi et al. for details.
Abdi et al. more thoroughly characterized arkypallidal and protoypic neurons by identifying population-specific transcription factors and describing the firing patterns of each population during slow-wave activity (SWA) and spontaneous cortical activation in normal rats. Although the rate and regularity of spiking varied greatly in both populations, arkypallidal neurons generally spiked more slowly and less regularly than protypic neurons. Furthermore, arkypallidal neuron activity was more likely to be phase-locked to SWA, and the neurons fired preferentially around the peak of the oscillation. Interestingly, most prototypic neurons that were phase-locked to SWA also fired preferentially around the peak in dopamine-intact rats. As the cortex transitioned to an activated state, the firing rate and regularity of arkypallidal and protoypic neurons increased, as did the overlap between the patterns.
Only protoypic neurons were noticeably affected by dopamine depletion. Their firing became more tightly phase-locked to SWA and they fired preferentially during the trough instead of the peak of the oscillation. In addition, firing of prototypic neurons was lower during cortical activation than during SWA after dopamine depletion. Therefore, the firing patterns of arkypallidal and prototypic became indistinguishable during cortical activation.
How changes in prototypic neuron activity relates to motor impairment remains unclear. Future studies must clarify this, as well as the functions of arkypallidal and prototypic neurons under normal conditions. By identifying clear markers for these populations, Abdi et al. have laid a good foundation for such studies.
