Highly Specific Role of Hypocretin (Orexin) Neurons: Differential Activation as a Function of Diurnal Phase, Operant Reinforcement versus Operant Avoidance and Light Level

Veterans Administration Greater Los Angeles Healthcare System, Neurobiology Research (151A3), North Hills, California 91343, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2011; 31(43):15455-67. DOI: 10.1523/JNEUROSCI.4017-11.2011
Source: PubMed


Hypocretin (Hcrt) cell loss is responsible for narcolepsy, but Hcrt's role in normal behavior is unclear. We found that Hcrt knock-out mice were unable to work for food or water reward during the light phase. However, they were unimpaired relative to wild-type (WT) mice when working for reward during the dark phase or when working to avoid shock in the light or dark phase. In WT mice, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. Expression was seen throughout the mediolateral extent of the Hcrt field. Fos was not expressed when expected or unexpected unearned rewards were presented, when working to avoid negative reinforcement, or when given or expecting shock, even though these conditions elicit maximal electroencephalogram (EEG) arousal. Fos was not expressed in the light phase when light was removed. This may explain the lack of light-induced arousal in narcoleptics and its presence in normal individuals. This is the first demonstration of such specificity of arousal system function and has implications for understanding the motivational and circadian consequences of arousal system dysfunction. The current results also indicate that comparable and complementary specificities must exist in other arousal systems.

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    • "There was a greater reduction in the number of OXA-ir cells in the PFA/DMH than LH region (50% vs. 35%) in DLD animals , suggesting that low light intensity may particularly affect arousal and stress responsiveness; however, the regional difference was not statistically significant so should be interpreted cautiously. It should be noted that in a recent study examining the response of OXA neurons to positive reinforcement also found the activation (measured by Fos-ir) of OXA neurons across the medial–lateral extent of the OX-containing region, without apparent subregional difference (McGregor et al., 2011), suggesting there may be overlapping functions between the two populations of cells. "
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    ABSTRACT: Light has profound effects on mood, as exemplified by seasonal affective disorder (SAD) and the beneficial effects of bright light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD (Leach et al., 2013a,b). By utilizing a 12:12-h dim light:dark (DLD) paradigm that simulates the lower light intensity of winter, we showed that the animals housed in DLD exhibited increased depression-like behaviors in the forced swim test (FST) and sweet solution preference (SSP) compared to animals housed in bright light during the day (BLD). The objective of the present study was to test the hypothesis that light affects mood by acting on the brain orexinergic system in the diurnal grass rat model of SAD. First, orexin A immunoreactivity (OXA-ir) was examined in DLD and BLD grass rats. Results revealed a reduction in the number of OXA-ir neurons in the hypothalamus and attenuated OXA-ir fiber density in the dorsal raphe nucleus of animals in the DLD compared to those in the BLD group. Then, the animals in BLD were treated systemically with SB-334867, a selective orexin 1 receptor (OX1R) antagonist, which led to a depressive phenotype characterized by increased immobility in the FST and a decrease in SSP compared to vehicle-treated controls. Results suggest that attenuated orexinergic signaling is associated with increased depression-like behaviors in grass rats, and support the hypothesis that the orexinergic system mediates the effects of light on mood.
    Neuroscience 07/2014; 272:252–260. DOI:10.1016/j.neuroscience.2014.04.069 · 3.36 Impact Factor
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    • "In sated rats, OX and c-Fos double-labeling is also increased by a tone that signals the availability of palatable food in the form of high-sucrose pellets [88]. Siegel and colleagues [89] demonstrated that the expression of Fos in OX neurons increases in animals working for chow during the light phase but not when working to avoid shock or when receiving unearned rewards. These results suggest that OX neurons are activated in conditions when animals expect to receive specific, often preferred foods. "
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    ABSTRACT: Transcribed within the lateral hypothalamus, the neuropeptides orexin/hypocretin (OX) and melanin-concentrating hormone (MCH) both promote palatable food intake and are stimulated by palatable food. While these two neuropeptides share this similar positive relationship with food, recent evidence suggests that this occurs through different albeit complementary effects on behavior, with OX promoting food seeking and motivation for palatable food and MCH functioning during ongoing food intake, reinforcing the consumption of calorically dense foods. Further differences are evident in their effects on physiological processes, which are largely opposite in nature. For example, activation of OX receptors, which is neuronally excitatory, promotes waking, increases energy expenditure, and enhances limbic dopamine levels and reward. In contrast, activation of MCH receptors, which is neuronally inhibitory, promotes paradoxical sleep, enhances energy conservation, reduces limbic dopamine, and increases depressive behavior. This review describes these different effects of the neuropeptides, developing the hypothesis that they stimulate the consumption of palatable food through excessive seeking in the case of OX and through excessive energy conservation in the case of MCH. It proposes that OX initiates food intake and subsequently stimulates MCH which then acts to prolong the consumption of palatable, energy-dense food.
    International Journal of Endocrinology 07/2013; 2013(1):983964. DOI:10.1155/2013/983964 · 1.95 Impact Factor
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    • "For example, studies looking at Fos expression show that hypocretin levels are not increased with footshock, a situation of strong negative valence (Furlong et al., 2009). Similarly, hypocretin unit activity decreases in novel situations eliciting withdrawal, but increases with novel situations eliciting exploration (Borgland et al., 2009; Sharf et al., 2010; McGregor et al., 2011). In addition, in humans, low cerebrospinal hypocretin levels are related to depression (Brundin et al., 2009). "
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    ABSTRACT: This study aimed to directly assess the effect of changes in blood glucose levels on the psychological processing of emotionally charged material. We used functional magnetic resonance imaging (fMRI) to evaluate the effect of blood glucose levels on three categories of visually presented emotional stimuli. Seventeen healthy young subjects participated in this study (eight females; nine males; body weight, 69.3 ± 14.9 kg; BMI, 22 ± 2.7; age, 24 ± 3 years), consisting of two functional MRI sessions: (1) after an overnight fast under resting conditions (before glucose administration); (2) after reaching the hyperglycemic state (after glucose administration). During each session, subjects were presented with visual stimuli featuring funny, neutral, and sad content. Single-subject ratings of the stimuli were used to verify the selection of stimuli for each category and were covariates for the fMRI analysis. Analysis of the interaction effect of the two sessions (eu- and hyperglycemia), and the emotional categories accounting for the single-subject glucose differences, revealed a single activation cluster in the hypothalamus. Analysis of the activation profile of the left amygdala corresponded to the three emotional conditions, and this profile was obtained for both sessions regardless of glucose level. Our results indicate that, in a hyperglycemic state, the hypothalamus can no longer respond to emotions. This study offers novel insight for the understanding of disease-related behavior associated with dysregulation of glucose and glucose availability, potentially offering improved diagnostic and novel therapeutic strategies in the future.
    Frontiers in Human Neuroscience 05/2013; 7:212. DOI:10.3389/fnhum.2013.00212 · 3.63 Impact Factor
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