Sleep-related c-Fos protein expression in the preoptic hypothalamus: effects of ambient warming

Preoptic area (POA) neuronal activity promotes sleep, but the localization of critical sleep-active neurons is not completely known. Thermal stimulation of the POA also facilitates sleep. This study used the c-Fos protein immunostaining method to localize POA sleep-active neurons at control (22 degrees C) and mildly elevated (31.5 degrees C) ambient temperatures. At 22 degrees C, after sleep, but not after waking, we found increased numbers of c-Fos immunoreactive neurons (IRNs) in both rostral and caudal parts of the median preoptic nucleus (MnPN) and in the ventrolateral preoptic area (VLPO). In animals sleeping at 31.5 degrees C, significantly more Fos IRNs were found in the rostral MnPN compared with animals sleeping at 22 degrees C. In VLPO, Fos IRN counts were no longer increased over waking levels after sleep at the elevated ambient temperature. Sleep-associated Fos IRNs were also found diffusely in the POA, but counts were lower than those made after waking. This study supports a hypothesis that the MnPN, as well as the VLPO, is part of the POA sleep-facilitating system and that the rostral MnPN may facilitate sleep, particularly at elevated ambient temperatures.     

Molecular mechanisms of sleep-wake regulation: a role of prostaglandin D2

Prostaglandin (PG) D2 is a major prostanoid in the brains of rats and other mammals, including humans. When PGD synthase (PGDS), the enzyme that produces PGD2 in the brain, was inhibited by the intracerebroventricular infusion of its selective inhibitors, i.e. tetravalent selenium compounds, the amount of sleep decreased both time and dose dependently. The amount of sleep of transgenic mice, in which the human PGDS gene had been incorporated, increased several fold under appropriate conditions. These data indicate that PGDS is a key enzyme in sleep regulation. In situ hybridization, immunoperoxidase staining and direct enzyme activity determination of tissue samples revealed that PGDS is hardly detectable in the brain parenchyma but is localized in the membrane systems surrounding the brain, namely, the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid (CSF) to become beta-trace, a major protein component of the CSF. PGD2 exerts its somnogenic activity by binding to PGD2 receptors exclusively localized at the ventrorostral surface of the basal forebrain. When PGD2 was infused into the subarachnoid space below the rostral basal forebrain, striking expression of proto-oncogene Fos immunoreactivity (FosIR) was observed in the ventrolateral preoptic area (VLPO), a putative sleep centre, concurrent with sleep induction. Fos expression in the VLPO was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus (TMN), a putative wake centre. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the VLPO neurons and downregulation of the wake neurons in the TMN area. Adenosine may be involved in the signal transduction associated with PGD2.     

Effects of estrogens on cholinergic neurons in the rat basal nucleus

Estrogen replacement in postmenopausal women may help prevent or delay development of Alzheimer's disease. Because loss of basal forebrain cholinergic neurons with reductions in choline acetyltransferase (ChAT) concentration are associated with Alzheimer's disease, we investigated the effect of estradiol (E(2)) and J 861, a non-feminizing estrogen, on cholinergic neurons in the basal forebrain. Ovariectomized rats received E(2), J 861 or vehicle, and basal forebrain sections through the substantia innominata, medial septum, and nucleus of the diagonal band were immunostained for ChAT. ChAT-immunoreactive cells in the basal forebrain were significantly reduced in the ovariectomized rats compared to intact rats, but those ovariectomized rats receiving estrogen replacement with E(2) and J 861 had near normal levels of ChAT-positive neurons. While retrograde tracing experiments with fluorogold injected into the prefrontal cortex showed no significant differences in the number of fluorogold-labeled cells among the groups, ChAT-immunoreactive cells and double-labeled cells were significantly lower in OVX rats than in intact and E(2) rats. Some substantia innominata cells in the J 861 rats were ChAT/estrogen receptor alpha-positive. These results suggest that E(2) and J 861 have positive effects on cholinergic neurons that project from the basal nucleus to the forebrain cortex.     

Compensatory sleep response to 12 h wakefulness in young and old rats

There is a pronounced decline in sleep with age. Diminished output from the circadian oscillator, the suprachiasmatic nucleus, might play a role, because there is a decrease in the amplitude of the day-night sleep rhythm in the elderly. However, sleep is also regulated by homeostatic mechanisms that build sleep drive during wakefulness, and a decline in these mechanisms could also decrease sleep. Because this question has never been addressed in old animals, the present study examined the effects of 12 h wakefulness on compensatory sleep response in young (3.5 mo) and old (21.5 mo) Sprague-Dawley and F344 rats. Old rats in both strains had a diminished compensatory increase in slow-wave sleep (SWS) after 12 h of wakefulness (0700-1900, light-on period) compared with the young rats. In contrast, compensatory REM sleep rebound was unaffected by age. To assess whether the reduced SWS rebound in old rats might result from loss of neurons implicated in sleep generation, we counted the number of c-Fos immunoreactive (c-Fos-ir) cells in the ventral lateral preoptic (VLPO) area and found no differences between young and old rats. These findings indicate that old rats, similar to elderly humans, demonstrate less sleep after prolonged wakefulness. The findings also indicate that although old rats have a decline in sleep, this cannot be attributed to loss of VLPO neurons implicated in sleep.     

Estradiol treatment increases feeding-induced c-Fos expression in the brains of ovariectomized rats

The steroid hormone estradiol decreases meal size by increasing the potency of negative-feedback signals involved in meal termination. We used c-Fos immunohistochemistry, a marker of neuronal activation, to investigate the hypothesis that estradiol modulates the processing of feeding-induced negative-feedback signals within the nucleus of the solitary tract (NTS), the first central relay of the neuronal network controlling food intake, and within other brain regions related to the control of food intake. Chow-fed, ovariectomized rats were injected subcutaneously with 10 microg 17-beta estradiol benzoate or sesame oil vehicle on 2 consecutive days. Forty-eight hours after the second injections, 0, 5, or 10 ml of a familiar sweet milk diet were presented for 20 min at dark onset. Rats were perfused 100 min later, and brain tissue was collected and processed for c-Fos-like immunoreactivity. Feeding increased the number of c-Fos-positive cells in the NTS, the paraventricular nucleus of the hypothalamus (PVN), and the central nucleus of the amygdala (CeA) in oil-treated rats. Estradiol treatment further increased this response in the caudal, subpostremal, and intermediate NTS, which process negative-feedback satiation signals, but not in the rostral NTS, which processes positive-feedback gustatory signals controlling meal size. Estradiol treatment also increased feeding-induced c-Fos in the PVN and CeA. These results indicate that modest amounts of food increase neuronal activity within brain regions implicated in the control of meal size in ovariectomized rats and that estradiol treatment selectively increases this activation. They also suggest that estradiol decreases meal size by increasing feeding-related neuronal activity in multiple regions of the distributed neural network controlling meal size.     

Sucrose self-administration and CNS activation in the rat

We have previously reported that administration of insulin into the arcuate nucleus of the hypothalamus decreases motivation for sucrose, assessed by a self-administration task, in rats. Because the pattern of central nervous system (CNS) activation in association with sucrose self-administration has not been evaluated, in the present study, we measured expression of c-Fos as an index of neuronal activation. We trained rats to bar-press for sucrose, according to a fixed-ratio (FR) or progressive-ratio (PR) schedule and mapped expression of c-Fos immunoreactivity in the CNS, compared with c-Fos expression in handled controls. We observed a unique expression of c-Fos in the medial hypothalamus (the arcuate, paraventricular, retrochiasmatic, dorsomedial, and ventromedial nuclei) in association with the onset of PR performance, and expression of c-Fos in the lateral hypothalamus and the bed nucleus of stria terminalis in association with the onset of FR performance. c-Fos expression was increased in the nucleus accumbens of both FR and PR rats. Our study emphasizes the importance of both hypothalamic energy homeostasis circuitry and limbic circuitry in the performance of a food reward task. Given the role of the medial hypothalamus in regulation of energy balance, our study suggests that this circuitry may contribute to reward regulation within the larger context of energy homeostasis.     

Maturation of sleep homeostasis in developing rats: a role for preoptic area neurons

The present study evaluated the hypothesis that developmental changes in hypothalamic sleep-regulatory neuronal circuits contribute to the maturation of sleep homeostasis in rats during the fourth postnatal week. In a longitudinal study, we quantified electrographic measures of sleep during baseline and in response to sleep deprivation (SD) on postnatal days 21/29 (P21/29) and P22/30 (experiment 1). During 24-h baseline recordings on P21, total sleep time (TST) during the light and dark phases did not differ significantly. On P29, TST during the light phase was significantly higher than during the dark phase. Mean duration of non-rapid-eye-movement (NREM) sleep bouts was significantly longer on P29 vs. P21, indicating improved sleep consolidation. On both P22 and P30, rats exhibited increased NREM sleep amounts and NREM electroencephalogram delta power during recovery sleep (RS) compared with baseline. Increased NREM sleep bout length during RS was observed only on P30. In experiment 2, we quantified activity of GABAergic neurons in median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) during SD and RS in separate groups of P22 and P30 rats using c-Fos and glutamic acid decarboxylase (GAD) immunohistochemistry. In P22 rats, numbers of Fos(+)GAD(+) neurons in VLPO did not differ among experimental conditions. In P30 rats, Fos(+)GAD(+) counts in VLPO were elevated during RS. MnPN neuronal activity was state-dependent in P22 rats, but Fos(+)GAD(+) cell counts were higher in P30 rats. These findings support the hypothesis that functional emergence of preoptic sleep-regulatory neurons contributes to the maturation of sleep homeostasis in the developing rat brain.     

Basal forebrain cholinergic neurons are necessary for estrogen to enhance acquisition of a delayed matching-to-position T-maze task

Intraseptal injections of the selective cholinergic immunotoxin 192 IgG-saporin (SAP) were performed to determine whether basal forebrain cholinergic neurons are necessary for hormone-mediated enhancement of acquisition in a delayed matching-to-position (DMP) T-maze task. The DMP task is a simple spatial learning task. Studies have shown that continuous estradiol replacement enhances acquisition of the DMP task in young ovariectomized rats and that long-term treatment with either estradiol or estradiol + progesterone can prevent a deficit in DMP acquisition in old rats. In the present study, continuous estradiol replacement significantly enhanced acquisition of the DMP task by non-SAP-treated, ovariectomized rats. In contrast, neither continuous estradiol nor weekly administration of estradiol + progesterone significantly enhanced acquisition of the DMP task in rats that received intraseptal injections of either a high dose (1.0 microg) or a low dose (0.22 microg) of SAP. Animals that reached criterion were significantly impaired by rotating the maze 180 degrees regardless of treatment, suggesting that animals in all groups used extramaze cues to at least some degree to solve the task. SAP-treated animals were slightly more sensitive to increasing the intertrial delay than non-SAP-treated controls, suggesting that the SAP lesions produced a modest deficit in spatial working memory. Immunohistochemistry confirmed the loss of cholinergic neurons in specific regions of the basal forebrain of SAP-treated animals. In addition, DMP acquisition correlated significantly with ChAT activity in the hippocampus and frontal cortex. The data suggest that basal forebrain cholinergic projections are necessary for hormone-mediated enhancement of DMP acquisition.     

Food entrainment modifies the c-Fos expression pattern in brain stem nuclei of rats

When food is restricted to a few hours daily, animals increase their locomotor activity 2-3 h before food access, which has been termed food anticipatory activity. Food entrainment has been linked to the expression of a circadian food-entrained oscillator (FEO) and the anatomic substrate of this oscillator seems to depend on diverse neural systems and peripheral organs. Previously, we have described a differential involvement of hypothalamic nuclei in the food-entrained process. For the food entrainment pathway, the communication between the gastrointestinal system and central nervous system is essential. The visceral synaptic input to the brain stem arrives at the dorsal vagal complex and is transmitted directly from the nucleus of the solitary tract (NST) or via the parabrachial nucleus (PBN) to hypothalamic nuclei and other areas of the forebrain. The present study aims to characterize the response of brain stem structures in food entrainment. The expression of c-Fos immunoreactivity (c-Fos-IR) was used to identify neuronal activation. Present data show an increased c-Fos-IR following meal time in all brain stem nuclei studied. Food-entrained temporal patterns did not persist under fasting conditions, indicating a direct dependence on feeding-elicited signals for this activation. Because NST and PBN exhibited a different and increased response from that expected after a regular meal, we suggest that food entrainment promotes ingestive adaptations that lead to a modified activation in these brain stem nuclei, e.g., stomach distension. Neural information provided by these nuclei to the brain may provide the essential entraining signal for FEO.     

Topography of oxytocinergic estradiol target neurons in the mouse hypothalamus

Combined (3H) estradiol autoradiography and oxytocin immunocytochemistry were used in order to study co-localization of cytoplasmic oxytocin immunoreactivity and nuclear uptake of (3H) estradiol in the forebrain of adult ovariectomized mice. Labelling with (3H) estradiol was found in subpopulations of neurons that constitute between 10 to 40% of the oxytocinergic cells in the paraventricular nucleus, the supraoptic nucleus and the intersupraoptico-paraventricular islands. Oxytocinergic neurons in the septohypothalamic nucleus, the anterior commissural nucleus, the periventricular nucleus and the zona incerta only occasionally showed nuclear uptake of (3H) estradiol. The results indicate that oxytocinergic cell groups within the classical magnocellular nuclei have much higher numbers of estrogen receptors than the so called accessory oxytocin neurons. Oxytocinergic neuronal systems seem to constitute functionally heterogenous populations of cells, differently influenced by estradiol.     

Rhythms in Fos expression in brain areas related to the sleep-wake cycle in the diurnal Arvicanthis niloticus

Most mammals show daily rhythms in sleep and wakefulness controlled by the primary circadian pacemaker, the suprachiasmatic nucleus (SCN). Regardless of whether a species is diurnal or nocturnal, neural activity in the SCN and expression of the immediate-early gene product Fos increases during the light phase of the cycle. This study investigated daily patterns of Fos expression in brain areas outside the SCN in the diurnal rodent Arvicanthis niloticus. We specifically focused on regions related to sleep and arousal in animals kept on a 12:12-h light-dark cycle and killed at 1 and 5 h after both lights-on and lights-off. The ventrolateral preoptic area (VLPO), which contained cells immunopositive for galanin, showed a rhythm in Fos expression with a peak at zeitgeber time (ZT) 17 (with lights-on at ZT 0). Fos expression in the paraventricular thalamic nucleus (PVT) increased during the morning (ZT 1) but not the evening activity peak of these animals. No rhythm in Fos expression was found in the centromedial thalamic nucleus (CMT), but Fos expression in the CMT and PVT was positively correlated. A rhythm in Fos expression in the ventral tuberomammillary nucleus (VTM) was 180 degrees out of phase with the rhythm in the VLPO. Furthermore, Fos production in histamine-immunoreactive neurons of the VTM cells increased at the light-dark transitions when A. niloticus show peaks of activity. The difference in the timing of the sleep-wake cycle in diurnal and nocturnal mammals may be due to changes in the daily pattern of activity in brain regions important in sleep and wakefulness such as the VLPO and the VTM.     

Intracerebroventricular administration of galanin or galanin receptor subtype 1 agonist M617 induces c-Fos activation in central amygdala and dorsomedial hypothalamus

The neuropeptide galanin and galanin receptors are widespread throughout cortical, limbic and midbrain areas implicated in reward, learning/memory, pain, drinking and feeding. While many studies have shown that galanin produces a variety of presynaptic and post-synaptic responses, work studying the effects of galanin on neural activation is limited. The present study examined patterns of c-Fos immunoreactivity resulting from intracerebroventricular administration of galanin versus saline injection in awake rats. An initial comprehensive qualitative survey was conducted to identify regions of high c-Fos expression followed up with quantitative analysis. Galanin induced a significant increase in c-Fos levels relative to saline-treated controls in dorsomedial hypothalamus and in the central nucleus of the amygdala. This pattern of activation was also produced by galanin receptor type 1 agonist M617. The present findings confirm that galanin upregulates c-Fos activation in hypothalamic nuclei, and supports roles for galanin in central amygdala-mediated regulation of stress-responses, food intake, and Pavlovian conditioning.     

The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis

Amylin is a peptide hormone that is cosecreted with insulin from the pancreas during and after food intake. Peripherally injected amylin potently inhibits feeding by acting on the area postrema (AP), a circumventricular organ lacking a functional blood-brain barrier. We recently demonstrated that AP neurons are excited by a near physiological concentration of amylin. However, the subsequent neuronal mechanisms and the relevance of endogenously released amylin for the regulation of food intake are poorly understood. Therefore, we investigated 1) amylin's contribution to feeding-induced c-Fos expression in the rat AP and its ascending projection sites, and 2) amylin's ability to reverse fasting-induced c-Fos expression in the lateral hypothalamic area (LHA). Similar to amylin (20 microg/kg sc), refeeding of 24-h food-deprived rats induced c-Fos expression in the AP, the nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. In AP-lesioned rats, the amylin-induced c-Fos expression in each of these sites was blunted, indicating an AP-mediated activation of these structures. Pretreatment with the amylin antagonist AC-187 (1 mg/kg sc) inhibited feeding-induced c-Fos expression in the AP. Food deprivation activated LHA neurons, a response known to be associated with hunger. This effect was reversed within 2 h after refeeding and also in nonrefed animals that received amylin. In summary, our data provide the first evidence that feeding-induced amylin release activates AP neurons projecting to subsequent relay stations known to transmit meal-related signals to the forebrain. Activation of this pathway seems to coincide with an inhibition of LHA neurons.     

Individual differences in rhythms of behavioral sleep and its neural substrates in Nile grass rats

Laboratory populations of grass rats (Arvicanthis niloticus) housed with a running wheel show considerable variation in patterns of locomotor activity. At the extremes are "day-active" (DA) animals with a monophasic distribution of running throughout the light phase and "night-active" (NA) animals exhibiting a biphasic pattern with an extended peak at the beginning of the dark phase and a brief peak shortly before lights-on. Here, the authors use this intraspecific variation to explore interactions between circadian and homeostatic influences on sleep and the effects of these interactions on the activity of brain regions involved in sleep regulation. Male animals were singly housed with running wheels in a 12:12 LD cycle, videotaped for 24 h, and perfused at ZT 4 or 16. Behavioral sleep was scored from the videotapes, and brains were processed for cFos immunoreactivity (cFos-ir). Sleep duration within the light and dark phases was higher in NA and DA animals, respectively, but these groups did not differ with respect to total sleep. In both groups, sleep bouts were shortest in the light phase and longest between ZT 20 and ZT 23. In the ventrolateral preoptic area (VLPO), cFos-ir was higher at ZT 16 than at ZT 4 in DA but not NA grass rats, and it was correlated with behavioral sleep at ZT 16 but not ZT 4. In OXA neurons, cFos-ir was high at ZT 4 in DA grass rats and at ZT 16 in NA grass rats, and it was correlated with behavioral sleep at both times. In the lower subparaventricular zone (LSPV), cFos-ir was higher at ZT 16 in both DA and NA animals, and it was unrelated to behavioral sleep. Thus, patterns of cFos-ir in the LSPV and OXA neurons were most tightly linked to time and sleep, respectively, whereas cFos-ir in the VLPO was influenced by an interaction between these 2 variables.     

Hormonal regulation of apoptosis in the endometrium of common marmosets (Callithrix jacchus)

Phase-dependent apoptotic changes in the human endometrium during an ovarian cycle imply a potential role of steroids in the regulation of apoptosis. The present study was undertaken to determine the direct role of hormones in endometrial apoptosis in marmosets (Callithrix jacchus), a primate species which shows similarity to humans in terms of the cycle length and pattern. Endometrial apoptosis was detected by 3'-end labeling (TUNEL) in various phases of ovarian cycle in naturally cycling healthy marmosets (n=14) and also in ovariectomized marmosets (n=13) treated with either estradiol alone (E) or progesterone alone (P) or estradiol followed by progesterone (E+P). Expressions of apoptosis associated genes such as Bcl-2 family members (Bax and Bcl-2), proliferating cell nuclear antigen (PCNA)--a proliferation marker and steroid receptors, ERalpha and PR A were analysed by immunohistochemical methods. Apoptosis was intense in the glandular epithelial cells of endometrium during the mid-luteal phase as compared to other phases in naturally cycling animals; in the E+P group as compared to other groups of ovariectomized animals (P<0.05). Pronounced apoptosis in the mid-luteal phase was accompanied by the increased expression of Bax in glandular epithelial cells; while Bcl-2 immunoreactivity remained unchanged. PCNA expression was higher in the naturally cycling animals in the follicular phase and in the E group of the ovariectomized animals as compared those in the other groups. Immunoreactive ERalpha and PR A in glandular epithelial cells were most abundant during early follicular phase in naturally cycling animals and in both E and E+P groups among the ovariectomized animals. The present study highlights the importance of apoptosis in endometrial remodeling during the ovarian cycle and secondly, the role of both estradiol and progesterone in the regulation of apoptosis.     

17β-雌二醇对去卵巢胰岛素抵抗大鼠主动脉舒缩功能损伤的保护作用

为观察17β-雌二醇（17beta-estradiol,17β-E2）对去卵巢胰岛素抵抗（insulin resistance,IR）大鼠主动脉结构和舒缩功能的影响及其可能机制,成年雌性Sprague-Dawley大鼠卵巢切除后,高果糖喂养8周诱导IR,同时给予生理剂量的17β-E2（30μg／kg）,每天皮下注射一次,并检测IR相关指标。大鼠胸主动脉石蜡切片,HE染色,图像分析系统测定其结构。采用血管环灌流法,观察各组大鼠胸主动脉环对新福林（L-phenylephrine,PE）的收缩反应和对ACh、硝普钠（sodium nitroprusside,SNP）的舒张反应以及一氧化氮合酶（nitric oxide synthase,NOS）抑制剂N-硝基-L-精氨酸甲脂（N-nitrl-L-arginine methylester,L-NAME）对卵巢切除＋果糖喂养＋17β-E2组大鼠胸主动脉ACh的舒张反应的影响;检测各组大鼠一氧化氮（nitric oxide,NO）含量。结果显示：（1）17β-E2能防止高果糖诱导的去卵巢IR人鼠收缩压升高、高胰岛素血症和胰岛素敏感性下降;（2）各组火鼠胸主动脉的结构无显著性差异;（3）卵巢切除＋果糖喂养组大鼠与卵巢切除组或果糖喂养组相比,血清NO显著降低,胸主动脉对PE的收缩反应显著增强,对ACh的舒张反应显著降低,17β-E2能逆转上述改变,L-NAME可部分阻断17β-E2的这种作用;（4）各组大鼠胸主动脉对SNP的舒张反应和去内皮后对PE的收缩反应均无显著差异。以上结果表明,17β-E2能抑制高果糖诱导的去卵巢IR大鼠血管舒缩功能的紊乱,其机制一方面可能是部分通过血管内皮细胞NOS途径促进NO的释放,保护内皮细胞;另一方面可能是通过降低血压,血清胰岛素水平,改善IR所致。     

Estradiol treatment increases CCK-induced c-Fos expression in the brains of ovariectomized rats

The ovarian hormone estradiol reduces meal size and food intake in female rats, at least in part by increasing the satiating potency of CCK. Here we used c-Fos immunohistochemistry to determine whether estradiol increases CCK-induced neuronal activation in several brain regions implicated in the control of feeding. Because the adiposity signals leptin and insulin appear to control feeding in part by increasing the satiating potency of CCK, we also examined whether increased adiposity after ovariectomy influences estradiol's effects on CCK-induced c-Fos expression. Ovariectomized rats were injected subcutaneously with 10 microg 17beta-estradiol benzoate (estradiol) or vehicle once each on Monday and Tuesday for 1 wk (experiment 1) or for 5 wk (experiment 2). Two days after the final injection of estradiol or vehicle, rats were injected intraperitoneally with 4 microg/kg CCK in 1 ml/kg 0.9 M NaCl or with vehicle alone. Rats were perfused 60 min later, and brain tissue was collected and processed for c-Fos immunoreactivity. CCK induced c-Fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), paraventricular nucleus of the hypothalamus (PVN), and central nucleus of the amygdala (CeA) in vehicle- and estradiol-treated ovariectomized rats. Estradiol treatment further increased this response in the caudal, subpostremal, and intermediate NTS, the PVN, and the CeA, but not in the rostral NTS or AP. This action of estradiol was very similar in rats tested before (experiment 1) and after (experiment 2) significant body weight gain, suggesting that adiposity does not modulate CCK-induced c-Fos expression or interact with estradiol's ability to modulate CCK-induced c-Fos expression. These findings suggest that estradiol inhibits meal size and food intake by increasing the central processing of the vagal CCK satiation signal.     

Age-related changes of hypocretin in basal forebrain of guinea pig

Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) have been implicated in a wide variety of functions including sleep and wakefulness as well as related behaviors. Many of these functions of the hypocretins involve the activation of cholinergic neurons in the basal forebrain (BF). These neurons have been shown to exhibit age-related changes in a variety of species. In the present experiment, in adult and aged guinea pigs, we compared hypocretin immunoreactivity in regions of the BF that include the medial septal nucleus (MS), the vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB) and the magocellular preoptic nucleus (MCPO). In adult guinea pigs (3–5 months of age), all of the preceding BF regions contained dense hypocretin fibers with varicosities. On the contrary, in old guinea pigs (27–28 months), although the MS exhibited a similar intensity of hypocretin immunoreactivity compared with the adult guinea pig, there was a significant decrease in the intensity of immunoreactivity of hypocretinergic fibers in the VDB, HDB and MCPO. These data indicate that the hypocretinergic innervation of specific nuclei of the BF is compromised during the aging process. We suggest that the reduction in hypocretinergic innervation of the BF nuclei may contribute to the age-related changes in the states of sleep and wakefulness as well as deficits in related systems that occur in old age.     

前列腺素D2与睡眠调节

前列腺素D2（PGD2）是目前已知最有潜力的内源性促睡眠物质之一。鼠脑脊液（CSF）中PGD2浓度与睡眠－觉醒周期一致,呈现节律性改变,并且随睡眠剥夺期间嗜睡倾向增加而增加,催化PGH2转变为PGD2的特生酶有两种：Lipocalin型前列腺素D合成酶（L－PGDS）和脾型PGDS。L－PGDS主要在大脑蛛网膜和脉络丛产生,并分泌入CSF。L－PGDS和PGD2在脑室系统、蛛网膜下腔及细胞外间隙中循环,循环中的PGD2可与前脑头端基底腹内侧面的化学感受器中的前列腺素D2受体（DPR）相互作用,通过活化具有腺苷A2a受体的元以产生促进睡眠的信号。PGD2敏感区内DPR的活化可导致腹侧视前区（VLPO）内神经元的活化,其可通过抑制结节乳头核（TMN）而促进睡眠。相反,PGE2在维持大脑清醒状态下起主要作用。PGD2和PGE2的平衡对正常睡眠－觉醒周期的维持十分关键。