Neuropsychological Profile of 25 Brazilian Patients with 22q11.2 Deletion Syndrome: Effects of Clinical and Socioeconomic Variables.

The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical ≈3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life.

Acute and chronic sleep restriction differentially modify maternal behavior and milk macronutrient composition in the postpartum rat.

BACKGROUNDS: Sleep restriction is considered a stressful condition itself, causing a wide variety of physiological alterations, from cognitive and hormonal to immunological status. In addition, it is established that stress in mother rats can modify milk ejection, milk composition, and maternal care of the pups. Also, sleep disturbances during the early stages of motherhood are a common feature of all studied species. In this context, while the impacts of sleep disruption in non-lactating animals were extensively investigated, its repercussions during the initial phases of motherhood have been poorly explored. Therefore, we wonder if maternal behavior, milk ejection and its macronutrient composition would be disrupted when mother rats are subjected to an additional acute or chronic sleep restriction to the already existing sleep disturbances. METHODS: Lactating rats were implanted with unilateral electrodes for polysomnographic recordings and for deep brain electrical stimulation into mesopontine waking-promoting area (for sleep deprivation). During the early postpartum period (postpartum day 5-9), mother rats were randomly assigned into one of three groups: chronic sleep restriction group (CSR; 6 h of sleep deprivation/day for five consecutive days), acute sleep restriction group (ASR; 6 h of sleep deprivation only for one day), or undisturbed group (control group). Active maternal behaviors (retrievals of the pups into the nest, mouthing, lickings [corporal and anogenital] and sniffing the pups) and passive maternal behaviors (kyphotic and supine nursing postures) were evaluated during a 30 min period without sleep restriction immediately after the sleep restriction or control period. The litter weight gain was assessed every day, and on the last experimental session mothers were milked for posterior macronutrients analysis (protein, carbohydrates and fat). RESULTS: When compared to control group, CSR decreased the amount of milk ejected in the middle days of the sleep restriction period, while ASR did not affect this parameter. Moreover, ASR reduced milk protein content compared to control and CSR groups. Finally, compared to the control group, CSR reduced active maternal behaviors towards the end of the treatment days. CONCLUSIONS: We demonstrated that not only acute but also chronic sleep restriction impacts on the postpartum period, each one affecting different aspects of maternal behavior and lactation. Our results suggest the existence of a homeostatic recovery mechanism in breastfeeding during CSR, possibly ensuring the survival of the litter, while the decline in active maternal behaviors appears to be cumulative.

Hypocretins, sleep, and maternal behavior.

The postpartum period is a demanding time during which mothers experience numerous physiological adaptations that enable them to care for their offspring while maintaining their wellbeing. Hypocretins, also known as orexins, are neuropeptides synthesized by hypothalamic neurons that play a fundamental role in several functions, including the promotion of wakefulness and motivated behaviors, such as maternal care. In this regard, several findings suggest that the activity of the hypocretinergic system increases in the early postpartum period and begins to decline as weaning approaches. In particular, hypocretins within the medial preoptic area, a crucial region during this period, modulate both maternal behavior and sleep. Although further studies are necessary to obtain a comprehensive understanding of the role of hypocretins in lactating females, current research suggests that this system participates in promoting active components of maternal behavior and regulating wakefulness and sleep adjustments during the postpartum period, potentially leading to increased wakefulness during this stage. These adaptive adjustments enable the mother to cope with the continuously changing demands of the pups.

Is sleep critical for lactation in rat?

Sleep deprivation is a feature shared by most studied mammals at some point during the postpartum period. Unlike the rabbit, the pig, or the human mother, sleep has been claimed as an essential state for milk ejection in mother rats, where sleep deprivation using gentle handling (GH) prevents milk ejection and pup weight gain. Though sleep deprivation is a stressful situation itself, most common methodologies used in laboratory animals, including GH, usually involve aversive stimulus to prevent sleep, adding further stress to the animal. Deep brain electrical stimulation (DBES) of the brainstem reticular formation is a less common technique used to prevent sleep, and while this methodology may also carry unwanted effects, it avoids stressful conditions. In the present study, we examined the relationship between sleep and nursing, and how different sleep deprivation methodologies impact nursing and lactation. For this purpose, we carried out two sets of experiments. First, we correlated sleep and waking states with different nursing parameters of lactating rats under undisturbed conditions. Second, we slept deprived another group of mother rats using two different techniques: GH and DBES. Our main findings show that sleeping time was positively correlated with the time devote to nurse the pups, but not either with milk ejection or pup weight gain. When mother rats were sleep deprived, maternal behavior was fragmented using both methods, but was substantially more disrupted when using GH. Additionally, lactating dams were capable of ejecting milk and their pups gained weight despite of being sleep deprived using both techniques, but these parameters were significantly reduced using GH compared to control values, while DBES did not differ from control group. Overall, these results suggest that sleep and nursing are behaviorally compatible, but in disagreement with previous findings, we concluded that sleep is not necessary for milk ejection. These observations have critical implications for using the rat as a model to explore sleep loss during the postpartum period.

Electrophysiological characterization of medial preoptic neurons in lactating rats and its modulation by hypocretin-1.

The medial preoptic area (mPOA) undergoes through neuroanatomical changes across the postpartum period, during which its neurons play a critical role in the regulation of maternal behavior. In addition, this area is also crucial for sleep-wake regulation. We have previously shown that hypocretins (HCRT) within the mPOA facilitate active maternal behaviors in postpartum rats, while the blockade of endogenous HCRT in this area promotes nursing and sleep. To explore the mechanisms behind these HCRT actions, we aimed to evaluate the effects of juxta-cellular HCRT-1 administration on mPOA neurons in urethane-anesthetized postpartum and virgin female rats. We recorded mPOA single units and the electroencephalogram (EEG) and applied HCRT-1 juxta-cellular by pressure pulses. Our main results show that the electrophysiological characteristics of the mPOA neurons and their relationship with the EEG of postpartum rats did not differ from virgin rats. Additionally, neurons that respond to HCRT-1 had a slower firing rate than those that did not. In addition, administration of HCRT increased the activity in one group of neurons while decreasing it in another, both in postpartum and virgin rats. This study suggests that the mechanisms by which HCRT modulate functions controlled by the mPOA involve different cell populations.

Role of Hypocretin in the Medial Preoptic Area in the Regulation of Sleep, Maternal Behavior and Body Temperature of Lactating Rats.

Hypocretins (HCRT), also known as orexins, includes two neuroexcitatory peptides, HCRT-1 and HCRT-2 (orexin A y B, respectively), synthesized by neurons located in the postero-lateral hypothalamus, whose projections and receptors are widely distributed throughout the brain, including the medial preoptic area (mPOA). HCRT have been associated with a wide range of physiological functions including sleep-wake cycle, maternal behavior and body temperature, all regulated by the mPOA. Previously, we showed that HCRT in the mPOA facilitates certain active maternal behaviors, while the blockade of HCRT-R1 increases the time spent in nursing. As mother rats mainly sleep while they nurse, we hypothesize that HCRT in the mPOA of lactating rats reduce sleep and nursing, while intra-mPOA administration of a dual orexin receptor antagonist (DORA) would cause the opposite effect. Therefore, the aim of this study was to determine the role of HCRT within the mPOA, in the regulation and integration of the sleep-wake cycle, maternal behavior and body temperature of lactating rats. For that purpose, we assessed the sleep-wake states, maternal behavior and body temperature of lactating rats following microinjections of HCRT-1 (100 and 200 µM) and DORA (5 mM) into the mPOA. As expected, our data show that HCRT-1 in mPOA promote wakefulness and a slightly increase in body temperature, whereas DORA increases both NREM and REM sleep together with an increment of nursing and milk ejection. Taken together, our results strongly suggest that the endogenous reduction of HCRT within the mPOA contribute to the promotion of sleep, milk ejection and nursing behavior in lactating rats.

Effects of sleep modulation during pregnancy in the mother and offspring: Evidences from preclinical research.

Disturbed sleep during gestation may lead to adverse outcomes for both mother and child. Animal research plays an important role in providing insights into this research field by enabling ethical and methodological requirements that are not possible in humans. Here, we present an overview and discuss the main research findings related to the effects of prenatal sleep deprivation in animal models. Using systematic review approaches, we retrieved 42 articles dealing with some type of sleep alteration. The most frequent research topics in this context were maternal sleep deprivation, maternal behaviour, offspring behaviour, development of sleep-wake cycles in the offspring, hippocampal neurodevelopment, pregnancy viability, renal physiology, hypertension and metabolism. This overview indicates that the number of basic studies in this field is growing, and provides biological plausibility to suggest that sleep disturbances might be detrimental to both mother and offspring by promoting increased risk at the behavioural, hormonal, electrophysiological, metabolic and epigenetic levels. More studies on the effects of maternal sleep deprivation are needed, in light of their major translational perspective.

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile.

Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.

Power and coherence of cortical high-frequency oscillations during wakefulness and sleep.

Recently, a novel type of fast cortical oscillatory activity that occurs between 110 and 160 Hz (high-frequency oscillations (HFO)) was described. HFO are modulated by the theta rhythm in hippocampus and neocortex during active wakefulness and REM sleep. As theta-HFO coupling increases during REM, a role for HFO in memory consolidation has been proposed. However, global properties such as the cortex-wide topographic distribution and the cortico-cortical coherence remain unknown. In this study, we recorded the electroencephalogram during sleep and wakefulness in the rat and analyzed the spatial extent of the HFO band power and coherence. We confirmed that the HFO amplitude is phase-locked to theta oscillations and is modified by behavioral states. During active wakefulness, HFO power was relatively higher in the neocortex and olfactory bulb compared to sleep. HFO power decreased during non-REM and had an intermediate level during REM sleep. Furthermore, coherence was larger during active wakefulness than non-REM, while REM showed a complex pattern in which coherence increased only in intra and decreased in inter-hemispheric combination of electrodes. This coherence pattern is different from gamma (30-100 Hz) coherence, which is reduced during REM sleep. This data show an important HFO cortico-cortical dialog during active wakefulness even when the level of theta comodulation is lower than in REM. In contrast, during REM, this dialog is highly modulated by theta and restricted to intra-hemispheric medial-posterior cortical regions. Further studies combining behavior, electrophysiology and new analytical tools are needed to plunge deeper into the functional significance of the HFO.

Hypocretinergic system in the medial preoptic area promotes maternal behavior in lactating rats.

Hypocretin-1 and 2 (HCRT-1 and HCRT-2, respectively) are neuropeptides synthesized by neurons located in the postero-lateral hypothalamus, whose projections are widely distributed throughout the brain. The hypocretinergic (HCRTergic) system has been associated with the generation and maintenance of wakefulness, as well as with the promotion of motivated behaviors. In lactating rats, intra-cerebroventricular HCRT-1 administration stimulates maternal behavior, whilst lactation per se increases the expression of HCRT type 1 receptor (HCRT-R1). Due to the fact that HCRTergic receptors are expressed in the medial preoptic area (mPOA), a region critically involved in maternal behavior, we hypothesize that HCRT-1 promotes maternal behavior acting on this region. In order to evaluate this hypothesis, we assessed the maternal behavior of lactating rats following microinjections of HCRT-1 (10 or 100µM) and the selective HCRT-R1 antagonist SB-334867 (250µM) into the mPOA, during the first and second postpartum weeks. While intra-mPOA microinjections of HCRT-1 (100µM) increased corporal pup licking during the second postpartum week, the blockade of HCRT-R1 significantly decreased active components of maternal behavior, such as retrievals, corporal and ano-genital lickings, and increased the time spent in nursing postures in both postpartum periods. We conclude that HCRTergic system in the mPOA may stimulate maternal behavior, suggesting that endogenous HCRT-1 is necessary for the natural display of this behavior.

Melanin-Concentrating Hormone (MCH): Role in REM Sleep and Depression.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.

Melanin-concentrating hormone in the medial preoptic area reduces active components of maternal behavior in rats.

Melanin-concentrating hormone (MCH) is an inhibitory neuropeptide mainly synthesized in neurons of the lateral hypothalamus and incerto-hypothalamic area of mammals that has been implicated in behavioral functions related to motivation. During lactation, this neuropeptide is also expressed in the medial preoptic area (mPOA), a key region of the maternal behavior circuitry. Notably, whereas MCH expression in the mPOA progressively increases during lactation, maternal behavior naturally declines, suggesting that elevated MCHergic activity in the mPOA inhibit maternal behavior in the late postpartum period. To explore this idea, we assessed the maternal behavior of early postpartum females following bilateral microinfusions of either MCH (50 and 100 ng/0.2 µl/side) or the same volume of vehicle into the mPOA. As expected, females receiving 100 ng MCH into the mPOA exhibited significant deficits in the active components of maternal behavior, including retrieving and nest building. In contrast, nursing, as well as other behaviors, including locomotor activity, exploration, and anxiety-like behavior, were not affected by intra-mPOA MCH infusion. The present results, together with previous findings showing elevated expression of this neuropeptide toward the end of the postpartum period, suggest that modulation of mPOA function by MCH may contribute to the weaning of maternal responsiveness characteristic of the late postpartum period.

Avances en el estudio de la neurobiología de la depresión: rol de la hormona concentradora de melanina / Progress made in studies in the neurobiology of depression: a role for the melanin-concentrating hormone

Introducción: la depresión mayor (DM) es una enfermedad psiquiátrica frecuente, con importante morbilidad y una relación estrecha con el suicidio. Objetivo: hacer una puesta a punto de los avances en el estudio de la neurobiología de la DM, enfocándonos en el posible rol de la hormona concentradora de melanina (MCH) en esta patología. Metodología: revisión de la bibliografía con énfasis en nuestros propios trabajos originales. Resultados: la MCH es un neuromodulador peptídico sintetizado por neuronas del hipotálamo. Las neuronas MCHérgicas envían proyecciones hacia diversas regiones del sistema nervioso central, incluyendo las áreas vinculadas con la regulación de la vigilia y del sueño, así como a diversas estructuras del sistema límbico que participan en la regulación del humor. Aunque numerosos estudios han relacionado el sistema MCHérgico con el control de la homeostasis energética, hallazgos recientes han permitido señalar un rol de este sistema en los mecanismos de generación del sueño. A su vez, una convergencia de datos provenientes de diversos estudios sugiere que la MCH estaría involucrada en la fisiopatología de la DM. Nuestros propios estudios preclínicos tienden a indicar que la MCH promueve la generación del sueño REM y un estado tipo depresivo. Ambos efectos estarían siendo mediados a través de la modulación de la actividad de las neuronas serotoninérgicas del núcleo dorsal del rafe. Conclusiones: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión. Resta confirmar si esta afirmación es cierta en pacientes con DM. (AU)

Introduction: major depression disorder (MDD) is a common psychiatric condition, it has high morbility rates and is closely related to suicide.Objective: to provide an update in the study of the neurobiology of depression, focusing on the potential role of the melanin-concentrating hormone (MCH) in this condition.Method: a bibliographical review with an emphasis on our own original studies.Results: the melanin-concentrating hormone is a peptide neuromodulator syhthetized by neurones in the hypothalamus. MCHergic neurons send projection towards different areas in the central nervous system, including areas associated to the regulation of the sleep-wake cycle, as well as different structures in the limbic system that take part in the regulation of mood. In spite of several studies having proved the MCHergic system with the control of energetic homeostasis, recent findings have enabled to identify a role for this system in the sleep generator mechanisms. Similarly, data arising from several studies suggests that MCH would be involved in the major depression disorder. Our own preclinical studies tend to pint out the MCH promotes the generation of REM sleep and a type of depression. Apparently both effects would be mediated through the modulation of the activity on the serotoninergic neurons in the dorsal raphe nucleus.Conclusions: paraclinical studies suggest the leading role of the MCHergic system in the pathophysiology of depression. It is to be proved still, whether this affirmation is true for patients with major depression disorder.

Introdução: a depressão maior (DM) é uma enfermidade psiquiátrica frequente, com morbidade considerável e estreitamente relacionada com o suicídio.Objetivo: fazer uma atualização dos avanços no estudo da neurobiologia da DM, focando no possível papel do hormônio concentrador melanina (MCH) nesta patologia.Metodologia: revisão da bibliografia com ênfase em nossos trabalhos originais.Resultados: o MCH é um neuromodulador peptídico sintetizado pelos neurônios do hipotálamo. Os neurônios MCHérgicos enviam projeções a diversas regiões del sistema nervoso central, incluindo as áreas vinculadas com a regulação da vigília e do sono, bem como a diversas estruturas do sistema límbico que participam na regulação do humor. Embora numerosos estudos hajam relacionado o sistema MCHérgico com o controle da homeostase energética, descobrimentos recentes permitiram identificar um papel deste sistema nos mecanismos de geração do sono. Por outro lado, uma convergência de dados provenientes de diversos estudos sugere que o MCH estaria relacionado com a fisiopatologia da DM. Nossos estudos preclínicos tendem a indicar que o MCH promove a geração do sono REM e um estado tipo depressivo. Ambos efeitos estariam sendo mediados pela modulação da atividade dos neurônios serotoninérgicos do núcleo dorsal do rafe.Conclusões: estudos preclínicos sugerem um protagonismo do sistema MCHérgico na fisiopatologia da depressão. É necessário confirmar se esta afirmação é correta em pacientes com DM.

Avances en el estudio de la neurobiología de la depresión: rol de la hormona concentradora de melanina / Progress made in studies in the neurobiology of depression: a role for the melanin-concentrating hormone

Introducción: la depresión mayor (DM) es una enfermedad psiquiátrica frecuente, con importante morbilidad y una relación estrecha con el suicidio. Objetivo: hacer una puesta a punto de los avances en el estudio de la neurobiología de la DM, enfocándonos en el posible rol de la hormona concentradora de melanina (MCH) en esta patología. Metodología: revisión de la bibliografía con énfasis en nuestros propios trabajos originales. Resultados: la MCH es un neuromodulador peptídico sintetizado por neuronas del hipotálamo. Las neuronas MCHérgicas envían proyecciones hacia diversas regiones del sistema nervioso central, incluyendo las áreas vinculadas con la regulación de la vigilia y del sueño, así como a diversas estructuras del sistema límbico que participan en la regulación del humor. Aunque numerosos estudios han relacionado el sistema MCHérgico con el control de la homeostasis energética, hallazgos recientes han permitido señalar un rol de este sistema en los mecanismos de generación del sueño. A su vez, una convergencia de datos provenientes de diversos estudios sugiere que la MCH estaría involucrada en la fisiopatología de la DM. Nuestros propios estudios preclínicos tienden a indicar que la MCH promueve la generación del sueño REM y un estado tipo depresivo. Ambos efectos estarían siendo mediados a través de la modulación de la actividad de las neuronas serotoninérgicas del núcleo dorsal del rafe. Conclusiones: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión. Resta confirmar si esta afirmación es cierta en pacientes con DM...

Microinjection of melanin concentrating hormone into the lateral preoptic area promotes non-REM sleep in the rat.

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5 min, P<0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5 min, P<0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

GABAergic processes within the median preoptic nucleus promote NREM sleep.

GABAergic mechanisms in the preoptic region of the hypothalamus (POA) have been implicated in the generation and maintenance of NREM (quiet) sleep. We recently reported that neurons in the median peptic nucleus (MnPN) in the POA of the cat are selectively activated during NREM sleep. In the present study, we explored the hypothesis that NREM sleep is controlled by GABAergic mechanisms within the MnPN. Consequently, adult cats were utilized to determine GABA immunorreactivity within the MnPN and to examine the effects on sleep of the microinjection of a GABA(A) agonist (muscimol) and a GABA(A) antagonist (bicuculline) into this area. GABAergic neurons were present throughout the MnPN. Compared with control microinjections, after the application of muscimol, the time spent in NREM sleep (59.8±7.5 min) and REM sleep (6.9±4.7 min) decreased compared with control microinjections (103.8±5.2 and 20.2±4.3 min, respectively; P<0.005). In contrast, bicuculline microinjections increased only NREM sleep time (103.0±23.0 vs 77.7±23.7 min; P<0.05). These results demonstrate that GABAergic processes within the MnPN are involved in the generation and maintenance of sleep, especially NREM sleep.

State-dependent pattern of Fos protein expression in regionally-specific sites within the preoptic area of the cat.

Clinical and experimental data have shown that the preoptic area of the hypothalamus (POA) is involved in the generation and maintenance of NREM sleep. However, the activity of specific populations of POA neurons during REM sleep, NREM sleep and different waking conditions is still not firmly established. Consequently, we performed a quantitative, regionally-specific analysis of the Fos immunoreactivity of neurons in the POA of the cat during NREM sleep and REM sleep induced by microinjections of carbachol into the nucleus pontis oralis (REMc), as well as during quiet and alert wakefulness. We observed that while the total number of Fos immunoreactive neurons in the POA did not change as a function of these behavioral states, state-specific differences in neuronal activity were detected in restricted regions of the POA. An increase in the number of Fos+ neurons was observed in the rostral tip of the suprachiasmatic nucleus (SCN) during NREM (83.4+/-25.6) compared to quiet wakefulness (5.1+/-1.3, p<0.05) but not with the other behavioral states. In the median preoptic nucleus (MnPN), the number of Fos immunoreactive neurons was greater during NREM sleep (39.5+/-6.1) compared with quiet wakefulness (13.5+/-1.4, p<0.05) and REMc (16.2+/-2.0, p<0.05). State-specific Fos immunoreactive neurons were not observed in the ventro-lateral preoptic nucleus (VLPO). Finally, there was no significant increase in the number of Fos+ neurons during REMc in any of the subregions of the POA. In conclusion, within the POA, a selective neuronal activation during NREM sleep was found only in the MnPN. In addition, our data suggest a potential role of the SCN in NREM sleep. Finally, based on the distribution of Fos+ neurons in the entire POA, we conclude that the neuronal network involved in the regulation of NREM sleep is dispersed and intermingled with waking-related neurons.