Ventromedial hypothalamic stimulation accelerates norepinephrine turnover in brown adipose tissue of rats

To establish a functional link between the ventromedial hypothalamus (VMH) and brown adipose tissue (BAT), effects of electrical stimulation of the VMH and the lateral hypothalamus (LH) on norepinephrine (NE) turnover in the interscapular BAT were examined in rats. Stimulation of the VMH elicited about 3-fold increase in the rate of NE turnover in BAT, whereas stimulation of the LH had no appreciable effects. The effect of VMH stimulation was abolished after sympathetic ganglion blockade or by surgical sympathetic denervation of BAT. It was concluded that there is a sympathetic nerve-mediated connection between the VMH and BAT, and that stimulation of the VMH induces metabolic activation and heat production in BAT through an increase in sympathetic nerve activity.     

Neuroregulative mechanism of hypothalamic paraventricular nucleus on gastric ischemia-reperfusion injury in rats

A rat model of gastric ischemia-reperfusion injury (GI-RI) was established by clamping the celiac artery for 30 min and allowing reperfusion for 1 h, on which the regulatory effect of the paraventricular nucleus (PVN) and its neural mechanisms were investigated. The results were: 1. Electrical stimulation of the PVN obviously attenuated the GI-RI. Microinjection of L-glutamic acid into PVN produced an effect similar to that of PVN stimulation. 2. Electrolytic ablation of the PVN aggravated the GI-RI. 3. Nucleus tractus solitarius (NTS) ablation could eliminate the protective effect of electrical stimulation of PVN on GI-RI. 4. Hypophysectomy did not alter the effect of electrical stimulation of PVN. 5. Vagotomy or sympathectomy both could increase the effect of PVN stimulation on GI-RI. These results indicate that the PVN participates in the development of GI-RI as a specific area in the CNS, exerting protective effects on the GI-RI. The NTS and vagus and sympathetic nerve may be involved in the regulative mechanism of PVN on GI-RI, but the PVN mechanism here is independent of the PVN-hypophyseal pathway.     

下丘脑室旁核的心血管调节功能研究进展

下丘脑室旁核 (PVN)是自主性和内分泌性反应的重要整合中枢 ,且在维持心血管活动的动态平衡中起着关键作用。本文简要归纳了PVN的形态结构、纤维联系 ,并详细叙述其对心血管活动的调节及与心血管疾病的关系。     

Injection of noradrenaline into the hypothalamic paraventricular nucleus produces vigorous gnawing in satiated rats

Single injections of noradrenaline (NA) into the hypothalamic paraventricular nucleus (PVN) initiate short bouts of eating in the rat. The effect of the injections of NA (40 nM) into the PVN on gnawing was studied in satiated male rats that had displayed a reliable eating response to NA. The NA injections produced numerous bouts of prolonged and vigorous gnawing of wood pieces shaped like food pellets. The gnawing response started 0.5-2 min after the injection of NA and lasted for 20-25 min. The results suggest that the increase in gnawing and eating evoked by NA might be related to facilitation of the oral responses, and a changed sensitivity to the food related stimuli, in addition to an intrinsic increase in appetite.     

Maternal attenuation of hypothalamic paraventricular nucleus norepinephrine switches avoidance learning to preference learning in preweanling rat pups

Infant rats learn to prefer stimuli paired with pain, presumably due to the importance of learning to prefer the caregiver to receive protection and food. With maturity, a more 'adult-like' learning system emerges that includes the amygdala and avoidance/fear learning. The attachment and 'adult-like' systems appear to co-exist in older pups with maternal presence engaging the attachment system by lowering corticosterone (CORT). Specifically, odor-shock conditioning (11 odor-0.5 mA shock trials) in 12-day-old pups results in an odor aversion, although an odor preference is learned if the mother is present during conditioning. Here, we propose a mechanism to explain pups ability to 'switch' between the dual learning systems by exploring the effect of maternal presence on hypothalamic paraventricular nucleus (PVN) neural activity, norepinephrine (NE) levels and learning. Maternal presence attenuates both PVN neural activity and PVN NE levels during odor-shock conditioning. Intra-PVN NE receptor antagonist infusion blocked the odor aversion learning with maternal absence, while intra-PVN NE receptor agonist infusion permitted odor aversion learning with maternal presence. These data suggest maternal control over pup learning acts through attenuation of PVN NE to reduce the CORT required for pup odor aversion learning. Moreover, these data also represent pups' continued maternal dependence for nursing, while enabling aversion learning outside the nest to prepare for pups future independent living.     

Orexin depolarizes rat hypothalamic paraventricular nucleus neurons

Orexins, also called hypocretins, are newly discovered hypothalamic peptides that are thought to be involved in various physiological functions. In spite of the fact that orexin receptors, especially orexin receptor 2, are abundant in the hypothalamic paraventricular nucleus (PVN), the effects of orexins on PVN neurons remain unknown. Using a whole cell patch-clamp recording technique, we investigated the effects of orexin-B on PVN neurons of rat brain slices. Bath application of orexin-B (0.01-1.0 microM) depolarized 80.8% of type 1 (n = 26) and 79.2% of type 2 neurons tested (n = 24) in the PVN in a concentration-dependent manner. The effects of orexin-B persisted in the presence of TTX (1 microM), indicating that these depolarizing effects were generated postsynaptically. Addition of Cd(2+) (1 mM) to artificial cerebrospinal fluid containing TTX (1 microM) significantly reduced the depolarizing effect in type 2 neurons. These results suggest that orexin-B has excitatory effects on the PVN neurons mediated via a depolarization of the membrane potential.     

下丘脑室旁核内雌激素受体的表达与意义

下丘脑室旁核 (paraventricularnucleus ,PVN)包括大细胞部、小细胞部和背侧帽部等几个部分 ,其中大细胞部主要合成催产素和加压素 ,小细胞部主要合成促肾上腺皮质激素释放激素、甘丙肽等多种神经肽。研究发现PVN的神经内分泌活动受到雌激素的调节 ,进而影响动物的分娩、摄食、脂肪代谢、体重增加等生理功能。雌激素有α和 β两种受体 (即ER α和ER β)。在不同种属动物的PNV内两种雌激素受体的表达水平不同 ,如大鼠PVN主要表达ER β ,而小鼠PVN内除了表达ER β以外也能表达少量ER α ,提示两种ER在不同动物的PVN内功能可能不同 ,它们单独或协同介导雌激素在PVN内参与多种肽能神经元有关的生理功能。     

Feeding inhibition by urocortin in the rat hypothalamic paraventricular nucleus

Ventricular administration of urocortin (UCN) inhibits feeding, but specific site(s) of UCN action are unknown. In the current studies we examined the effect of UCN in the hypothalamic paraventricular nucleus (PVN) on feeding. We tested UCN administered into the PVN in several paradigms: deprivation-induced, nocturnal, and neuropeptide Y (NPY)-induced feeding. We compared the effect of equimolar doses of UCN and corticotrophin releasing hormone (CRH) on NPY-induced and nocturnal feeding, determined whether UCN in the PVN produced a conditioned taste aversion (CTA) and induced changes in c-Fos immunoreactivity (c-Fos-ir) after UCN and NPY administration in the PVN. UCN in the PVN significantly decreased NPY and nocturnal and deprivation-induced feeding at doses of 1, 10, and 100 pmol, respectively. UCN anorectic effects lasted longer than those attributed to CRH. Ten and thirty picomoles UCN did not induce a CTA, whereas 100 pmol UCN produced a CTA. UCN (100 pmol) in the PVN neither increased c-Fos-ir in any brain region assayed nor altered c-Fos-ir patterns resulting from PVN NPY administration. These data suggest the hypothalamic PVN as a site of UCN action.     

Role of AgRP on Ghrelin-induced feeding in the hypothalamic paraventricular nucleus

MT II, agonist for MC3/4-Rs, inhibited Ghrelin's orexigenic effect in the paraventricular nucleus of the hypothalamus (PVN). To further investigate the role of the melanocortin system as mediator of ghrelin's orexigenic actions, we explored the involvement of AgRP in Ghrelin's orexigenic effect by testing the effect on food intake after their co-administration in the PVN, during the light and dark phases of feeding in rats. During both the phases of feeding, co-administration of Ghrelin with either AgRP 50 or AgRP 100 pmol into the PVN did not produce a synergistic effect on the food intake, suggesting that ghrelin induction of feeding occurs by recruiting Agrp as one of the obligatory mediators of its orexigenic effect.     

The neurosteroid allopregnanolone modulates oxytocin expression in the hypothalamic paraventricular nucleus

Virgin, ovariectomized rats exposed to 2 wk of sequential estradiol (E(2)) and progesterone (P) followed by P withdrawal have increased hypothalamic oxytocin (OT) mRNA and peptide levels relative to sham-treated animals. This increase is prevented if P is sustained. In the central nervous system, P is metabolized to the neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), which exerts effects by acting as a positive allosteric modulator of GABA(A) receptor/Cl(-)-channel complexes. In the present study, ovariectomized rats that received sequential E(2) and P for 2 wk followed by P withdrawal were administered allopregnanolone at the time of P withdrawal. Hypothalamic and plasma allopregnanolone concentrations, serum E(2) and P concentrations, and hypothalamic OT mRNA levels were measured at death. Steroid-induced increases in OT mRNA were attenuated in animals treated with allopregnanolone at the time of P withdrawal. The results suggest that allopregnanolone plays an important modulatory role in steroid-mediated increases in hypothalamic OT.     

Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reduces energy intake

Recent studies show that brain-derived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF in the hypothalamic paraventricular nucleus (PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0- to 24-h and 24- to 48-h postinjection intervals. Effective doses producing inhibition of feeding behavior did not establish a conditioned taste aversion. PVN BDNF significantly decreased PVN neuropeptide Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF administration in the PVN abolished food-restriction-induced NPY gene expression in the hypothalamic arcuate nucleus. In conclusion, BDNF in the PVN significantly decreases food intake and body weight gain, suggesting that the PVN is an important site of action for BDNF in its effects on energy metabolism. Furthermore, BDNF appears to interact with NPY in its anorectic actions, although a direct effect on NPY remains to be established.     

Purinergic and glutamatergic interactions in the hypothalamic paraventricular nucleus modulate sympathetic outflow

P2X receptors are expressed on ventrolateral medulla projecting paraventricular nucleus (PVN) neurons. Here, we investigate the role of adenosine 5′-triphosphate (ATP) in modulating sympathetic nerve activity (SNA) at the level of the PVN. We used an in situ arterially perfused rat preparation to determine the effect of P2 receptor activation and the putative interaction between purinergic and glutamatergic neurotransmitter systems within the PVN on lumbar SNA (LSNA). Unilateral microinjection of ATP into the PVN induced a dose-related increase in the LSNA (1 nmol: 38 ± 6 %, 2.5 nmol: 72 ± 7 %, 5 nmol: 96 ± 13 %). This increase was significantly attenuated by blockade of P2 receptors (pyridoxalphosphate-6-azophenyl-20,40-disulphonic acid, PPADS) and glutamate receptors (kynurenic acid, KYN) or a combination of both. The increase in LSNA elicited by L-glutamate microinjection into the PVN was not affected by a previous injection of PPADS. Selective blockade of non-N-methyl-D-aspartate receptors (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt, CNQX), but not N-methyl-D-aspartate receptors (NMDA) receptors (DL-2-amino-5-phosphonopentanoic acid, AP5), attenuated the ATP-induced sympathoexcitatory effects at the PVN level. Taken together, our data show that purinergic neurotransmission within the PVN is involved in the control of SNA via P2 receptor activation. Moreover, we show an interaction between P2 receptors and non-NMDA glutamate receptors in the PVN suggesting that these functional interactions might be important in the regulation of sympathetic outflow.     

Agouti-related protein in the hypothalamic paraventricular nucleus: effect on feeding

Agouti-related protein (Agrp) is an endogenous melanocortin-4 receptor antagonist implicated in the regulation of food intake. Effects of Agrp on feeding under varying conditions were investigated. Agrp (10 to 100 pmol) was injected into the hypothalamic paraventricular nucleus of satiated (a.m. and p.m. injections) and food-deprived rats, or was co-administered with 117 pmol Neuropeptide Y (NPY). Agrp significantly stimulated light-phase feeding by 24 h post-injection. However, Agrp stimulated dark-phase and deprivation-induced feeding by 4 and 2 h, respectively. Animals receiving NPY and Agrp consumed more than animals receiving either peptide alone, the effect remaining by 24 h.     

Relationship between norepinephrine release in the hypothalamic paraventricular nucleus and circulating prolactin levels in the Siberian hamster: role of photoperiod and the pineal gland

The impact of norepinephrine (NE) and its metabolite, 3-methoxy4-hydroxyphenylglycol (MHPG), on circulating prolactin (PRL) was evaluated in the paraventricular region of the hypothalamus as a function of photoperiod and integrity of the pineal gland. In Experiment 1, whole tissue content of NE and MHPG was assessed in male and female hamsters that had been pinealectomized or sham-pinealectomized and exposed to long or short photoperiods for 5 weeks. The results revealed a marginal effect of photoperiod in males, but no overall effects of surgery. Because analysis of whole tissue content can be complicated by concurrent changes in synthesis and storage rates, Experiment 2 was conducted using microdialysis to assess extracellular levels of NE and MHPG in female hamsters. Pinealectomy completely prevented the short-day-induced suppression of luteinizing hormone, but it only partially prevented the effects of short days on PRL. Furthermore, both NE and MHPG levels were significantly elevated in short-day-exposed pinealectomized and sham-operated animals. These results suggest that NE release within the paraventricular nucleus inhibits the circulating PRL levels and is one mechanism by which direct photic information can influence the neuroendocrine axis independently of the pineal melatonin signal.     

Topography of the subnuclei of the paraventricular hypothalamic nucleus in rats and the sensitivity of their neurons to insulin deficiency

Light microscopy was used to investigate the morphology and topography of hypothalamic paraventricular subnuclei in adult male rats. The subnuclear cell reaction to experimental alloxan diabetes was studied by karyometry. The paraventricular nucleus was established to contain 10 subnuclei, 8 of which responded to disorders in carbohydrate metabolism. The data obtained are consistent with the hypothesis of the involvement of the paraventricular nucleus in the control of carbohydrate homeostasis.     

Expression of NPY Y1 and Y5 receptors in the hypothalamic paraventricular nucleus of aged Fischer 344 rats

Many mammals, nearing the end of life, spontaneously decrease their food intake and body weight, a stage we refer to as senescence. The spontaneous decrease in food intake and body weight is associated with attenuated responses to intracerebroventricular injections of neuropeptide Y (NPY) compared with old presenescent or with young adult rats. In the present study, we tested the hypothesis that this blunted responsiveness involves the number and expression of hypothalamic paraventricular nucleus (PVN) Y(1) and/or Y(5) NPY receptors, both of which are thought to mediate NPY-induced food intake. We found no significant difference in mRNA levels, via quantitative PCR, for Y(1) and Y(5) receptors in the PVN of senescent vs. presenescent rats. In contrast, immunohistochemistry indicated that the number of PVN neurons staining for Y(1) receptor protein was greater in presenescent compared with senescent rats. We conclude that a decreased expression and number of Y(1) or Y(5) receptors in the PVN cannot explain the attenuated responsiveness of the senescent rats to exogenous NPY.     

Acute inhibition of the hypothalamic paraventricular nucleus decreases renal sympathetic nerve activity and arterial blood pressure in water-deprived rats

The present study was performed to determine whether sympathetic outflow and arterial blood pressure in water-deprived rats are dependent on the ongoing neuronal activity of the hypothalamic paraventricular nucleus (PVN). Renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate were recorded in urethane-alpha-chloralose-anesthetized rats that were deprived of water but not food for 48 h before experiments. Acute inhibition of the PVN by bilateral microinjection of the GABA(A) agonist muscimol (100 pmol/side) significantly decreased RSNA in water-deprived rats (-26.7 +/- 4.7%, n = 7) but was without effect in control rats (1.3 +/- 6.3%, n = 7). Similarly, injection of muscimol produced a greater decrease in MAP in water-deprived rats than in control rats (-46 +/- 3 vs. -16 +/- 3 mmHg, respectively), although baseline MAP was not different between groups (105 +/- 4 vs. 107 +/- 4 mmHg, respectively). Neither bilateral microinjection of isotonic saline vehicle (100 nl/side) into the PVN nor muscimol (100 pmol/side) outside the PVN altered RSNA or MAP in either group. In addition, ganglionic blockade with hexamethonium (30 mg/kg i.v.) significantly decreased MAP in both groups; however, the decrease in MAP was significantly greater in water-deprived rats than in control rats (62 +/- 2 vs. 48 +/- 2 mmHg, respectively). Collectively, these findings suggest that sympathetic outflow contributes more to the maintenance of blood pressure in the water-deprived rat, and this depends, at least partly, on the ongoing activity of PVN neurons.     

Differential effects of galanin and neuropeptide Y on extracellular norepinephrine levels in the paraventricular hypothalamic nucleus of the rat: a microdialysis study.

Evidence suggests that the peptides galanin (GAL) and neuropeptide Y (NPY) interact with the amine norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) to stimulate feeding behavior. To directly investigate the nature of these interactions, extracellular levels of PVN NE were monitored in freely-moving rats using the microdialysis/HPLC technique. Following PVN administration of GAL (0.3 nmol), NPY (78 pmol) or Ringer's solution, local NE levels were measured at 20-min intervals for 2 hrs postinjection, under two feeding conditions, namely, in the presence or absence of food. The results demonstrate different effects of these peptides on endogenous NE levels. Following GAL administration, PVN NE levels were enhanced by 80 to 90%, up to 40 min postinjection, independent of food availability. In contrast, following NPY injection, NE levels were significantly reduced 20 min postinjection with food absent, and when food was available, NE levels tended to be enhanced. These results, consistent with pharmacological and biochemical studies, reveal different patterns of peptide-amine interactions in the PVN.     

Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats

In humans, nonexercise activity thermogenesis (NEAT) increases with positive energy balance. The mediator of the interaction between positive energy balance and physical activity is unknown. In this study, we address the hypothesis that orexin A acts in the hypothalamic paraventricular nucleus (PVN) to increase nonfeeding-associated physical activity. PVN-cannulated rats were injected with either orexin A or vehicle during the light and dark cycle. Spontaneous physical activity (SPA) was measured using arrays of infrared activity sensors and night vision videotaped recording (VTR). O(2) consumption and CO(2) production were measured by indirect calorimetry. Feeding behavior was assessed by VTR. Regardless of the time point of injection, orexin A (1 nmol) was associated with dramatic increases in SPA for 2 h after injection (orexin A: 6.27 +/- 1.95 x 10(3) beam break count, n = 24; vehicle: 1.85 +/- 1.13 x 10(3), n = 38). This increase in SPA was accompanied by compatible increase in O(2) consumption. Duration of feeding was increased only when orexin A was injected in the early light phase and accounted for only 3.5 +/- 2.5% of the increased physical activity. In a dose-response experiment, increases in SPA were correlated with dose of orexin A linearly up to 2 nmol. PVN injections of orexin receptor antagonist SB-334867 were associated with decreases in SPA and attenuated the effects of PVN-injected orexin A. Thus orexin A can act in PVN to increase nonfeeding-associated physical activity, suggesting that this neuropeptide might be a mediator of NEAT.