Parvocellular Paraventricular Hypothalamic Nucleus Research Articles

Prolonged functional cerebral asymmetry as a consequence of dysfunctional parvocellular paraventricular hypothalamic nucleus signaling: An integrative model for the pathophysiology of bipolar disorder

Approximately 45 million people worldwide are diagnosed with bipolar disorder (BD). While there are many known risk factors and models of the pathologic processes influencing BD, the exact neurologic underpinnings of BD are unknown. We attempt to integrate the existing literature and create a unifying hypothesis regarding the pathophysiology of BD with the hope that a concrete model may potentially facilitate more specific diagnosis, prevention, and treatment of BD in the future. We hypothesize that dysfunctional signaling from the parvocellular neurons of the paraventricular hypothalamic nucleus (PVN) results in the clinical presentation of BD. Functional damage to this nucleus and its signaling pathways may be mediated by myriad factors (e.g. immune dysregulation and auto-immune processes, polygenetic variation, dysfunctional interhemispheric connections, and impaired or overactivated hypothalamic axes) which could help explain the wide variety of clinical presentations along the BD spectrum. The neurons of the PVN regulate ultradian rhythms, which are observed in cyclic variations in healthy individuals, and mediate changes in functional hemispheric lateralization. Theoretically, dysfunctional PVN signaling results in prolonged functional hemispheric dominance. In this model, prolonged right hemispheric dominance leads to depressive symptoms, whereas left hemispheric dominance correlated to the clinical picture of mania. Subsequently, physiologic processes that increase signaling through the PVN (hypothalamic-pituitaryadrenal axis, hypothalamic- pituitary-gonadal axis, and hypothalamic-pituitary-thyroid axis activity, suprachiasmatic nucleus pathways) as well as, neuro-endocrine induced excito-toxicity, auto-immune and inflammatory flairs may induce mood episodes in susceptible individuals. Potentially, ultradian rhythms slowing with age, in combination with changes in hypothalamic axes and maturation of neural circuitry, accounts for BD clinically presenting more frequently in young adulthood than later in life.

Differential effects of central administration of relaxin-3 on food intake and hypothalamic neuropeptides in male and female rats.

Relaxin-3 (RLN3) is an orexigenic neuropeptide that produces sex-specific effects on food intake by stronger stimulation of feeding in female compared with male rats. This study determined which hypothalamic nuclei and associated neuropeptides may be involved in the sex-specific orexigenic effects of RLN3. Relaxin-3 (800 pmol) or vehicle was injected into the lateral ventricle of female and male rats. Food and water intake were measured after the first injection, and rats were euthanized after the second injection to determine the mRNA expression of the hypothalamic neuropeptides. Food but not water intake showed sex-specific effects of RLN3. Stimulation of food intake by RLN3 was significantly higher in female than in male rats. No effect of RLN3 injection was found on c-fos mRNA expression in the arcuate, dorsomedial and ventromedial hypothalamic nuclei. Increased c-fos mRNA expression was observed in the paraventricular hypothalamic nucleus (PVN) in both sexes and in the lateral hypothalamic area (LHA) in female rats. Relaxin-3 injections led to a sex-nonspecific increase in the expression of oxytocin mRNA in the magnocellular PVN. Conversely, RLN3-induced expression of anorexigenic neuropeptide arginine vasopressin (AVP) was significantly higher in the parvocellular PVN in male compared with female rats. Finally, RLN3 administration significantly increased the expression of orexin (ORX) mRNA in the LHA in female but not in male rats. Stronger expression of anorexigenic AVP in the PVN in male rats and increased expression of ORX in the LHA in female rats may contribute to stronger orexigenic effects of RLN3 in female rats compared with male rats.

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it develops in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in the ad libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitum -fed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype.

Regulation of expression of relaxin-3 and its receptor RXFP3 in the brain of diet-induced obese rats

An animal model closely related to human obesity is diet-induced obesity in Sprague–Dawley rats. These rats placed on a high-energy (HE) diet show wide distribution in body weight gain with a subset of animals developing diet-induced obesity (DIO) and the remaining animals showing a diet-resistant (DR) phenotype. Once obesity is established, DIO rats strongly defend their increased body weight against caloric restriction. There is evidence that neuropeptide relaxin-3 is involved in food intake regulation, but the levels of expression of relaxin-3 and its receptor have not been yet demonstrated in the DIO model. The present study investigated the brain expression of relaxin-3 and its cognate receptor RXFP3 in DIO and DR rats maintained on an HE diet since weaning. Expression of relaxin-3 and RXFP3 mRNAs was assessed by in situ hybridization in ad libitum, food-deprived (12h) and refed (1h) feeding states. The levels of expression of relaxin-3 in the medial portion of the nucleus incertus (NI) were higher in the DIO rats compared to the DR rats in the ad libitum-fed state. Food deprivation increased the levels of expression of relaxin-3 in the medial NI in DR but not DIO rats. The stronger expression of relaxin-3 in the ad libitum-fed state in the DIO rats was accompanied by low expression of the RXFP3 receptor in the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus, central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Refeeding increased expression of RXFP3 in the paraventricular thalamic nucleus, parvocellular PVN, CeA, NI, and NTS in the DIO rats. These results provide evidence that DIO rats show a constitutive increase in relaxin-3 expression in the medial NI and that refeeding after food deprivation may enhance the orexigenic effects of relaxin-3 in DIO rats by rapid upregulation of the expression of RXFP3 in the specific brain regions involved in food intake regulation.

Effects of Estrogen on Stress‐induced Activation of Peptide Neurons in PVN of Ovariectomized Rats

Estrogen has been implicated in brain function related to stress responses. We investigated whether estrogen affects psychological stress-induced activation of peptide-containing or nitric oxide-producing neurons in the paraventricular hypothalamic nucleus (PVN) in ovariectomized (OVX) rats, both placebo-treated (OVX + Pla) and estrogen-treated (OVX + E2) by comparison of c-Fos expression using immunohistochemistry. Cage-switch stress increased activation in oxytocinergic neurons in the parvocellular PVN (pPVN) in OVX + Pla, but not in that of OVX + E2, rats. Moreover, the stress-induced activation in NADPH-diaphorase-positive neurons in the pPVN was larger in the OVX + E2 than in the OVX + Pla group. These findings suggest that estrogen attenuates the activation of oxytocinergic neurons in the pPVN, at least in part via nitric oxide.

Corticotropin-releasing factor and its receptors in the brain of rats with insulin and corticosterone deficits

The expression of genes encoding corticotropin-releasing factor (CRF) and its receptor type-1 (CRF1R) and type-2alpha (CRF2R) has been studied in the brain of rats with streptozotocin (STZ)-induced diabetes and adrenalectomy (ADX). Diabetic rats had a lower body weight compared to control rats. Food and water intake were increased in diabetic rats and decreased in ADX animals. The plasma corticosterone levels measured at the nadir of the circadian rhythm were significantly higher in diabetic rats compared to non-diabetic animals. STZ-diabetic rats demonstrated an induction of expression of CRF mRNA in the magnocellular part of the paraventricular hypothalamic nucleus (PVN) and in the supraoptic nucleus (SON), whereas the CRF transcript in the parvocellular PVN was significantly lower in rats with insulin deficiency. ADX strongly triggered the expression of CRF mRNA in the parvocellular neurons of the PVN in both non-diabetic and diabetic rats, and it decreased magnocellular CRF mRNA in diabetic animals. The expression of the CRF1R in the parvocellular and magnocellular PVN and in the SON was induced by diabetes and decreased after ADX. The levels of the CRF2R mRNA in the ventromedial hypothalamic nucleus (VMH) were significantly lower in diabetic rats without any noticeable effects of ADX. The present results suggest opposite effects of insulin and corticosterone deficiency on the hypophysiotropic CRF and the CRF1R mRNA contents, whereas the expression of CRF2R was mostly related to insulin, but not to the corticosterone status.

Electroacupuncture Reduces Stress-Induced Expression of c-Fos in the Brain of the Rat

We have previously shown that electroacupuncture (EA) at Shaohai and Neiguan (HT3-PC6) points significantly attenuated stress-induced peripheral responses, including increases in blood pressure, heart rate and plasma catecholamines. In this study, we examined the central effect of EA on the expression of c-fos, one of the immediate-early genes in the brain of rats subjected to immobilization stress. Immobilization stress (180 minutes) preferentially produced a significant increase in Fos-like immunoreactivity (FLI) in stress-relevant regions including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARN), supraoptic nucleus (SON), suprachiasmatic nucleus (SCN), medial amygdaloid nucleus (AMe), bed nucleus of the stria terminalis (BST), hippocampus, lateral septum (LS), nucleus accumbens, and the locus coeruleus (LC). EA (3 Hz, 0.2 ms rectangular pulses, 20 mA) at HT3-PC6 on the heart and pericardium channels for 30 minutes during stress, significantly attenuated stress-induced FLI in the parvocellular PVN, SON, SCN, AMe, LS and the LC. However, EA stimulations at HT3-PC6 had no effect on FLI in the magnocelluar PVN, ARN, BST or the hippocampus. EA stimulation at HT3-PC6 had a greater inhibitory effect on stress-induced FLI than that at TE5-LI11, the triple energizer and large intestine meridian, or non-acupoints. These results demonstrated that EA attenuated stress-induced c-fos expression in brain areas. These results suggest that decreased c-fos expression in hypothalamic and LC neurons, among stress-related areas, may reflect the integrative action of acupuncture in stress response.

Presynaptic NMDA receptor subunit immunoreactivity in GABAergic terminals in rat brain.

N-methyl-D-aspartate (NMDA) receptors are commonly found post-synaptically; they mediate fast excitatory neurotransmission in the central nervous system. In this study, we provide immunocytochemical data supporting the existence of presynaptic NMDA receptors in GABAergic terminals using polyclonal antisera raised against the C-terminus of the NMDAR1 subunit. At the light microscope level, rich plexuses of NMDAR1-positive varicose fibers were found in various nuclei in the basal forebrain (bed nucleus of stria terminalis, septum, parastrial nucleus, vascular organ of the lamina terminalis), thalamus (paraventricular nucleus, midline nuclei), and hypothalamus (parvocellular paraventricular nucleus, arcuate nucleus, preoptic nucleus, suprachiasmatic nucleus). In the brainstem, labeled fibers were much less abundant and were confined to the ventral tegmental area, periaqueductal gray, parabrachial nucleus, and locus coeruleus. At the electron microscope level, NMDAR1-immunoreactive terminals examined in the bed nucleus of stria terminalis, parvocellular paraventricular hypothalamic nucleus, and arcuate nucleus formed symmetric synapses, contained darkly stained large dense-core vesicles, and displayed gamma-aminobutyric acid (GABA) immunoreactivity. Terminals with similar ultrastructural features were found in the paraventricular thalamic nucleus. These findings demonstrate the existence of NMDAR1 subunit immunoreactivity in subsets of GABAergic terminals, which raises questions about the potential roles and mechanisms of activation of presynaptic NMDA heteroreceptors in the rat central nervous system. The pattern of distribution and ultrastructural features of these boutons suggest that they may arise from local GABAergic projections interconnecting a group of brain structures mediating stress responses and/or other endocrine, autonomic, and limbic functions.

A 'sticky' interhemispheric switch in bipolar disorder?

Despite years of research into bipolar disorder (manic depression), its underlying pathophysiology remains elusive. It is widely acknowledged that the disorder is strongly heritable, but the genetics are complex with less than full concordance in monozygotic twins and at least four susceptibility loci identified. We propose that bipolar disorder is the result of a genetic propensity for slow interhemispheric switching mechanisms that become 'stuck' in one or the other state. Because slow switches are also 'sticky' when compared with fast switches, the clinical manifestations of bipolar disorder may be explained by hemispheric activation being 'stuck' on the left (mania) or on the right (depression). Support for this 'sticky' interhemispheric switching hypothesis stems from our recent observation that the rate of perceptual alternation in binocular rivalry is slow in euthymic subjects with bipolar disorder (n = 18, median = 0.27 Hz) compared with normal controls (n = 49, median = 0.60 Hz, p < 0.0005). We have presented evidence elsewhere that binocular rivalry is itself an interhemispheric switching phenomenon. The rivalry alternation rate (putative interhemispheric switch rate) is robust in a given individual, with a test-retest correlation of more than 0.8, making it suitable for genetic studies. The interhemispheric switch rate may provide a trait-dependent biological marker for bipolar disorder.

Metabolic mapping of the brain in pregnant, parturient and lactating rats using Fos immunohistochemistry

The present study was designed to investigate Fos-positive neurons of the female rat brain at various reproductive states in order to analyze the metabolic map connected with pregnancy, parturition and lactation. The number of Fos-positive neurons in each brain nucleus was analyzed with a quantitative immunohistochemical method in virgin, pregnant, parturient, lactating and arrested lactating rats. In parturient rats, a significant number of Fos-positive neurons was observed as compared to virgin or pregnant females in the following brain regions; the bed nucleus of the stria terminalis (BST), lateral septal nucleus (LS), medial preoptic area (MPA), periventricular hypothalamic nucleus (Pe), parvocellular paraventricular hypothalamic nucleus (PaPVN), magnocellular paraventricular hypothalamic nucleus (MaPVN), supraoptic nucleus (SON), paraventricular thalamic nucleus (PV), anterior hypothalamic area (AHA), lateral hypothalamic area (LH), amygdaloid nucleus (AM), supramammillary nucleus (SuM), substantia nigra (SN), central grey (CG), microcellular tegmental nucleus (MiTg), subparafascicular thalamic nucleus (SPF), posterior hypothalamic area (PH), dorsal raphe nucleus (DR), locus coeruleus (LC), dorsal parabrachial nucleus (DPB), nucleus of solitary tract (Sol), and ventrolateral medulla (VLM). Significant differences were found in the number of Fos-positive neurons between parturient and lactating females, although localization of Fos-positive neurons in lactating females was quite similar to parturient ones. Between parturient and lactating rats: (1) In the MPA, PaPVN, AHA, arcuate hypothalamic nucleus (Arc), ventromedial hypothalamic nucleus (VMH), mesencephalic lateral tegmentum (MLT), and genual nucleus (Ge), the number of Fos-positive neurons of lactating females were significantly higher than those of parturient ones; (2) In the LS, Pe, PV, LH, AM, SuM, CG, MiTg, SPF, PH, DR, LC, and VLM, there was no significant differences in the number of Fos-positive neurons; (3) In the BST, MaPVN, SON, SN, DPB and Sol, the number of Fos-positive neurons of lactating rats were significantly lower than those of parturient ones. These different patterns of Fos expression among many brain regions may be owing to the functional differences in each region. Fos expression in lactating rats was apparently induced by suckling stimulation because the removal of their litters immediately after parturition completely eliminated expression of Fos protein in each nucleus. These results suggest that the localization of Fos-positive neurons in a number of neural populations throughout the brain may be revealing the neural circuits in response to parturition or lactation.

Effect of chronic dexfenfluramine on Fos in rat brain

The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-IR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.

Effect of chronic dexfenfluramine on Fos in rat brain

The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-IR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.

Central mechanism of neural activation with cold acclimation of rats using Fos immunohistochemistry

The expression of Fos protein in the rat diencephalon, brain stem, cerebellum, and spinal cord was investigated using immunohistochemistry during chronic cold exposure, in order to clarify the neural regions involved in the thermoregulatory responses and the central mechanism of neural activation with cold acclimation. Numerous Fos-positive cells were observed in many brain regions after cold exposure and changes in the number of Fos-positive cells were analyzed quantitatively. Fos-positive regions were classified into three groups on the basis of the expression period of Fos protein. The first group was where a significant number of Fos-positive cells were seen 3 h and 24 h after cold exposure, but not observed 14 days after exposure; the regions included the lateral septal nucleus (LS), parvocellular paraventricular hypothalamic nucleus (pPVN), posterior hypothalamic area (PH), supramammillary nucleus (SuM), locus coeruleus (LC), dorsal tegmental nucleus (DTg), vestibular nucleus (Ves), and nucleus of solitary tract (Sol). The second group was where a significant number of Fos-positive cells were found 3 h, 24 h and 14 days after cold exposure; the regions included the preoptic hypothalamic area (POA), paraventricular thalamic nucleus (PV), lateral preoptic area (LPO), zona incerta (ZI), subparafascicular thalamic nucleus (SPF), lateral dorsal central grey (CGLD), lateral ventral central grey (CGLV), microcellular tegmental nucleus (MiTg), lateral lemniscus nucleus (LL), dorsal parabrachial nucleus (DPB), and the cerebellum. The third group was where Fos-positive cells were more numerous 14 days after cold exposure than they were after 3 h and 24 h of exposure; these regions included the ventromedial hypothalamic nucleus (VMH) and the spinal cord. These results demonstrate that the numbers and regions of Fos-positive cells in the rat brains changed during chronic cold exposure, and such changes may reveal the cellular adaptation of the thermogenic responsive neurons in the rat brain to cold acclimation.

Thyroidectomy induces fos-like immunoreactivity in the parvocellular paraventricular hypothalamic nucleus of the rat

Thyroidectomy induces fos-like immunoreactivity in the parvocellular paraventricular hypothalamic nucleus of the rat