The findings suggest that lysozomal storage abnormalities in Niemann-Pick disease patients may impact the hypothalamus and, more specifically, hypocretin-containing cells. These changes might be partially responsible for sleep abnormalities and cataplexy in patients with Niemann-Pick disease.

CSF hypocretin-1 levels at 6 PM did not significantly differ between patients with restless legs syndrome (RLS) and control subjects as measured by direct radioimmunoassay and after acid extraction. The authors did not observe significant differences between early onset and late onset RLS. Hypocretin-1 levels did not correlate with RLS severity or polysomnographic measures. These results contrast with previous findings reporting significantly increased CSF hypocretin-1 in the late evening and mostly in early onset RLS.

Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood. Here we show that generalized fear in mice in response to footshock results from a transmitter switch from glutamate to GABA in serotonergic neurons of the lateral wings of the dorsal raphe. We observe a similar change in transmitter identity in the postmortem brains of PTSD patients. Overriding the transmitter switch in mice using viral tools prevents the acquisition of generalized fear. Corticosterone release and activation of glucocorticoid receptors trigger the switch, and prompt antidepressant treatment blocks the co-transmitter switch and generalized fear. Our results provide new understanding of the plasticity involved in fear generalization.

The hypocretins (Hcrts, also known as orexins) are two peptides, both synthesized by a small group of neurons, most of which are in the lateral hypothalamic and perifornical regions of the hypothalamus. The hypothalamic Hcrt system directly and strongly innervates and potently excites noradrenergic, dopaminergic, serotonergic, histaminergic, and cholinergic neurons. Hcrt also has a major role in modulating the release of glutamate and other amino acid transmitters. Behavioral investigations have revealed that Hcrt neurons are maximally active in active waking. In rats, hypocretin neuronal activity is maximal during exploration and minimal during quiet waking and sleep. Degeneration of Hcrt neurons or genetic mutations that prevent the normal synthesis of Hcrt or of its receptors causes human and animal narcolepsy. Administration of Hcrt can reverse symptoms of narcolepsy in animals, may be effective in treating human narcolepsy, and may affect a broad range of motivated behaviors.The lateral hypothalamus (LH) has been implicated in wakefulness. One possibility is that it induces wakefulness by driving the basal forebrain (BF) wake-active neurons (Gerashchenko and Shiromani 2004). The activity of the BF wake-active neurons is hypothesized to release the sleep-inducing factor adenosine (AD), which begins to accumulate as wakefulness progresses. The AD is then hypothesized to inhibit the wake-active neurons (Strecker et al. 2000) and their silence allows the VLPO and median preoptic GABAergic sleep-active neurons to fire and sleep ensues. Here we measure AD levels in the BF and test the LH-BF circuit in Sprague-Dawley rats with lesions of the LH induced by hypocretin-2-saporin. 64 days after lesions the rats were implanted with sleep-recording electrodes and a guide cannula into the basal forebrain. Two weeks later, the rats were kept awake (gentle handling) for six hours (ZT 3-9) and microdialysis samples (5 mL) were collected hourly for 9 h (24 h after probe stabilization). AD levels were assessed using HPLC (see Murillo-Rodriguez et al. 2004 for details).Hypocretin-saporin ablated 95% of the hypocretin neurons with a resultant decline in CSF levels (-75% vs. control). AD levels increased with 6 h waking in saline control rats (n = 9), consistent with previous studies in cats (Strecker et al. 2000) and rats (Murillo-Rodriguez et al. 2004). However, in rats with LH lesions (n = 5) such an increase with waking did not occur. The homeostatic response to sleep loss was measured by conducting a rodent version of an MSLT where the rats were kept awake for 20 min and then allowed 20 min to sleep. This protocol was started at ZT2 and continued until lights were turned off. The lesioned rats were found to have more sleep during the 20 min sleep periods indicating a higher sleep drive in these rats.Previously, we (Gerashchenko et al. 2001) found that rats with LH lesions had increased sleep during the night, and here we found that they have increased sleep drive as measured by an MSLT. The increased sleep drive in thes...