It is well established that increased excitability of the presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) during hypertension leads to heightened sympathetic outflow and hypertension. However, the mechanism underlying the overactivation of PVN presympathetic neurons remains unclear. This study aimed to investigate the role of endogenous corticotropin-releasing factor (CRF) on the excitability of presympathetic neurons in PVN using Western blot, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) recording, CRISPR/Cas9 technique and patch-clamp technique. The results showed that CRF protein expression in PVN was significantly upregulated in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. Besides, PVN administration of exogenous CRF significantly increased RSNA, heart rate and ABP in WKY rats. In contrast, knockdown of upregulated CRF in PVN of SHRs inhibited CRF expression, led to membrane potential hyperpolarization, and decreased the frequency of current-evoked firings of PVN presympathetic neurons, which were reversed by incubation of exogenous CRF. Perfusion of rat brain slices with artificial cerebrospinal fluid containing CRF receptor 1 (CRFR1) blocker, NBI-35965, or CRF receptor 2 (CRFR2) blocker, Antisauvagine-30, showed that blocking CRFR1, but not CRFR2, hyperpolarized the membrane potential and inhibited the current-evoked firing of PVN presympathetic neurons in SHRs. However, blocking CRFR1 or CRFR2 did not affect the membrane potential and current-evoked firing of presympathetic neurons in WKY rats. Overall, these findings indicate that increased endogenous CRF release from PVN CRF neurons enhances the excitability of presympathetic neurons via activation of CRFR1 in SHRs.
Rats ; Animals ; Rats, Inbred SHR ; Paraventricular Hypothalamic Nucleus/physiology* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Rats, Inbred WKY ; Corticotropin-Releasing Hormone/metabolism* ; Neurons/physiology* ; Hypertension ; Sympathetic Nervous System

The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity. Phenotypically-characterized NTS neurons have been implicated in the differential regulation of blood pressure (BP). Here, we investigated whether phenylethanolamine N-methyltransferase (PNMT)-expressing NTS (NTS^PNMT) neurons contribute to the control of BP. We demonstrate that photostimulation of NTS^PNMT neurons has variable effects on BP. A depressor response was produced during optogenetic stimulation of NTS^PNMT neurons projecting to the paraventricular nucleus of the hypothalamus, lateral parabrachial nucleus, and caudal ventrolateral medulla. Conversely, photostimulation of NTS^PNMT neurons projecting to the rostral ventrolateral medulla produced a robust pressor response and bradycardia. In addition, genetic ablation of both NTS^PNMT neurons and those projecting to the rostral ventrolateral medulla impaired the arterial baroreflex. Overall, we revealed the neuronal phenotype- and circuit-specific mechanisms underlying the contribution of NTS^PNMT neurons to the regulation of BP.
Solitary Nucleus/metabolism* ; Blood Pressure/physiology* ; Phenylethanolamine N-Methyltransferase/metabolism* ; Neurons/metabolism* ; Paraventricular Hypothalamic Nucleus/metabolism*

Olfaction and food intake are interrelated and regulated. In the process of feeding, the metabolic signals in the body and the feeding signals produced by food stimulation are first sensed by the arcuate nucleus of hypothalamus and the nucleus tractus solitarius of brain stem, and then these neurons project to the paraventricular nucleus of hypothalamus. The paraventricular nucleus transmits the signals to other brain regions related to feeding and regulates feeding behavior. In this process, olfactory signals can be transmitted to hypothalamus through olfactory bulb and olfactory cortex to regulate feeding behavior. At the same time, gastrointestinal hormones (ghrelin, insulin, leptin, etc.) and some neurotransmitters (acetylcholine, norepinephrine, serotonin, endocannabinoid, etc.) produced in the process of feeding act on the olfactory system to regulate olfactory function, which in turn affects the feeding itself. This review summaries the research progress of the interaction between olfaction and food intake and its internal mechanism from the aspects of neuronal and hormonal regulation.
Arcuate Nucleus of Hypothalamus/metabolism* ; Feeding Behavior/physiology* ; Hypothalamus ; Paraventricular Hypothalamic Nucleus ; Smell

Objective: To explore the effects of the mu-opioid receptor (MOR) in the paraventricular nucleus (PVN) on the ejaculatory behaviors of male rats and its potential mechanisms. METHODS: Male SD rats with normal ejaculation ability were mated with female ones in hormone-induced estrus. After bilateral PVN microinjection of D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) with an inserted catheter, the male animals were observed for mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL), ejaculation frequency (EF), post-ejaculation interval (PEI), and intromission ratio (IR). The lumbar sympathetic nerve activity (LSNA) of the rats was recorded using the PowerLab data acquisition hardware device, and the levels of norepinephrine (NE) in the peripheral plasma were measured by ELISA following microinjection of saline or different doses of DAGO or CTAP. RESULTS: Neither CTAP nor DGAO significantly affected the ML of the male rats (P > 0.05). DGAO remarkably increased IF (P < 0.01) and MF (P < 0.01), prolonged IL (P < 0.01), EL (P < 0.01) and PEI (P < 0.01), and reduced EF (P <0.01) and IR (P < 0.05). On the contrary, CTAP markedly decreased IF (P < 0.01) and MF (P < 0.01), shortened IL (P < 0.01), EL (P < 0.01) and PFI (P < 0.01), and elevated EF (P < 0.01) and IR (P < 0.01). Additionally, DAGO decreased LSNA in a dose-dependent manner and reduced the NE level in the peripheral plasma. CTAP, however, not only offset the effects of DAGO on LSNA, but also significantly increased LSNA. CONCLUSIONS MOR in PVN inhibits ejaculatory behaviors in male rats by weakening LSNA, which has provided some theoretical evidence for the use of highly selective opioids in the treatment of premature ejaculation.
Animals ; Ejaculation ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology* ; Female ; Male ; Paraventricular Hypothalamic Nucleus/physiology* ; Peptide Fragments/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu/physiology* ; Somatostatin/pharmacology* ; Sympathetic Nervous System/physiology*

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
Animals ; Blood Pressure ; physiology ; Excitatory Postsynaptic Potentials ; physiology ; Humans ; Hypertension ; physiopathology ; Hypothalamus ; physiology ; Neurons ; physiology ; Paraventricular Hypothalamic Nucleus ; physiology

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.
Animals ; Copulation ; Ejaculation/physiology* ; Female ; Male ; Neurons/physiology* ; Paraventricular Hypothalamic Nucleus/physiology* ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Sexual Behavior, Animal/physiology* ; Splanchnic Nerves/physiology* ; Sympathetic Nervous System/physiology*

OBJECTIVETo assess the inhibitory modulation of blood pressure by stimulation of the deep peroneal nerve (DPN) and to determine the involvement of nociceptive fibers in the modulation.

METHODSAll the animals were divided into six groups (A-F). The rats in groups A and B received no pretreatment. The rats in groups C and D received subcutaneous injection of capsaicin or control vehicle, respectively, near the DPN for 2 days. Those in groups E and F had the DPN exposed to capsaicin or control vehicle, respectively, for 20 min. Subsequently, pressor responses were induced by stimulation of paraventricular nucleus (PVN) either electrically (groups A and C C-F) or chemically via injection of glutamate (group B). After two stable pressor responses (baseline), all groups were subject to 5-min DPN stimulation followed by PVN stimulation for 10 s. Arterial blood pressure, heart rate, and electrocardiogram were recorded. The pressor response was calculated as the difference in the mean arterial pressure (MAP) before and after PVN stimulation, and changes from baseline in pressor response after DPN stimulation were compared between the groups.

RESULTSIncreases of MAP of 22.88±2.18 mm Hg and 20.32±5.25 mm Hg were induced by electrical (group A) or chemical (group B) stimulation of the PVN, respectively. These pressor responses were inhibited by stimulation of the DPN, and the MAP was reduced to 12.00±2.10 mm Hg in group A (n=6, P<0.01) and 7.00±2.85 mm Hg in group B (n=6, P<0.01). Subcutaneous injection of capsaicin (125 mg/kg) near the DPN in group C (n=7) had no effect on the inhibitory effect of DPN stimulation compared with the group D (n=9), and neither did blockade of nociceptive fibers with capsaicin in group E (n=6) compared with group F (n=8).

CONCLUSIONStimulation of the DPN mimicking acupuncture has an inhibitory effect on the pressor response, and the effect is mediated by capsaicin-insensitive afferent fibers in the DPN.

Acupuncture Therapy ; Anesthesia ; Animals ; Blood Pressure ; drug effects ; Capsaicin ; administration & dosage ; pharmacology ; Electric Stimulation ; Injections, Subcutaneous ; Male ; Paraventricular Hypothalamic Nucleus ; cytology ; drug effects ; Peroneal Nerve ; drug effects ; physiology ; Pressoreceptors ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley

AIMTo investigate the possible involvement of gamma-aminobutyric acid (GABA) in the paraventricular nucleus (PVN) in cardiovascular responses induced by central salt loading.

METHODSDirect perfusion into PVN region with hypertonic saline (0.6 mol/L) was performed in conscious rats by using an in vivo brain microdialysis technique. Then, the extracellular concentration of GABA in the PVN region was measured by microdialysis and high performance liquid chromatography (HPLC) techniques, and the blood pressure (BP) and heart rate (HR) were with recorded simultaneously. Bicuculline (an antagonist of GABAA receptor) or saclofen (an antagonist of GABAB receptor) were coperfused hypertonic saline into PVN region, then the cardiovascular responses were examined.

RESULTS(1) The local perfusion of 0.6 mol/L saline elicited significant increases on BP and HR (P < 0.01). In addition, perfusion of 0.6 mol/L saline increased the extracellular GABA levels in the PVN region, which reached 561.96% +/- 173.96% (P < 0.05) of the basal level. (2) Bicuculline or salcofen significantly attenuated the in-response of BP (P < 0.01, respectively), whereas the antagonists did not influence the response of HR induced by hypertonic saline.

CONCLUSIONLocal perfusion of hypertonic saline in the PVN region elicits a local release of GABA, which may act via GABA(A) and GABA(B) receptors to produce pressor response.

Animals ; Blood Pressure ; drug effects ; physiology ; Male ; Microdialysis ; methods ; Paraventricular Hypothalamic Nucleus ; metabolism ; physiology ; Pressoreceptors ; drug effects ; Rats ; Rats, Wistar ; Saline Solution, Hypertonic ; administration & dosage ; pharmacology ; gamma-Aminobutyric Acid ; metabolism

The hypothalamic paraventricular nucleus (PVN) is a central site for integration of the endocrine system and the autonomic nervous system. Despite a number of studies have pointed out the importance of the PVN in the central regulation of cardiovascular functions, the chemical mediators in the PVN responsible for mediating baroreflex are not well understood. In the present study, we used the conscious rats to investigate the possible involvement of glycine (Gly) in PVN in the central regulation of baroreflex induced by intravenous injection of phenylephrine (0.8 mug/0.04 mL, in 3 min). Then, the microdialysis sampling was performed in the PVN and the concentration of Gly in the microdialysate was measured by high performance liquid chromatography (HPLC) combined with electrochemical techniques, and mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously. Injection of phenylephrine elicited a significant increase (P<0.01) in MAP from the baseline of (99.5+/-14.2) mmHg to the maximum of (149.8+/-19.5) mmHg and a decrease (P<0.01) in HR from the baseline of (400.8+/-33.1) beats/min to the minimum of (273.4+/-40.8) beats/min, respectively. Synchronously, the injection of phenylephrine increased the level of Gly in the microdialysate from the PVN to (162.9+/-27.3)% of the basal level (P<0.05). Perfusion of strychnine (100 mumol/L), an antagonist of Gly receptor, into the PVN enhanced the pressor response and attenuated the bradycardic response during the baroreflex, resulting in a decrease in baroreflex sensitivity (P<0.001). Whereas, the perfusion of Gly (1 mmol/L) into the PVN did not affect the pressor response but enhanced the bradycardic response during the baroreflex, resulting in an increase in baroreflex sensitivity (P<0.001). These results suggest that endogenous Gly in the PVN may act via strychnine-sensitive Gly receptor to produce a facilitative effect on baroreflex.
Animals ; Baroreflex ; drug effects ; Glycine ; pharmacology ; Heart Rate ; Microinjections ; Paraventricular Hypothalamic Nucleus ; physiology ; Phenylephrine ; pharmacology ; Rats

AIMTo investigate the possible involvement of glutamate(Glu) in the paraventricular nucleus (PVN) in the central regulation of baroreflex.

METHODSThe baroreflex was induced by intravenous injection of phenylephrine in conscious rats, and the extracellular concentration of Glu in the PVN region was measured by microdialysis and high performance liquid chromatography (HPLC) techniques. To determine whether the observed Glu release was involved in the baroreflex, NMDA and non-NMDA receptor antagonists, MK-801 and CNQX, were perfused in the PVN region during baroreflex.

RESULTSDuring baroreflex, the Glu concentration in the PVN region immediately increased to 384.82% +/- 91.77% of basal level (P < 0.01). (2) During baroreflex, direct perfusion of MK-801 and CNQX in the PVN were attenuated the increase of blood pressure and enhanced the decrease of HR (P < 0.01),resulting a significant increase in baroreflex sensitivity (P < 0.01).

CONCLUSIONGlutamate in PVN is involved in central regulation of baroreflex, which may inhibit baroreflex via ionothopic glutamate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione ; pharmacology ; Animals ; Baroreflex ; drug effects ; physiology ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Male ; Paraventricular Hypothalamic Nucleus ; physiology ; Rats ; Rats, Wistar