Hruda Nanda Mallick

Activation of the gut-brain axis by dietary glutamate and physiologic significance in energy homeostasis

l-Glutamate is a multifunctional amino acid involved in taste perception, intermediary metabolism, and excitatory neurotransmission. In addition, recent studies have uncovered new roles for l-glutamate in gut-brain axis activation and energy homeostasis. l-Glutamate receptors and their cellular transduction molecules have recently been identified in gut epithelial cells. Stimulation of such l-glutamate receptors by luminal l-glutamate activates vagal afferent nerve fibers and then parts of the brain that are targeted directly or indirectly by these vagal inputs. Notably, 3 areas of the brain-the medial preoptic area, the hypothalamic dorsomedial nucleus, and the habenular nucleus-are activated by intragastric l-glutamate but not by glucose or sodium chloride. Furthermore, the chronic, ad libitum ingestion of a palatable solution of monosodium l-glutamate (1% wt:vol) by rats has also been found to reduce weight gain, fat deposition, and plasma leptin concentrations compared with rats that ingest water alone. No difference in food intake was observed. Such effects may also be vagally mediated. Together, such findings contribute to the growing knowledge base that indicates that l-glutamate signaling via taste and gut l-glutamate receptors may influence multiple physiologic functions, such as thermoregulation and energy homeostasis.

Orexin A (hypocretin-1) application at the medial preoptic area potentiates male sexual behavior in rats.

The medial preoptic area plays an important role in the regulation of male sexual behavior in rats, and this area receives orexinergic inputs. The role of orexinergic inputs in the medial preoptic area in sexual behavior has not been studied, though they have been shown to play a role in some other physiological functions. In this study, the changes in male sexual behavior in rats were studied after local injection of orexin A (Hypocretin-1) at the medial preoptic area. The results of the study showed that orexin A application at the medial preoptic area increased sexual arousal as well as the copulatory performance. Sexual arousal is one of the physiological stimuli, which influences wakefulness. It is possible that the earlier reports showing increased wakefulness, on application of orexin A at the medial preoptic area/basal forebrain, has a contribution from sexual arousal.

Noradrenergic afferents and receptors in the medial preoptic area: neuroanatomical and neurochemical links between the regulation of sleep and body temperature.

Several studies have shown the importance of the medial preoptic area in the regulation of sleep-wakefulness and of body temperature. The medial preoptic area has a rich noradrenergic innervation, coming mostly from the lateral tegmental noradrenergic system. The accumulating evidences show that the noradrenergic afferents to the medial preoptic area are involved in the induction of sleep. This hypnogenic mechanism operates through the postsynaptic alpha1 and alpha2-adrenergic receptors. Noradrenergic afferents are also involved in the thermoregulatory mechanisms, and the activation of these fibers brings about a fall in body temperature. Though the body temperature changes are brought about by the same receptor subtypes as those involved in hypnogenesis, observations suggest the possibility of separate sets of noradrenergic afferents in the medial preoptic area for sleep regulation and thermoregulation. In this review, we present the compelling evidences, which showed that the noradrenergic afferents of the medial preoptic area bring about a fall in body temperature and other thermoregulatory behavioral alterations associated with sleep.

Changes in thermal preference, sleep-wakefulness, body temperature and locomotor activity of rats during continuous recording for 24 hours

This study was aimed at correlating diurnal changes in thermal preference of rats with their body temperature (Tb), sleep-wakefulness (S-W) and locomotor activity (LMA). Electroencephalogram (EEG), electromyogram (EMG), electrooculogram (EOG) and Tb were recorded by telemetry, while an activity monitor measured LMA and thermal preference. A special environmental chamber, which was designed and fabricated, enabled for the first time, simultaneous measurement of thermal preference, along with S-W and Tb. S-W, thermal preference and LMA were recorded continuously in six adult male Wistar rats, for 24 h, for 3 days, and Tb with thermal preference and LMA were recorded for another 3 days. LMA and Tb were higher at night than during day. The rats slept less during the night time. Increased frequency of sleep episodes contributed towards increased sleep during day time. They preferred an ambient temperature (Tamb) of 24 degrees C at night and 27 degrees C during the day. Though the preference for higher Tamb during day time coincided with increased sleep, the rats did not move over to higher Tamb prior to the onset of sleep episodes. Though the diurnal alterations in sleep, Tb and LMA were similar to those reports from animals kept in constant Tamb, the day-night variation of paradoxical sleep (PS) was exaggerated when the rats selected their own preferred Tamb.

Role of the lateral septal noradrenergic system in the elaboration of male sexual behavior in rats.

The study was aimed at investigating the possible involvement of noradrenergic mechanisms in the lateral septum (LS) for elaboration of male sexual behavior in rats. In this study, norepinephrine (NE), yohimbine (YOH), isoproterenol (ISOP), propranolol (PROP), saline (SAL) and dimethyl sulfoxide (DMSO) were injected bilaterally in the LS in six different groups of sexually active male rats, and various components of sex behavior were recorded. The application of NE (3 microg) and alpha(2)-antagonist YOH (1 microg) produced a stimulation of most of the components of male sexual behavior, and there was increase in sexual arousal as well as performance. The microinfusion of nonspecific beta-agonist ISOP (2 microg) also produced a stimulation of copulatory behavior whereas beta-antagonist PROP (2 microg) produced an inhibition. The stimulation of male sexual behavior by YOH application at the LS could be due to an increased release of NE by its blocking effect on presynaptic alpha(2)-receptors. These results suggest that the noradrenergic system in the LS has stimulatory effect upon male sexual behavior, probably acting through beta-receptors.

Changes in sleep-wakefulness in the medial preoptic area lesioned rats: role of thermal preference

Changes in sleep-wakefulness (S-W) were studied in adult male Wistar rats, along with body temperature (T(b)), locomotor activity (LMA) and thermal preference, after the lesion of the medial preoptic area (mPOA) with N-methyl-D-aspartic acid (NMDA). The sleep was decreased after the lesion of the mPOA, but there was recovery when the rats were given freedom to stay in an ambient temperature (T(amb)) which they preferred. When given a choice between three T(amb) (24, 27 and 30 degrees C), the rats preferred 27 degrees C before the mPOA lesion, and 24 degrees C during the initial days after the lesion. There was a shift in the thermal preference to 30 degrees C, on the fourth week after the lesion, which coincided with the considerable recovery of sleep. The preference for higher T(amb) probably helped to improve sleep, as T(amb) of 30 degrees C is known to promote sleep. When the lesioned rats were not given the freedom to select the T(amb), there was no recovery in sleep. The mPOA seems to be essential for increasing the durations of slow wave sleep (SWS) episodes, especially the light SWS (S1), as they remained shorter than the pre-lesion value, even when the rats were given freedom to stay in a preferred T(amb). The homeostatic recovery of sleep, especially the night time sleep, resulted in the disruption of circadian sleep rhythm. But, the LMA, T(b) and thermal preference maintained their diurnal variation. T(b) and LMA were elevated after the mPOA lesion and they remained so till the end of the study.

Changes in sleep on chronic exposure to warm and cold ambient temperatures

Alterations in sleep induced by chronic exposure to mild changes in ambient temperature (Ta) were studied in male Wistar rats with chronically implanted electrodes for recording electrooculogram (EOG), electroencephalogram (EEG) and electromyogram (EMG), and a thermocouple to record the brain temperature (Tbr). Changes in sleep-wakefulness (S-W) and Tbr on exposure to warm (30+/-1 degrees C) and cold (18+/-1 degrees C) Ta for 4 weeks were studied in two groups of five rats each. Chronic heat exposure produced a persistent increase in sleep, primarily due to an increase in the durations of sleep episodes. A disproportionate increase in sleep during the dark period resulted in reduced circadian variation. The paradoxical sleep (PS)/total sleep time (TST) ratio also remained increased, during heat exposure. On chronic cold exposure, the sleep was decreased initially, but it recovered after 3 weeks, due to an increase in the frequency of slow wave sleep (SWS) episodes. The Tbr was not altered on exposure to warm Ta, but it remained high throughout the 4 weeks of cold exposure. The increase in the amount of sleep, especially the PS with enhanced ambient temperature, may be considered as an adaptation to thermal load aimed at energy conservation. Though the increased wakefulness is suggested to enable the organism to optimize thermoregulation during acute cold stress, thermoregulation itself may be readjusted to ensure homeostatic restoration of sleep during chronic cold exposure.

Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep.

Orexins are important regulators of sleep-wakefulness (S-W). Rats were intracerebroventricularly (ICV) administered selective orexin-2 receptor antagonist, TCS-OX2-29. There was decreased wakefulness due to a decrease in the average wake episode duration and an increased REM sleep due to an increase in the number of REM episodes, indicating an inhibitory role of the central orexin-2 receptors on REM sleep generation.

Ambient temperature that induces maximum sleep in rats

Changes in sleep and body temperature in rats at ambient temperatures below and above the self-selected temperature zone, are lacking in literature. In this report, the temperature preferred by the rats was first assessed before studying the changes in their sleep and body temperature, when they were exposed to ambient temperatures ranging from 18 degrees C to 36 degrees C. The rats preferred to stay at 27 degrees C when they were allowed to select their own ambient temperature, but maximum sleep was recorded when the rats were maintained at 30 degrees C. The ambient temperature-related changes in rapid eye movement sleep and deep slow wave sleep followed a bell-shaped curve, with a maximum at 30 degrees C. Of all the sleep parameters, rapid eye movement sleep showed a more marked ambient temperature-related change. Ambient temperatures above 33 degrees C and below 24 degrees C produced a significant reduction in sleep. Increase in sleep at 30 degrees C was associated with a slight elevation in body temperature, but a steep increase in body temperature at very high ambient temperature was associated with a decrease in sleep. Decrease in sleep at ambient temperatures below 24 degrees C was not related to any significant decrease in body temperature. Though maximum sleep was recorded at 30 degrees C, the sleep regulatory and thermoregulatory systems were at a functional equilibrium at 27 degrees C.

Basal forebrain thermoregulatory mechanism modulates auto-regulated sleep

Regulation of body temperature and sleep are two physiological mechanisms that are vital for our survival. Interestingly neural structures implicated in both these functions are common. These areas include the medial preoptic area (POA), the lateral POA, the ventrolateral POA, the median preoptic nucleus, and the medial septum, which form part of the basal forebrain (BF). When given a choice, rats prefer to stay at an ambient temperature of 27°C, though the maximum sleep was observed when they were placed at 30°C. Ambient temperature around 27°C should be considered as the thermoneutral temperature for rats in all sleep studies. At this temperature the diurnal oscillations of sleep and body temperature are properly expressed. The warm sensitive neurons of the POA mediate the increase in sleep at 30°C. Promotion of sleep during the rise in ambient temperature from 27 to 30°C, serve a thermoregulatory function. Autonomous thermoregulatory changes in core body temperature and skin temperature could act as an input signal to modulate neuronal activity in sleep-promoting brain areas. The studies presented here show that the neurons of the BF play a key role in regulating sleep. BF thermoregulatory system is a part of the global homeostatic sleep regulatory mechanism, which is auto-regulated.