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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Available from: Lalini Ramanathan
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    • "Physiological studies demonstrate that orexinergic neuronal firing patterns are greatest during periods of wakefulness, motor activation and sustained attentiveness to external stimuli and the environment (Datta and MacLean, 2007; Alexandre et al., 2013). Thus, the orexinergic system has been implicated in several functions including the promotion and maintenance of arousal and wakefulness (Alexandre et al., 2013), the regulation of food consumption (Edwards et al., 1999), energy metabolism, thermoregulation and locomotion (Peyron et al., 1998; Mintz et al., 2001; Spinazzi et al., 2006), with an overall involvement in ''work for reward'' behaviours, or in the case of humans, for alertness linked to being happy (Mileykovskiy et al., 2005; McGregor et al., 2011; Blouin et al., 2013). While cetaceans and artiodactyls both belong to the order Cetartiodactyla (Price et al., 2005), there are substantial differences in their life history, all of which appear to be related to functions associated with the orexinergic system. "

    Full-text · Dataset · Nov 2015
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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.
    Full-text · Article · Jul 2014 · Neuroscience
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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.
    Full-text · Article · Jul 2013 · International Journal of Endocrinology
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