c-Fos expression in the limbic thalamus following thermoregulatory and wake-sleep changes in the rat.

A cellular degeneration of two thalamic nuclei belonging to the "limbic thalamus", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (Ta, - 10 °C) and in the first hours of the subsequent recovery period at normal laboratory Ta (25 °C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation.

c-Fos expression in preoptic nuclei as a marker of sleep rebound in the rat.

Thermoregulation is known to interfere with sleep, possibly due to a functional interaction at the level of the preoptic area (POA). Exposure to low ambient temperature (T(a)) induces sleep deprivation, which is followed by sleep rebound after a return to laboratory T(a). As two POA subregions, the ventrolateral preoptic nucleus (VLPO) and the median preoptic nucleus (MnPO), have been proposed to have a role in sleep-related processes, the expression of c-Fos and the phosphorylated form of the cAMP/Ca(2+)-responsive element-binding protein (P-CREB) was investigated in these nuclei during prolonged exposure to a T(a) of -10 degrees C and in the early phase of the recovery period. Moreover, the dynamics of the sleep rebound during recovery were studied in a separate group of animals. The results show that c-Fos expression increased in both the VLPO and the MnPO during cold exposure, but not in a specific subregion within the VLPO cluster counting grid (VLPO T-cluster). During the recovery, concomitantly with a large rapid eye movement sleep (REMS) rebound and an increase in delta power during non-rapid eye movement sleep (NREMS), c-Fos expression was high in both the VLPO and the MnPO and, specifically, in the VLPO T-cluster. In both nuclei, P-CREB expression showed spontaneous variations in basal conditions. During cold exposure, an increase in expression was observed in the MnPO, but not in the VLPO, and a decrease was observed in both nuclei during recovery. Dissociation in the changes observed between c-Fos expression and P-CREB levels, which were apparently subject to state-related non-regulatory modulation, suggests that the sleep-related changes observed in c-Fos expression do not depend on a P-CREB-mediated pathway.

Lithium affects REM sleep occurrence, autonomic activity and brain second messengers in the rat.

The effects of a single intraperitoneal administration of lithium, a drug used to prevent the recurrence of mania in bipolar disorders, were determined in the rat by studying changes in: (i) the wake-sleep cycle; (ii) autonomic parameters (hypothalamic and tail temperature, heart rate); (iii) the capacity to accumulate cAMP and IP(3) in the preoptic-anterior hypothalamic region (PO-AH) and in the cerebral cortex (CC) under an hypoxic stimulation at normal laboratory and at low ambient temperature (T(a)). In the immediate hours following the injection, lithium induced: (i) a significant reduction in REM sleep; (ii) a non-significant reduction in the delta power density of the EEG in NREM sleep; (iii) a significant decrease in the concentration of cAMP in PO-AH at normal laboratory T(a); (iv) a significant increase of IP(3) concentration in CC following exposure to low T(a). The earliest and most sensitive effects of lithium appear to be those concerning sleep. These changes are concomitant with biochemical effects that, in spite of a systemic administration of the substance, may be differentiated according to the second messenger involved, the brain region and the ambient condition.

Specific changes in cerebral second messenger accumulation underline REM sleep inhibition induced by the exposure to low ambient temperature.

In the rat the exposure to an ambient temperature (Ta) of -10 degrees C induces an almost total REM sleep deprivation that results in a proportional rebound in the following recovery at normal laboratory Ta when the exposure lasts for 24 h, but in a rebound much lower than expected when the exposure lasts 48 h. The possibility that this may be related to plastic changes in the nervous structures involved in the control of thermoregulation and REM sleep has been investigated by measuring changes in the concentration of adenosine 3':5'-cyclic monophosphate (cAMP) and D-myo-inositol 1,4,5-trisphosphate (IP(3)) in the preoptic-anterior hypothalamic area (PO-AH), the ventromedial hypothalamic nucleus (VMH) and, as a control, the cerebral cortex (CC). Second messenger concentration was determined in animals either stimulated by being exposed to hypoxia, a depolarizing condition that induces maximal second messenger accumulation or unstimulated, at the end of a 24-h and a 48-h exposure to -10 degrees C and also between 4 h 15 min and 4 h 30 min into recovery (early recovery). At the end of both exposure conditions, cAMP concentration significantly decreased in PO-AH-VMH, but did not change in CC, whilst changes in IP(3) concentration were similar in all these regions. The low cAMP concentration in PO-AH-VMH was concomitant with a significantly low accumulation in hypoxia. The normal capacity of cAMP accumulation was only restored in the early recovery following 24 h of exposure, but not following 48 h of exposure, suggesting that this may be a biochemical equivalent of the REM sleep inhibition observed during 48 h of exposure and which is carried over to the recovery.