AT1a-dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH-dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH for 8 h a day for 7 days. In vitro, loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. In addition, MnPO K-Cl cotransporter isoform 2 (KCC2) protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II-mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA-mediated inhibition, and CIH with AT1a knockdown produced GABAA-mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA-mediated inhibition in the MnPO and contribute to sustained hypertension.

TMEM16C is involved in thermoregulation and protects rodent pups from febrile seizures.

Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274-1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.

Medial preoptic area antagonistically mediates stress-induced anxiety and parental behavior.

Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain networks, key components for its initiation, maintenance and coordination with behavioral state remain poorly understood. Here, we report that anxiogenic stressors elicit acute and prolonged responses in glutamatergic neurons of the mouse medial preoptic area (mPOA). These neurons encode extremely negative valence and mediate the induction and expression of anxiety-like behaviors. Conversely, mPOA GABA-containing neurons encode positive valence and produce anxiolytic effects. Such opposing roles are mediated by competing local interactions and long-range projections of neurons to the periaqueductal gray. The two neuronal populations antagonistically regulate anxiety-like and parental behaviors: anxiety is reduced, while parenting is enhanced and vice versa. Thus, by evaluating negative and positive valences through distinct but interacting circuits, the mPOA coordinates emotional state and social behavior.

Functional role for preoptic CB1 receptors in breathing and thermal control.

The anteroventral preoptic region (AVPO) of the hypothalamus is involved in both temperature and breathing regulation. This area densely express cannabinoid receptors type 1 (CB1) that modulate both excitatory and inhibitory synaptic transmission. However, it is still unknown if the endocannabinoid system located in the AVPO participates in breathing control and thermoregulation. Therefore, we tested the participation of CB1 in the AVPO in the modulation of ventilation and thermal control during normoxia and hypoxia. To this end, body temperature (Tb) of Wistar rats was monitored by datallogers and ventilation (VE) by whole body plethysmography before and after intra-AVPO microinjection of AM-251 (CB1 antagonist, 50 and 100 pmol) followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of the higher dose of AM-251 increased VE but did not change Tb under resting conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced anapyrexia and hyperventilation after vehicle microinjection. The higher dose of the cannabinoid antagonist increased the hypoxia-induced hyperventilation, in the same magnitude as observed under normoxic condition, whereas the drop in Tb elicited by hypoxia was attenuated. Therefore, the present results demonstrate that the endocannabinoid system acting on CB1 receptors in the AVPO exerts a tonic inhibitory modulation on breathing but seem not be involved in thermoregulation during resting conditions. In addition, activation of CB1 receptors in the AVPO stimulate thermal response during hypoxia, reducing energetically expensive responses, such as the hypoxic hyperventilation.

Adaptations in reward-related behaviors and mesolimbic dopamine function during motherhood and the postpartum period.

Initiation and maintenance of maternal behavior is driven by a complex interaction between the physiology of parturition and offspring stimulation, causing functional changes in maternal brain and behavior. Maternal behaviors are among the most robust and rewarding motivated behaviors. Mesolimbic dopamine (DA) system alterations during pregnancy and the postpartum enable enhanced reward-related responses to offspring stimuli. Here, we review behavioral evidence demonstrating postpartum rodents exhibit a bias towards pups and pup-related stimuli in reward-related tasks. Next, we provide an overview of normative adaptations in the mesolimbic DA system induced by parturition and the postpartum, which likely mediate shifts in offspring valence. We also discuss a causal link between dopaminergic dysfunction and disrupted maternal behaviors, which are recapitulated in postpartum depression (PPD) and relevant rodent models. In sum, mesolimbic DA system activation drives infant-seeking behavior and strengthens the mother-infant bond, potentially representing a therapeutic target for reward-related deficits in PPD.

EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever.

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPOEP3R neurons). To investigate the identity of MnPOEP3R neurons, we first used in situ hybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPOVGluT2 but few from MnPOVgat neurons to a key site for fever production, the raphe pallidus. Ablation of MnPOVGluT2 but not MnPOVgat neurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPOEP3R neurons being GABAergic.SIGNIFICANCE STATEMENT Body temperature is regulated by the CNS. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses.

Caspase lesions of PVN-projecting MnPO neurons block the sustained component of CIH-induced hypertension in adult male rats.

Obstructive sleep apnea is characterized by interrupted breathing that leads to cardiovascular sequelae including chronic hypertension that can persist into the waking hours. Chronic intermittent hypoxia (CIH), which models the hypoxemia associated with sleep apnea, is sufficient to cause a sustained increase in blood pressure that involves the central nervous system. The median preoptic nucleus (MnPO) is an integrative forebrain region that contributes to blood pressure regulation and neurogenic hypertension. The MnPO projects to the paraventricular nucleus (PVN), a preautonomic region. We hypothesized that pathway-specific lesions of the projection from the MnPO to the PVN would attenuate the sustained component of chronic intermittent hypoxia-induced hypertension. Adult male Sprague-Dawley rats (250-300 g) were anesthetized with isoflurane and stereotaxically injected bilaterally in the PVN with a retrograde Cre-containing adeno-associated virus (AAV; AAV9.CMV.HI.eGFP-Cre.WPRE.SV40) and injected in the MnPO with caspase-3 (AAV5-flex-taCasp3-TEVp) or control virus (AAV5-hSyn-DIO-mCherry). Three weeks after the injections the rats were exposed to a 7-day intermittent hypoxia protocol. During chronic intermittent hypoxia, controls developed a diurnal hypertension that was blunted in rats with caspase lesions. Brain tissue processed for FosB immunohistochemistry showed decreased staining with caspase-induced lesions of MnPO and downstream autonomic-regulating nuclei. Chronic intermittent hypoxia significantly increased plasma levels of advanced oxidative protein products in controls, but this increase was blocked in caspase-lesioned rats. The results indicate that PVN-projecting MnPO neurons play a significant role in blood pressure regulation in the development of persistent chronic intermittent hypoxia hypertension.NEW & NOTEWORTHY Chronic intermittent hypoxia associated with obstructive sleep apnea increases oxidative stress and leads to chronic hypertension. Sustained hypertension may be mediated by angiotensin II-induced neural plasticity of excitatory median preoptic neurons in the forebrain that project to the paraventricular nucleus of the hypothalamus. Selective caspase lesions of these neurons interrupt the drive for sustained hypertension and cause a reduction in circulating oxidative protein products. This indicates that a functional connection between the forebrain and hypothalamus is necessary to drive diurnal hypertension associated with intermittent hypoxia. These results provide new information about central mechanisms that may contribute to neurogenic hypertension.

Prenatal Testosterone Exposure Alters GABAergic Synaptic Inputs to GnRH and KNDy Neurons in a Sheep Model of Polycystic Ovarian Syndrome.

Prenatal testosterone (T)-treated female sheep display reproductive deficits similar to women with polycystic ovarian syndrome (PCOS), including an increase in LH pulse frequency due to actions of the central GnRH pulse generator. In this study, we used multiple-label immunocytochemistry to investigate the possibility of changes in the γ-aminobutyric acid (GABA) neurotransmitter system at two key components of the GnRH pulse generator in prenatal T-treated sheep: kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus, and GnRH neurons in the preoptic area (POA) and mediobasal hypothalamus (MBH). We observed a significant decrease and increase, respectively, in the number of GABAergic synapses onto POA and MBH GnRH neurons in prenatal T-treated ewes; additionally, there was a significant increase in the number of GABAergic inputs onto KNDy neurons. To determine the actions of GABA on GnRH and KNDy neurons, we examined colocalization with the chloride transporters NKCC1 and KCC2, which indicate stimulatory or inhibitory activation of neurons by GABA, respectively. Most GnRH neurons in both POA and MBH colocalized NKCC1 cotransporter whereas none contained the KCC2 cotransporter. Most KNDy neurons colocalized either NKCC1 or KCC2, and 28% of the KNDy population contained NKCC1 alone. Therefore, we suggest that, as in the mouse, GABA in the sheep is stimulatory to GnRH neurons, as well as to a subset of KNDy neurons. Increased numbers of stimulatory GABAergic inputs to both MBH GnRH and KNDy neurons in prenatal T-treated animals may contribute to alterations in steroid feedback control and increased GnRH/LH pulse frequency seen in this animal model of PCOS.

Prenatal Allergen Exposure Perturbs Sexual Differentiation and Programs Lifelong Changes in Adult Social and Sexual Behavior.

Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. We have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.

Angiotensin type 1a receptors in the median preoptic nucleus support intermittent hypoxia-induced hypertension.

Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

Proteomic Analysis of the Maternal Preoptic Area in Rats.

The behavior of female rats changes profoundly as they become mothers. The brain region that plays a central role in this regulation is the preoptic area, and lesions in this area eliminates maternal behaviors in rodents. The molecular background of the behavioral changes has not been established yet; therefore, in the present study, we applied proteomics to compare protein level changes associated with maternal care in the rat preoptic area. Using 2-dimensional fluorescence gel electrophoresis followed by identification of altered spots with mass spectrometry, 12 proteins were found to be significantly increased, and 6 proteins showed a significantly reduced level in mothers. These results show some similarities with a previous proteomics study of the maternal medial prefrontal cortex and genomics approaches applied to the preoptic area. Gene ontological analysis suggested that most altered proteins are involved in glucose metabolism and neuroplasticity. These proteins may support the maintenance of increased neuronal activity in the preoptic area, and morphological changes in preoptic neuronal circuits are known to take place in mothers. An increase in the level of alpha-crystallin B chain (Cryab) was confirmed by Western blotting. This small heat shock protein may also contribute to maintaining the increased activity of preoptic neurons by stabilizing protein structures. Common regulator and target analysis of the altered proteins suggested a role of prolactin in the molecular changes in the preoptic area. These results first identified the protein level changes in the maternal preoptic area. The altered proteins contribute to the maintenance of maternal behaviors and may also be relevant to postpartum depression, which can occur as a molecular level maladaptation to motherhood.

Efferent thermoregulatory pathways regulating cutaneous blood flow and sweating.

Cutaneous vasoconstrictor nerves regulate heat retention, and are activated by falls in skin or core temperature. The efferent pathways controlling this process originate within the preoptic area. A descending GABAergic pathway, activated by warm skin or core, indirectly inhibits sympathetic premotor neurons in the medullary raphé. Those premotor neurons drive cutaneous vasoconstriction via excitatory glutamatergic and serotonergic connections to spinal preganglionic neurons. Cold skin and/or cold core temperatures activate a direct preoptic-to-raphé excitatory pathway. The balance of inhibitory and excitatory influences reaching the medullary raphé determines cutaneous blood flow. During fever, prostaglandin E2 inhibits preoptic GABAergic neurons, resulting in disinhibition of the excitatory preoptic-to-raphé pathway, and hence, cutaneous vasoconstriction. A weaker, parallel source of descending excitatory drive reaches cutaneous preganglionic neurons from the rostral ventrolateral medulla. Sweating follows local heating of the preoptic area in cats and monkeys, and heated humans show sweating-related activation of this same region in functional magnetic resonance imaging (fMRI) studies. A descending pathway that drives sweating has been traced in cats from the hypothalamus to putative premotor neurons in the parafacial region at the pontomedullary junction. The homologous parafacial region in humans also shows sweating-related activation in fMRI studies. The central pathways that drive active vasodilatation in human nonacral skin remain unknown.

The medial preoptic area modulates autonomic function under resting and stress conditions.

The medial preoptic area (mPOA) participates in the temperature and cardiovascular control. The mPOA receives inputs from limbic structures and sends projections to hypothalamus and brainstem. Moreover, stress elicits pronounced neuronal activation in mPOA, suggesting its involvement in central neural pathway mediating stress responses. In the present study, we report the effect of acute mPOA neurotransmission inhibition using cobalt chloride (CoCl2-nonselective synapse blocker) on the mean arterial pressure (MAP), heart rate (HR), body and tail temperature (Tbody and Ttail, respectively), as well as on the HR component of baroreflex. We also verified the participation of mPOA in the autonomic changes evoked by acute restraint stress (RS). Our results demonstrated that microinjection of CoCl2 into mPOA caused tachycardia, hyperthermia and a Ttail decrease, without altering MAP. The inhibition of mPOA with CoCl2 increased the sympathetic component of cardiac baroreflex when assessed 10min after its administration. In addition, pretreatment of mPOA with CoCl2 increased RS-evoked tachycardic and hyperthermic responses evoked by RS when compared with aCSF-treated animals, without affecting the RS-evoked pressor response and the fall in Ttail. In summary, our results suggest that mPOA exerts a tonic inhibitory influence on the sympathetic cardiac tone under both rest and stress conditions, modulating negatively the sympathetic component of baroreflex. Results also confirm the mPOA involvement in the control of body temperature because its inhibition was followed by a sustained increase in body temperature and vasoconstriction in the tail artery territory.

GABAergic ventrolateral pre­optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol.

Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic­induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endoge-nous sleep­arousal circuits. However, few studies focus on the ventrolateral pre­optic (VLPO) to locus coeruleus (LC) sleep­arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol. The present study additionally investigated if the inhibitory effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target lesion and extracellular single­unit recordings were used to study the role of the VLPO­LC pathway in propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist (gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC noradrenergic neurons. There was no significant difference observed in firing activity between VLPO sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in propofol­induced unconsciousness, however are unlikely to contribute to the inhibitory effect of propofol on LC spontaneous firing activity.

A Comprehensive Method To Quantify Adaptations by Male and Female Mice With Hot Flashes Induced by the Neurokinin B Receptor Agonist Senktide.

Vasomotor symptoms (VMS; or hot flashes) plague millions of reproductive-aged men and women who have natural or iatrogenic loss of sex steroid production. Many affected individuals are left without treatment options because of contraindications to hormone replacement therapy and the lack of equally effective nonhormonal alternatives. Moreover, development of safer, more effective therapies has been stymied by the lack of an animal model that recapitulates the hot-flash phenomenon and enables direct testing of hypotheses regarding the pathophysiology underlying hot flashes. To address these problems, we developed a murine model for hot flashes and a comprehensive method for measuring autonomic and behavioral thermoregulation in mice. We designed and constructed an instrument called a thermocline that produces a thermal gradient along which mice behaviorally adapt to a thermal challenge to their core body temperature set point while their thermal preference over time is tracked and recorded. We tested and validated this murine model for VMS by administration of a TRPV1 agonist and a neurokinin B receptor agonist, capsaicin and senktide, respectively, to unrestrained mice and observed their autonomic and behavioral responses. Following both treatments, the mice exhibited a VMS-like response characterized by a drop in core body temperature and cold-seeking behavior on the thermocline. Senktide also caused a rise in tail skin temperature and increased Fos expression in the median preoptic area, a hypothalamic temperature control center. This dynamic model may be used to fully explore the cellular and molecular bases for VMS and to develop and test new therapeutic options.

Prenatal Hyperhomocysteinemia Impairs Hypothalamic Regulation of Reproductive Cycles in Rat Progeny.

Effects of prenatal hyperhomocysteinemia on hypothalamic regulation of estrous cycles were studied in female rats. In mature rats exposed to prenatal hyperhomocysteinemia, changes in the catecholamine content in hypothalamic areas responsible for the formation of the preovulatory surge of gonadotropin-releasing hormone were revealed: the level of norepinephrine in the medial preoptic area decreased and concentration of dopamine in the median eminence with arcuate nuclei increased. Administration of melatonin attenuated the observed changes, which can be related to neuroprotective effects of this hormone determined by its antioxidant properties.

Effect of Physical Exercise on the Febrigenic Signaling is Modulated by Preoptic Hydrogen Sulfide Production.

We tested the hypothesis that the neuromodulator hydrogen sulfide (H2S) in the preoptic area (POA) of the hypothalamus modulates the febrigenic signaling differently in sedentary and trained rats. Besides H2S production rate and protein expressions of H2S-related synthases cystathionine ß-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MPST) and cystathionine γ-lyase (CSE) in the POA, we also measured deep body temperature (Tb), circulating plasma levels of cytokines and corticosterone in an animal model of systemic inflammation. Rats run on a treadmill before receiving an intraperitoneal injection of lipopolysaccharide (LPS, 100 µg/kg) or saline. The magnitude of changes of Tb during the LPS-induced fever was found to be similar between sedentary and trained rats. In sedentary rats, H2S production was not affected by LPS. Conversely, in trained rats LPS caused a sharp increase in H2S production rate that was accompanied by an increased CBS expression profile, whereas 3-MPST and CSE expressions were kept relatively constant. Sedentary rats showed a significant LPS-induced release of cytokines (IL-1ß, IL-6, and TNF-α) which was virtually abolished in the trained animals. Correlation between POA H2S and IL-6 as well as TNF-α was observed. Corticosterone levels were augmented after LPS injection in both groups. We found correlations between H2S and corticosterone, and corticosterone and IL-1ß. These data are consistent with the notion that the responses to systemic inflammation are tightly regulated through adjustments in POA H2S production which may play an anti-inflammatory role downmodulating plasma cytokines levels and upregulating corticosterone release.

Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia.

Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

The transition to reproductive senescence is characterized by increase in A6 and AVPV neuron activity with attenuation of noradrenaline content.

During the course of life, cyclic females face a state of midlife transition that occurs in a fully functioning neurological system, and results in reproductive senescence. The authors' hypothesis was that changes in the activity noradrenergic neurons may be one of the factors involved in this phenomenon. The aim of this study was to investigate the activity of the neurons in the anteroventral periventricular nucleus (AVPV) and locus coeruleus (LC), to analyze their role in determining reproductive senescence. Adult female Wistar rats in the diestrus phase (4months/cyclic) and old females (18-20months/acyclic) in persistent diestrus, were decapitated or perfused at three different time intervals (10, 14 and 18h) throughout the day. In acyclic rats, the gonadotropin-releasing hormone (GnRH) and noradrenaline (NE) content were reduced; Fos-related antigen (FRA) in AVPV and Fos-related antigen/Tyrosine hydroxylase (FRA/TH) in LC showed immunolabeling of a higher number of neurons in these animals. The 3-methoxy-4-hydroxyphenylglycol/noradrenaline (MHPG/NE) ratio was higher and plasma LH was lower in the acyclic rats. Furthermore, the estradiol level was higher, and the progesterone level was lower after 14h of persistent diestrus. These findings suggested that during the periestropause, there was a higher level of POA/AVPV and NE neuronal activity in the LC of acyclic rats, associated with a lower capacity of synthesis and storage of neurotransmitters and neurohormones contributed to changes in the temporal pattern of neuroendocrine signaling, thereby compromising the accuracy of inhibitory and stimulatory effects, causing irregularity in the estrous cycle and determining reproductive senescence.

Does the median preoptic nucleus contribute to sympathetic hyperactivity in spontaneously hypertensive rats?

The present study sought to determine the involvement of median preoptic nucleus (MnPO) in the regulation of the cardiovascular function and renal sympathetic activity in normotensive (NT) and spontaneously hypertensive rats (SHR). MnPO inhibition evoked by Muscimol (4mM) nanoinjections, elicited fall in MAP and renal sympathoinhibition in NT-rats. Surprisingly, in SHRs these responses were greater than in NT-rats. These results demonstrated, for the first time that MnPO was involved in the tonic control of sympathetic activity in NT and SHRs. Furthermore, our data suggest the MnPO involvement in the increased sympathetic outflow and consequent arterial hypertension observed in SHRs.