Preoptic Area Of The Hypothalamus Research Articles

Role of the Preoptic Area in Sleep and Thermoregulation.

Sleep and body temperature are tightly interconnected in mammals: warming up our body helps to fall asleep and the body temperature in turn drops while falling asleep. The preoptic area of the hypothalamus (POA) serves as an essential brain region to coordinate sleep and body temperature. Understanding how these two behaviors are controlled within the POA requires the molecular identification of the involved circuits and mapping their local and brain-wide connectivity. Here, we review our current understanding of how sleep and body temperature are regulated with a focus on recently discovered sleep- and thermo-regulatory POA neurons. We further discuss unresolved key questions including the anatomical and functional overlap of sleep- and thermo-regulatory neurons, their pathways and the role of various signaling molecules. We suggest that analysis of genetically defined circuits will provide novel insights into the mechanisms underlying the coordinated regulation of sleep and body temperature in health and disease.

QPLOT Neurons-Converging on a Thermoregulatory Preoptic Neuronal Population.

The preoptic area of the hypothalamus is a homeostatic control center. The heterogeneous neurons in this nucleus function to regulate the sleep/wake cycle, reproduction, thirst and hydration, as well as thermogenesis and other metabolic responses. Several recent studies have analyzed preoptic neuronal populations and demonstrated neuronal subtype-specific roles in suppression of thermogenesis. These studies showed similar thermogenesis responses to chemogenetic modulation, and similar synaptic tracing patterns for neurons that were responsive to cold, to inflammatory stimuli, and to violet light. A reanalysis of single-cell/nucleus RNA-sequencing datasets of the preoptic nucleus indicate that these studies have converged on a common neuronal population that when activated, are sufficient to suppress thermogenesis. Expanding on a previous name for these neurons (Q neurons, which reflect their ability to promote quiescence and expression of Qrfp), we propose a new name: QPLOT neurons, to reflect numerous molecular markers of this population and to capture its broader roles in metabolic regulation. Here, we summarize previous findings on this population and present a unified description of QPLOT neurons, the excitatory preoptic neuronal population that integrate a variety of thermal, metabolic, hormonal and environmental stimuli in order to regulate metabolism and thermogenesis.

Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses.

Maintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic area of the hypothalamus (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate that the opioid system within the POA is vital in regulating body temperature. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides dynorphin and enkephalin. Using mouse models, we determine that warm-activated PBN neuronal populations overlap with both prodynorphin (Pdyn) and proenkephalin (Penk) expressing PBN populations. Here we report that in the PBN Prodynorphin (Pdyn) and Proenkephalin (Penk) mRNA expressing neurons are partially overlapping subsets of a glutamatergic population expressing Solute carrier family 17 (Slc17a6) (VGLUT2). Using optogenetic approaches we selectively activate projections in the POA from PBN Pdyn, Penk, and VGLUT2 expressing neurons. Our findings demonstrate that Pdyn, Penk, and VGLUT2 expressing PBN neurons are critical for physiological and behavioral heat defense.

Glutamatergic Neurons in the Preoptic Hypothalamus Promote Wakefulness, Destabilize NREM Sleep, Suppress REM Sleep, and Regulate Cortical Dynamics.

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study, we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate, for the first time, that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, decreases body temperature, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons can initiate, but not maintain, arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the hypothesis that the preoptic area causally contributes to the regulation of both sleep and wakefulness.SIGNIFICANCE STATEMENT Historically, the preoptic area of the hypothalamus has been considered a key site for sleep generation. However, emerging modeling and empirical data suggest that this region might play a dual role in sleep-wake control. We demonstrate that chemogenetic stimulation of preoptic glutamatergic neurons produces brief arousals that fragment sleep, persistently suppresses REM sleep, causes hypothermia, and shifts EEG patterns toward a "lighter" NREM sleep state. We propose that preoptic glutamatergic neurons can initiate, but not maintain, arousal from sleep and gate REM sleep generation, possibly to block REM-like intrusions during NREM-to-wake transitions. In contrast to the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic, we provide further evidence that preoptic neurons also generate wakefulness.

Chapter 30 - The neuroendocrinology of the preoptic area in menopause: Symptoms and therapeutic strategies

The preoptic area of the hypothalamus is the central hub of thermoregulation in mammals, coordinating autonomic heat-effector pathways in response to sensory information from the ambient and internal environment. This aims to maintain temperature homeostasis at a predetermined thermoregulatory set-point. However, hormonal and neuronal changes during the menopause, including estrogen deficiency, disrupt these normal thermoregulatory responses. This results in abnormal activation of heat dissipation effectors, manifesting clinically as hot flush symptoms. Neurokinin B (NKB) signaling via the neurokinin-3 receptor (NK3R) within the preoptic area is thought to play an important role in the pathophysiology of hot flushes. Therefore attenuation of the NKB/NK3R signaling pathway has garnered much interest as a novel therapeutic target for the amelioration of menopausal hot flushes. Recent clinical trials have demonstrated that NK3R antagonists can produce rapid and sustained improvements in hot flush frequency, severity, and quality of life, without the need for estrogen exposure. Therefore NK3R antagonists are fast emerging as a safe and efficacious alternative to hormone replacement therapy, the current gold standard of treatment.

Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization.

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here, we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray (PAG) that gate the production of ultrasonic vocalizations (USVs) in mice (i.e. PAG-USV neurons). Activating PAG-projecting neurons in the preoptic area of the hypothalamus (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/M-PAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.

Effect of estrogen and stress on estrogen receptor 1 in the HPG axis of immature male Gallus gallus domesticus: Involvement of anti-oxidant system

Estrogen plays a key role in the regulation of reproductive behavior and control of the neuroendocrine system in both males and females. However, excessive quantity of exogenous estrogen produces a deleterious effect on the male reproductive system. To elucidate the mechanism by which estrogen modulates its receptor alpha (ESR1) in immature chicken during stress the study has been undertaken. The experiment investigated the physiological changes in the abundance of ESR1 in brain, pituitary and testes of immature male chickens after stress like water restriction. Twenty four immature male chickens were randomly assigned into four groups. The control group was provided with food and water ad libitum, second was water restricted 9 h each day for seven days (WR), third was treated with estradiol benzoate (EB) and fourth group was treated with EB followed by water restriction during last seven days of treatment (EB + WR). EB was administered at a dose of 0.5 mg/100 g/day for 12 days. EB administration as well as WR increases both the H2O2 and Malondialdehyde levels indicating oxidative stress in brain as well as in testis. Plasma corticosterone significantly increased in all groups while estradiol significantly decreased after water restriction. ESR1 protein was detected by immuno-fluorescence predominantly in the pre-optic area of the hypothalamus, pituitary and testes after EB administration. EB administration increases ESR1 proteins abundantly in the Sertoli cells, Leydig cells, spermatogonia and spermatids while WR decreases it. The decline in ESR1 proteins after EB administration during stress appears to be mediated by interaction of estrogen with hypothalamo-pituitary-adrenal (HPA) axis. Therefore, the findings substantiate the fact that WR and EB treatment increase the stress and alter the anti-oxidant enzymes via its receptor ESR1 in the brain, pituitary and testis of immature chicks. Moreover, these findings highlight the effect of estradiol in male chicks causing stress which is disrupting the normal physiological feedback mechanism in hormone release and the expression of receptor ESR1 along the hypothalamo-pituitary-gonadal (HPG) axis.

0154 Role of Noradrenergic Projection to the Preoptic Area in Regulation of Arousal

Abstract Introduction Locus coeruleus (LC) is a noradrenergic nucleus in the brainstem involved in the regulation of attention, arousal, mood and sensory gating. LC projects to multiple brain regions and recent development of novel systems neuroscience tools allows the dissection of projection-specific LC function in more detail. One of the regions with noradrenergic projection is the preoptic area of the hypothalamus (POA). POA has been shown to contain neurons that are important for regulating sleep, and we have examined the function of the LC projection to the POA in sleep and arousal. Methods We used optogenetics, chemogenetics, fiber photometry and in vivo electrophysiology to study the function of LC noradrenergic projection to the POA. Results Norepinephrine release in the POA fluctuates with brain state changes indicating that the LC to POA projection may be involved in regulating sleep and arousal. Optogenetic stimulation of LC fibers in the POA promotes wakefulness. Furthermore, optogenetic stimulation of the LC fibers in the POA modulates the activity of sleep- and wake-active neurons. Conclusion We have identified the role of the LC noradrenergic projection to the POA in the regulation of brain states. Stimulation of the LC fibers in the POA promotes wakefulness and modulates the activity dynamics of sleep- and wake-active neurons in the POA. Our results provide more detailed information about the role of this specific projection, which has been known to exist for a long time, but with insufficient in vivo evidence of its precise function. Support Sigrid Juselius foundation, Alfred P. Sloan Research Fellowship in Neuroscience, The Whitehall foundation grant, McCabe Fund Award, NARSAD Young Investigator Award.

SUN-234 Brain-Selective Estrogen Therapy to Prevent Androgen Deprivation Therapy-Related Hot Flushes

Synthetic estrogens are used in the clinic to alleviate debilitating neurological symptoms associated with androgen deprivation therapy (ADT), an effective treatment improving survival in prostate cancer patients when administered timely in the course of the cancer. However, this therapy to relieve the symptoms, most commonly hot flushes, causes feminizations that significantly diminishes patients’ compliance because of physical and psychological discomfort. Because only estrogens can provide adequate therapy of hot flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to alleviate these vasomotor symptoms distressing prostate cancer patients on ADT. The goal with our experiments was to show that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED, a brain-selective bioprecursor prodrug of 17β-estradiol (E2) will ease ADT-associated hot flushes without feminizing side-effects.To evaluate the effect of DHED on hot flushes the pharmacological rat hot flush model was used. Orchiectomized (ORDX) rats were treated orally with three different doses (10, 30, and 100 µg/kg) of DHED or ethynyl estradiol (EE, 200 µg/kg) for ten days. They were addicted to morphine and the tail skin temperature (TST) of saline-treated rats raised by 4.4±0.5 °C when morphine effect was withdrawn with naloxone injection. DHED and EE treatments significantly lowered such TST rise from 4.4 °C to 2.9 ±0.5°C and 1.8 ±0.5°C, respectively.The conversion of DHED to E2 in the brain was confirmed by measuring the effect of DHED-derived E2 on the expression of progesterone receptors (PR) in the preoptic area of the hypothalamus with in situ hybridization histochemistry. Both DHED and EE treatment stimulated PR expression compared to saline-treatment in ORDX rats.In our previous studies, we have shown the lack of conversion of DHED to E2 in the periphery in ovariectomized female rats; i.e., DHED treatment did not have uterotrophic, mammotrophic activities and did not stimulate galanin expression in the anterior pituitary. In these studies, the lack of conversion of DHED to E2 was also confirmed in male rats by measuring the expression of galanin, a highly estrogen-regulated gene, in the pituitary with quantitative RT-PCR. Contrary to EE, DHED treatment did not stimulate galanin expression in this estrogen target.These observations support subsequent translational research focusing on DHED’s therapeutic use to remedy hot flushes and potentially other neurological symptoms in prostate cancer patients undergoing ADT to manage their malignancy. An estrogen therapy with the brain-selective DHED would provide a safe approach to prevent these neurological symptoms without causing peripheral estrogenic side effects such as gynecomastia or deep vein thrombosis.

Activation of Preoptic GABAergic or Glutamatergic Neurons Modulates Sleep-Wake Architecture, but Not Anesthetic State Transitions.

The precise mechanism of general anesthesia remains unclear. In the last two decades, there has been considerable focus on the hypothesis that anesthetics co-opt the neural mechanisms regulating sleep. This hypothesis is supported by ample correlative evidence at the level of sleep-promoting nuclei, but causal investigations of potent inhaled anesthetics have not been conducted. Here, we tested the hypothesis that chemogenetic activation of discrete neuronal subpopulations within the median preoptic nucleus (MnPO) and ventrolateral preoptic nucleus (VLPO) of the hypothalamus would modulate sleep/wake states and alter the time to loss and resumption of consciousness associated with isoflurane, a potent halogenated ether in common clinical use. We show that activating MnPO/VLPO GABAergic or glutamatergic neurons does not alter anesthetic induction or recovery time. However, activation of these neuronal subpopulations did alter sleep-wake architecture. Notably, we report the novel finding that stimulation of VLPO glutamatergic neurons causes a strong increase in wakefulness. We conclude that activation of preoptic GABAergic or glutamatergic neurons that increase sleep or wakefulness does not substantively influence anesthetic state transitions. These data indicate that the correlative evidence for a mechanistic overlap of sleep and anesthesia at the level of an individual nucleus might not necessarily have strong causal significance.

Mechanisms of Convergent Egg Provisioning in Poison Frogs.

Parental provisioning of offspring with physiological products (nursing) occurs in many animals, yet little is known about the neuroendocrine basis of nursing in non-mammalian species. Within amphibians, maternal provisioning has evolved multiple times, with mothers of some species feeding unfertilized eggs to their developing offspring until tadpoles complete metamorphosis [1-3]. We conducted field studies in Ecuador and Madagascar to ask whether convergence at the behavioral level provides similar benefits to offspring and relies on shared neural mechanisms in dendrobatid and mantellid poison frogs. At an ecological level, we found that nursing allows poison frogs to provide chemical defenses to their tadpoles in both species. At the neural level, nursing was associated with increased activity in the lateral septum and preoptic area, demonstrating recruitment of shared brain regions in the convergent evolution of nursing within frogs and across vertebrates [4]. In contrast, only mantellids showed increased oxytocin neuron activity akin to that in nursing mammals [5], suggesting evolutionary versatility in molecular mechanisms. Our findings demonstrate that maternal provisioning provides similar potential benefits to offspring and relies on similar brain regions in poison frog species with convergently evolved toxicity and maternal care. VIDEO ABSTRACT.

Slow-Wave Sleep and Anxiety Levels in Rats in Chronic Deficiency of Chaperone Hsp70i in the Preoptic Area of the Hypothalamus

The preoptic area of the hypothalamus (POA) is regarded as an integrative “center” regulating sleep and behavior, though the involvement of chaperones in the molecular mechanisms controlling the sleep–waking cycle and anxiety-like behavior has received little study. Using a model based on suppression of the synthesis of inducible chaperone Hsp70i in the POA of rats using RNA interference, the present studies provided the first demonstration that long-term (1–2.5 months) 45–55% decreases in Hsp70i levels in the POA leads to reductions in slow-wave sleep in the dark phase of the day and increases in the level of anxiety. The study results may be of clinical value in seeking means of mobilizing the activity of chaperones for the treatment of sleep and behavioral disorders, particularly in aging and a number of neuropathologies, which are characterized by an imbalance in the chaperone systems and decreases in slow-wave sleep.

Central Circuits Inhibiting Skeletal Muscle Shivering

BackgroundSkeletal muscle shivering is the most important source of thermogenesis in the human cold‐defensive maintenance of core body temperature (Tcore) and the elevated Tcore during fever. We have described the thermoregulatory reflex pathway through which skin and core cooling, or injection of prostaglandin E2 into the preoptic area of the hypothalamus, leads to activation of skeletal muscle shivering (J Physiol 589.14: 3641–3658, 2011). Here we describe brain regions containing neurons that can provide an inhibitory regulation of shivering.ResultsEMG activities in masseter, neck and gastrocnemius muscles were recorded in Inactin‐anesthetized rats during cold exposure or injection of PGE2 into the preoptic hypothalamus. Cold‐evoked and febrile shivering EMGs were eliminated by activation of neurons in the ventral part of the lateral preoptic nucleus (vLPO), or by increasing the discharge of neurons in the paraventricular hypothalamus, in the nucleus of the tractus solitarii, or in the ventrolateral medulla. Inhibiting neuronal discharge or blocking glutamate receptors in the vLPO elicited a sustained increase in shivering EMGs in warm rats.ConclusionThese results indicate the strong, tonic inhibitory influence of neurons in the vLPO on skeletal muscle shivering, likely through a GABAergic input to shivering premotor neurons in the rostral raphe pallidus. The discovery of the vLPO and other neuronal populations capable of inhibiting shivering supports the potential for the therapeutic control of shivering in the settings of neurogenic fever, brain injury, or induction of hypothermia.Support or Funding InformationSupported by NIH grants NS040987 and NS091066This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In ovo leptin administration modulates glucocorticoid receptor mRNA expression specifically in the hypothalamus of broiler chickens

The glucocorticoid receptor (GR) is well documented to play a crucial role in the central control of energy homeostasis in mammals. However, the distribution and function of the GR in the chicken brain are less clear. Leptin is a key hormone regulating energy homeostasis in mammals, yet its action in the chicken is still under debate. In this study, the distribution of GR mRNA in the chicken brain and the effects of in ovo administration of leptin and its antagonist on early post-hatch growth and GR mRNA expression in different hypothalamic nuclei were investigated via in situ hybridization (ISH) and quantitative PCR. GR mRNA was widely expressed in the chicken brain, mainly in the corpus striatum, nucleus rotundus, dorsolateral nucleus, nucleus ovoidalis, nucleus reticularis superior and the hippocampus (Hp) and in the preoptic area of the hypothalamus. High doses of leptin (5.0μg) significantly promoted post-hatch growth, resulting in a significant high body weight increased by 24.64% at day (D) 21 of life. Meanwhile, hypothalamic expression of GR mRNA in the LL and HL groups was down-regulated significantly by 7.02% and 13.65% respectively (P<0.05). ISH revealed region-specific changes: GR mRNA was found to be significantly decreased (P<0.05) in the paraventricular nucleus, periventricular nucleus and ventromedial nucleus but not in the Hp, infundibular nucleus or lateral hypothalamus of D21 broiler chickens. The leptin antagonist was able to reverse the effect of leptin on the growth rate and hypothalamic GR mRNA expression. These results provide evidence that in ovo administration of leptin influences early post-hatch growth and the hypothalamic expression of GR mRNA in broiler chickens.

How brain neurons turn down the heat

Neuroscience The preoptic area of the hypothalamus serves as the brain's thermostat. Song et al. found that a particular set of neurons mediate this function and identified the molecular heat sensor that they use (see the Perspective by Bartfai). Neurons in cultures of mouse brain that were activated in response to warming expressed temperature-sensitive TRPM2 ion channels. In mice lacking these channels, body temperature increased more in response to an induced fever than it did in control animals. In mice engineered to allow specific control of the TRPM2-containing neurons, the activity of the neurons was shown to modulate core body temperature. Science , this issue p. [1393][1]; see also p. [1363][2] [1]: /lookup/doi/10.1126/science.aaf7537 [2]: /lookup/doi/10.1126/science.aai8465

The discovery of hatching and transition to feeding young by male Mountain Bluebirds

In many bird species, only females incubate the eggs, but both sexes feed nestlings. The means by which males of such species discover hatching and transition to feeding their offspring remains almost completely unexplored. Of particular interest are species with nests whose contents are concealed from view. During June and early July 2015 in the Bighorn Mountains of Wyoming, we used continuous video-recording of nests of cavity-nesting Mountain Bluebirds (Sialia currucoides) to document the transition to feeding young by males. We saw no evidence that females used distinct vocal or visual displays to signal hatching to males. Observing mates carrying eggshells away from, or food into, nest boxes did not appear to trigger provisioning by males. Rather, at all 24 nests observed, males did not begin feeding until they had come to nest boxes and presumably sensed the presence of hatchings directly. Individual males varied, however, in both the manner in which they inspected nest contents and the number of times they did so before starting to feed young. Although most males fully entered nest boxes where they could see, touch, hear, and possibly smell hatchlings (or eggshell parts), other males may have detected hatchlings only by sound or possibly smell while perched at a nest-box entrance. Based on past studies of mice and doves, we suggest that, for provisioning behavior to begin, some kind of direct sensation of offspring may be necessary to activate relevant neurons in the medial preoptic area of the hypothalamus of males, an area of the brain important in parental care. Additional research is necessary to test this, and to examine the effects of factors such as hormone levels and breeding experience on the means and rapidity by which males discover hatching and transition to nestling provisioning.

Slow-wave sleep and molecular chaperones

From ancient times the mankind has been interested in a topical issue: why is it necessary to spend about one-third of human life for sleep? This review considers the main data on the key function of slow-wave sleep (SWS) and the molecular mechanisms of its regulation; the basic conclusions are presented below as a summary and hypotheses. 1. SWS has an energy-conserving function developed simultaneously with the evolution of tachimetabolism and endothermy/homoiothermy. 2. The most significant reduction of energy demands in the brain occurs during the deep SWS (characterized by increased EEG-delta power), thus creating the optimal conditions for enhancing anabolic processes and realizing the key biological function of sleep--the increase in protein synthesis rate in the brain. 3. The conditions of the paradoxical sleep (PS) as an 'archeowakefulness' state, containing the elements of endogenous stress, seem to be acceptable for expression of chaperones required for repairing misfolded proteins newly synthesized during the deep SWS. 4. The close integration of two molecular systems, HSP70 and HSP40, contained in the sleep 'center' in the preoptic area of the hypothalamus, and their compensatory interrelations contribute significantly to the maintenance of sleep homeostasis and to implementation of its functions under non-stress conditions and during long-term deficiency of chaperones in the brain that is intrinsic for aging and various neuropathologies. 5. Occurring daily throughout the lifetime cyclical changes of the protein synthesis rate (during the deep SWS) and the expression of HSP70 chaperonez (during wakefulness and, possibly, during PS) are crucial for functions of homeothermic organisms, including recuperation of the nervous system's structure and functions.

Reproduction and beyond, kisspeptin in ruminants

Kisspeptin (Kp) is synthesized in the arcuate nucleus and preoptic area of the hypothalamus and is a regulator of gonadotropin releasing hormone in the hypothalamus. In addition, Kp may regulate additional functions such as increased neuropeptide Y gene expression and reduced proopiomelanocortin (POMC) gene expression in sheep. Other studies have found a role for Kp to release growth hormone (GH), prolactin and luteinizing hormone (LH) from cattle, rat and monkey pituitary cells. Intravenous injection of Kp stimulated release LH, GH, prolactin and follicle stimulating hormone in some experiments in cattle and sheep, but other studies have failed to find an effect of peripheral injection of Kp on GH release. Recent studies indicate that Kp can stimulate GH release after intracerebroventricular injection in sheep at doses that do not release GH after intravenous injection. These studies suggest that Kp may have a role in regulation of both reproduction and metabolism in sheep. Since GH plays a role in luteal development, it is tempting to speculate that the ability of Kp to release GH and LH is related to normal control of reproduction.

Demethylating the Male Brain

An area of the brain that regulates mating behavior is masculinized through the removal of methyl groups from DNA, according to a new study in rats and mice [1]. The preoptic area of the hypothalamus, which regulates mating behavior such as mounting, is highly distinct between males and females. For instance, males have more neurons and excitatory synapses in this region than females. Previous studies have shown that the female phenotype is the ‘default’ state, and that testicular androgens promote conversion to the male phenotype. In rats and mice, conversion occurs during a critical developmental window, during the first few days after birth. Androgens drive this masculinization via the metabolite estradiol, produced locally in the preoptic area (local levels of estradiol can have development effects independent of circulating levels of the hormone). In the new study, Bridget Nugent et al. found that male rodents had lower levels of DNA methyltransferase activity in the preoptic area than did females. The researchers observed this difference one or two days after birth, but not later in life or during embryogenesis. During this sensitive period—but not later in life—administration of estradiol caused reductions in methyltransferase activity in the preoptic area. Moreover, quelling DNA methyltransferase activity during development—via inhibitors or genetically—caused females to have male mating behavior as adults. The researchers found that male rats had fewer highly methylated DNA sites in this brain region than did females, and they identified genes and gene isoforms that may be involved in masculinization or feminization. For instance, 24 genes were up-regulated in response to methyltransferase inhibitors in females, and were also found at higher levels in the preoptic area in males compared to normal females—these genes are presumably involved in masculinization. It also seems that rodents can be flexible in their mating behavior. Though the sensitivity of the preoptic area to estradiol only occurs in a window after birth, interfering with DNA methylation outside of this window affected mating behavior. For instance, DNA methyltransferase inhibitors administered after this time period caused female rats to have male mating behaviors. These findings counter previous thinking that sexual differentiation of the brain can occur only during a sensitive period and cannot be undone.

Inhibitory Regulation of Skeletal Muscle Shivering

Skeletal muscle shivering thermogenesis contributes to the cold‐defensive maintenance of core body temperature and to the elevated body temperature during fever. The thermoregulatory reflex pathway through which skin and core cooling, or injection of prostaglandin E2 into the preoptic area of the hypothalamus, leads to activation of skeletal muscle shivering has been described (J Physiol 589.14: 3641–3658, 2011). Although this pathway influences the discharge of alpha‐motoneurons in the ventral horn, rather than sympathetic preganglionic neurons in the intermediolateral nucleus, it is remarkably parallel to the thermoregulatory pathway mediating cold‐defensive activation of brown adipose tissue (Cell Metabolism 19: 741‐756, 2014). To determine if this similarity extends to the central and vagal afferent inhibitory regulation of skeletal muscle shivering, neurons in the paraventricular hypothalamus, in the nucleus of the tractus solitarii, or in the ventrolateral medulla were activated; or electrical stimuli were applied to afferents in the cervical vagus nerve, during cold‐ or PGE2 injection‐evoked increases in masseter, neck and gastrocnemius muscle EMGs in Inactin‐anesthetized rats. Activation of neurons in each of these regions, or vagus nerve stimulation elicits a marked inhibition of cold‐evoked and PGE2‐evoked brown adipose tissue sympathetic outflow and thermogenesis. Overall, the results, indicate strong parallels between the inhibitory regulation of shivering and brown adipose tissue thermogenesis and energy consumption. The specific physiological stimuli for, and the synaptic integration sites supporting these inhibitions of shivering remain to be determined. Supported by NIH grant NS40987.