ROLES OF HYPOTHALAMIC PEPTIDES IN ADDICTION AND OBESITY
Dissecting Neural Circuits That Control Feeding
Scott M. Sternson, Ph.D.
[Slides not available]
In the hypothalamic arcuate nucleus (ARC), pro-opiomelanocortin (POMC) neurons inhibit feeding, and neuropeptide-Y/agouti-related protein (NPY/AgRP) neurons stimulate feeding. These neuron populations are important for the anorexigenic action of leptin. We have used laser-scanning photostimulation to map the functional connectivity between the ventromedial hypothalamic nucleus (VMH) and these molecularly defined neurons in the ARC. We show that POMC and NPY neurons, which are interspersed in the ARC, are nevertheless regulated by anatomically distinct synaptic inputs from the VMH. We are also investigating the functional contribution of these individual cell types to the physiologic effects of leptin. To address this, we have developed a chimeric receptor with variants of the FK506 binding protein (Fv2) fused to the cytoplasmic signaling domain of LepR (Fv2-LepR). A dimeric small molecule ligand that tightly binds Fv is used to activate LepR-like signaling. Using BAC transgenesis, we targeted this receptor specifically to the anorexigenic POMC-expressing neurons and, in a separate mouse line, to the orexigenic AgRP-expressing neurons. When these mice receive the small molecule dimerizer, leptin-receptor signaling is activated only in POMC or AgRP neurons, respectively, allowing the role of these neurons in leptin physiology to be dissected. These mouse lines are currently being characterized in studies of feeding and energy homeostasis. Both of these approaches can be applied to other molecularly defined neuron populations controlling feeding and body weight.
Stress, Arousal, and Addiction: The Hypocretin Connection
Luis de Lecea, Ph.D.
Hypocretins, also known as orexins, are two neuropeptides now commonly described as critical components to maintain and regulate the stability of arousal. Several lines of evidence have raised the hypothesis that hypocretin-producing neurons are part of the circuitries that mediate the hypothalamic response to acute stress. Intracerebral administration of hypocretin leads to a dose-related reinstatement of drug- and food-seeking behaviors. Furthermore, stress-induced reinstatement can be blocked with hypocretin receptor 1 antagonism. These results, together with recent data showing that hypocretin is critically involved with cocaine sensitization through the recruitment of NMDA receptors in the ventral tegmental area, strongly suggest that the activation of hypocretin neurons play a critical role in the development of the addiction process. The activity of hypocretin neurons may affect addictive behavior by contributing to brain sensitization or by modulating the brain reward system. Hypocretinergic cells, in coordination with brain stress systems, may lead to a vulnerable state that facilitates the resumption of drug-seeking behavior. Hence, the hypocretinergic system is a new drug target that may be used to prevent the relapse of drug seeking.
Orexin Neurons, Reward-Seeking, and Addiction: It All Comes Together in the Lateral Hypothalamus
Gary Aston-Jones, Ph.D.
The lateral hypothalamus (LH) is a brain region historically implicated in reward and motivation, but the neurotransmitters of LH neurons involved with these functions are unknown. The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in LH neurons. Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep, many orexin cells project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area (VTA). This indicates a possible role for these neurons in reward function and motivation, which is consistent with previous studies implicating these neurons in feeding. We found that the activation of LH orexin neurons is strongly linked to preferences for cues associated with morphine, cocaine, or food reward. In addition, we showed that the chemical activation of LH orexin neurons reinstates an extinguished conditioned place preference (CPP). This reinstatement effect was completely blocked by the prior administration of an orexin A antagonist. Moreover, the administration of the orexin A peptide directly into the VTA also reinstated CPP. Finally, we discovered that specific lesion of the LH orexin projection to the VTA prevents learning a morphine CPP. All these findings were found specifically for LH orexin neurons; orexin neurons in the perifornical or dorsomedial hypothalamus did not exhibit these reward-linked properties. These data reveal a novel role for LH orexin neurons in reward-seeking, drug relapse, and addiction.
Hypocretin Enhances Synaptic Strength in VTA Dopamine Neurons
Stephanie L. Borgland, Ph.D.
Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that hypocretin neurons play a critical role in motivation, feeding, and adaptive behaviors. However, the role of hypocretin signaling in neural plasticity is poorly understood. We demonstrate that in vitro application of hypocretin 1 induces the potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Interestingly, this hypocretin-mediated acute potentiation of NMDARs resulted in an augmentation of AMPAR-mediated synaptic transmission several hours later. We examined the behavioral relevance of this plasticity using locomotor sensitization. This behavioral paradigm is characterized by an augmented locomotor response to repeated injections of cocaine, and its initiation is largely dependent on NMDAR receptor activation in the VTA. In vivo administration of a hypocretin 1 receptor antagonist systemically or within the VTA blocked locomotor sensitization to cocaine and occluded cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence of a critical role for hypocretin signaling in the VTA in neural plasticity relevant to addiction. Furthermore, data regarding the role of hypocretin signaling in cocaine self-administering rats will be discussed. Thus, hypocretin receptors may provide novel pharmacotherapeutic targets for motivational disorders, such as drug-craving.
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