Effects Of Stress On Orexinaproducing Neurons

Accumulating evidence suggests that various kinds of stressors activate orexin-A-contain-ing neurons with increased transcripts of the prepro-orexin gene (4-9). Central administration of orexin-A and -B regulates feeding behavior (4). Thus, the effects of feeding-related stressors such as fasting and hypoglycemia on orexin-A-containing neurons were examined by using molecular techniques such as Northern blot analysis and in situ hybridization histochemistry for prepro-orexin mRNA or immunohistochemistry for Fos; Fos protein and c-fos mRNA are widely used as markers of neuronal activity in the CNS.

In rats, Northern blot analysis showed that fasting for 48 h upregulated hypothalamic pre-pro-orexin mRNA (4,10). Hypoglycemia induced by intraperitoneal (ip) administration of insulin increased prepro-orexin mRNA in the LHA (5). On the other hand, glucodeprivation induced by ip administration of 2-deoxy-D-glucose (2-DG) either decreased prepro-orexin mRNA levels (11) or had no effects (10,12). Dual immunohistochemical staining for Fos and orexin-A was performed after similar stimuli. Hypoglycemia induced by ip administration of insulin induced Fos expression in up to 33% of orexin-A-containing neurons (6). Administration ip or icv of 2-DG induced Fos expression in orexin-A-containing neurons (7,13,14; Fig. 1). Similar Fos expression induced by food restriction was also observed in orexin-A-containing neurons (7; Fig. 2), suggesting that orexin-A-containing neurons in the LHA are glucose sensitive.

From: Contemporary Clinical Neuroscience: The Orexin/Hypocretin System: Physiology and Pathophysiology Edited by: S. Nishino and T. Sakurai © Humana Press Inc., Totowa, NJ

Fig. 1. Localization of neurons containing Fos-like immunoreactivity (LI) and orexin-A-LI 90 min after intracerebroventricular (icv) administration of vehicle (A-C) or 2-deoxy-D-glucose, (8 mg/rat; D-F). Fos-LI, orexin-A-LI cells, and colocalized cells are indicated by dots, crosses, and filled squares, respectively. Sections were taken from the rostral to caudal regions of the hypothalamus, including the lateral hypothalamic area. Scale bar = 200 pm. (Data from ref. 7.)

Fig. 1. Localization of neurons containing Fos-like immunoreactivity (LI) and orexin-A-LI 90 min after intracerebroventricular (icv) administration of vehicle (A-C) or 2-deoxy-D-glucose, (8 mg/rat; D-F). Fos-LI, orexin-A-LI cells, and colocalized cells are indicated by dots, crosses, and filled squares, respectively. Sections were taken from the rostral to caudal regions of the hypothalamus, including the lateral hypothalamic area. Scale bar = 200 pm. (Data from ref. 7.)

It is well known that stress stimuli modulate food intake (15). For example, noxious stimuli cause increased food intake, and emotional stimuli suppress feeding. Zhu et al. (16) clearly demonstrated that noxious but not conditioned fear stimuli caused Fos expression in almost all orexin-A-containing neurons. In addition to feeding-related stress, it has been reported that other stressors cause changes in prepro-orexin mRNA levels and induction of Fos expression in orexin-A-containing neurons. Cold and immobilization stress caused elevation of prepro-orexin mRNA levels in the LHA (8). Sakamoto et al. (9) demonstrated that cold exposure at 4°C for 30 min or immobilized stress for 20 min caused Fos expression in approximately 15 and 24% of orexin-A-containing neurons, respectively (Figs. 3 and 4).

In general, stress activates the HPA axis, and orexins may be involved in regulation of this axis because adrenectomy (ADX) strongly reduced prepro-orexin mRNA levels in the LHA, which were restored to normal by peripheral replacement with dexamethasone in ADX (17).

Fig. 2. Localization of neurons containing Fos-like immunoreactivity (LI) and orexin-A-LI in control rats (A-C) or rats food-restricted for 3 wk (D-F). Fos-LI, orexin-A-LI cells, and colocalized cells are indicated by dots, crosses, and filled squares, respectively. Sections were taken from the rostral to caudal levels of the hypothalamus, including the lateral hypothalamic area. Scale bar = 200 |im. (Data from ref. 7.)

Fig. 2. Localization of neurons containing Fos-like immunoreactivity (LI) and orexin-A-LI in control rats (A-C) or rats food-restricted for 3 wk (D-F). Fos-LI, orexin-A-LI cells, and colocalized cells are indicated by dots, crosses, and filled squares, respectively. Sections were taken from the rostral to caudal levels of the hypothalamus, including the lateral hypothalamic area. Scale bar = 200 |im. (Data from ref. 7.)

Expression of the prepro-orexin gene was unaffected by short-term sleep deprivation in both rats and mice (18). Selective REM sleep deprivation also did not affect expression of the prepro-orexin gene in rats (19). However, orexin-A-containing neurons exhibited Fos during the night period. Sleep deprivation or treatment with methamphetamine increased Fos expression in orexin-A-containing neurons (20), and modafinil, a wake-promoting drug used for narcolepsy, induced marked increases of Fos expression in orexin-A-containing neurons (21,22). There is no doubt that activation of orexin-A-containing neurons is involved in promoting or maintaining wakefulness.

Sleeping Solace

Sleeping Solace

How To Better Your Sleep For A Better Life. Understanding the importance of good sleeping habits is very beneficial to the overall health of an individual in both mental and physical levels. Learn all the tricks here.

Get My Free Ebook


Post a comment