Analyses of a mouse model for familial neurohypophysial diabetes insipidus (FNDI), a disease characterized by progressive polyuria due to progressive decreases in arginine vasopressin (AVP) release, revealed that mutant proteins are accumulated in a sub-compartment of the endoplasmic reticulum (ER) of AVP neurons. By forming such a structure called ER-associated compartment (ERAC), AVP neurons are likely to reduce ER stress. However, the formation of ERAC is hampered in FNDI mice which are relatively old or subjected to chronic dehydration. Failure of ERAC formation induces autophagy in AVP neurons, which are finally lost through autophagy-associated cell death. It is also worthwhile that enlargement of a sub-compartment of ER, a structure similar to ERAC, was observed in the AVP neurons in wild-type mice subjected to dehydration. Activating transcription factor 6α (ATF6α), one of three ER stress sensors, contributes to the formation of ERAC, as the ER was dilated diffusely in AVP neurons of dehydrated ATF6α knockout mice. Thus, our data suggest that misfolded proteins are sensed via ER stress sensors including ATF6α, and confined to the ERAC in AVP neurons. This mechanism seems to apply to the AVP neurons of not only FNDI but also wild-type mice.
Expression of social behaviors is regulated by various neuroendocrine and neurochemical factors. Among them, estradiol is known to have a profound influence on female sexual behavior as well as various types of social interactive behaviors, through its binding to two types of estrogen receptors, ERα or ERβ. Since male gonadal hormone, testosterone, is aromatized to estradiol in neuronal cells in the brain, ERs are also essential for the regulation of male-type social behavior and the development of their neural network. In this article, we discuss how each type of ER plays a role in the expression of sex-typical social behavior in males and females by focusing on both organizational and activational action of estradiol. For this purpose we overview behavioral and neuroanatomical studies reported in knockout as well as brain site-specific knockdown models of ER genes. We also discuss how early life experiences may affect subsequent expression of social and socio-emotional behavior.
Oxytocin plays an essential role in milk ejection and parturition in mammals. Oxytocin has also been shown to be involved in the control of various behaviors, including anxiety-related behaviors, food intake and affiliative behaviors. We previously showed that noxious stimuli or stimuli previously paired with noxious stimuli (conditioned fear stimuli) activate hypothalamic oxytocin neurons via activation of brainstem catecholaminergic/prolactin-releasing peptide (PrRP)-positive neurons. Oxytocin neurons are activated not only by noxious stimuli but also by non-noxious touch stimuli. Social contact has been suggested to activate oxytocin neurons. Non-noxious tactile stimuli induce 50-kHz ultrasonic vocalization, an index of positive states in rats, and activate hypothalamic oxytocin neurons, suggesting that pleasant tactile stimuli activate oxytocin neurons. Physiological roles of oxytocin released during noxious or non-noxious tactile stimuli remain to be clarified. Noxious stimuli increase anxiety-related behavior, while pleasant sensory stimuli have pro-social actions. We have shown that endogenous oxytocin reduces anxiety-related behaviors, induces a decrease in amounts of food intake per meal, and facilitates social recognition via distinct neural pathways. Roles of oxytocin released during sensory stimuli may be dependent upon the sensory stimuli used, and oxytocin may contribute to the prevention of overreactions to noxious stimuli or mediate pro-social or anxiolytic actions of pleasant tactile stimuli.
Arginine vasopressin (AVP) and oxytocin (OXT) are synthesized in the magnocellular neurosecretory cells (MNCs) of the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) that terminate their axons in the posterior pituitary (PP). Recently, we generated transgenic rats that express AVP-enhanced green fluorescent protein (eGFP) fusion gene and OXT-monomeric red fluorescent protein 1 (mRFP1) fusion gene in order to visualize AVP or OXT in the hypothalamo-neurohypophysial system (HNS). Colchicine is known to block axonal transport, resulting in peptide accumulation in the cell body. We investigated the effects of intracerebroventricular (icv) administration of colchicine on the expression of AVP-eGFP fusion or OXT-mRFP1 fusion gene products. Icv administration of colchicine caused a marked increase of AVP-eGFP and OXT-mRFP1 fluorescence in the hypothalamic MNCs, and a decrease in the PP in comparison with control rats. The expected changes of AVP-eGFP and OXT-mRFP1 fluorescence in the HNS after icv administration of colchicine indicate that AVP-eGFP and OXT-mRFP1 fusion protein may be transported by axonal flow and secreted from the PP into the systemic circulation. These transgenic rats are new tools to study the physiological role of AVP and OXT in the HNS.
Vasopressin and oxytocin are well-known neurohypophysial and posterior pituitary hormones that are synthesized in the paraventricular and supraoptic nuclei of the hypothalamus and are secreted from the posterior pituitary into the systemic circulation. It is known that vasopressin plays an important role in maintaining body fluid homeostasis, and that oxytocin plays an essential role in mammalian labor and lactation through its peripheral action. In addition to these classic physiological actions, vasopressin and oxytocin have been attracting considerable attention in recent years because of their effects in their involvement in social recognition, and in the regulation of the cardiovascular system, the central nervous system and stress responses. Their analgesic effects have also been mentioned among these newly-recognized physiological actions. This review focuses on pain modulation by vasopressin and oxytocin.
Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal axis. In order to unravel unsolved issues underlying the regulatory mechanisms for CRF neurons, modified yellow fluorescent protein (Venus) gene was inserted into the CRF gene in frame, and CRF neurons were visualized by the Venus fluorescence. Venus expression is overlapped with CRF expression in most brain regions, including the paraventricular nucleus of the hypothalamus (PVH). This mouse is a useful tool especially for conducting electrophysiological recordings from CRF neurons. In the first half of the present review, the backgrounds of the generation of the mouse are described based on the previous literature: first, the anatomical distribution of CRF-immunoreactive neurons in the rat brain is overviewed, and then the knowledge on the electrophysiological properties of the parvocellular neuroendocrine neurons that constitute a subpopulation of neurons in the PVH (including PVH-CRF neurons) is described. These sections may help the readers in understanding the purpose of generating the CRF-Venus mouse. In the second half of the manuscript, the distribution of Venus-expressing neurons is characterized in the CRF-Venus mouse, and preliminary results of electrophysiological recordings from the Venus-expressing neurons are shown. CRF driver mouse lines are also referred to as a means for the CRF neuron-selective gene transfer or targeting. Novel mouse lines may serve as tools for disclosing the regulatory mechanisms for CRF neurons in the PVH, as well as other brain regions.
Vasopressin is a peptide hormone secreted from the posterior pituitary gland in response to various physiological and/or pathological stimuli, including changes in body fluid volume and osmolality and stress exposure. Vasopressin secretion is controlled by the electrical activity of the vasopressinergic magnocellular neurosecretory cells located in the hypothalamic supraoptic nucleus and paraventricular nucleus. Vasopressin release can occur somatodendritically in the hypothalamus or at the level of pituitary axon terminals. The electrical activity of the vasopressin neurons assumes specific patterns of electrical discharge that are under the control of several factors, including the intrinsic properties of the neuronal membrane and synaptic and hormonal inputs. It is increasingly clear that glial cells perform critical signaling functions that contribute to signal transmission in neural circuits. Astrocytes contribute to neuronal signaling by regulating synaptic and extrasynaptic neurotransmission, as well as by mediating bidirectional neuronal-glial transmission. We recently discovered a novel form of neuronal-glial signaling that exploits the full spatial domain of astrocytes to transmit dendritic retrograde signals from vasopressin neurons to distal upstream neuronal targets. This retrograde trans-neuronal-glial transmission allows the vasopressin neurons to regulate their synaptic inputs by controlling upstream presynaptic neuron firing, thus providing a powerful means of autocontrol of hormonal output.
Neural circuits underlying male sexual function comprise several nuclei located in the brain and spinal cord. We have previously demonstrated in rats that the gastrin-releasing peptide (GRP) system influences spinal centers promoting penile reflexes. Moreover, a group of oxytocin (OXT) neurons, situated in the parvocellular part of the paraventricular nucleus of the hypothalamus, project into the spinal cord and control penile reflexes. Therefore, it has been hypothesized that OXT is transported by long descending paraventriculospinal pathways and activates proerectile spinal centers. Consequently, we have shown that in rats, axonal distribution of OXT in the lumbar spinal cord exhibits a male-dominant sexual dimorphism. Furthermore, OXT binding is observed in the spinal GRP neurons. Thus, OXT axons may secrete OXT from spinal axonal terminals and regulate male sexual function via an OXT receptor-mediated mechanism in spinal GRP neurons. Future studies should address the relationship between the hypothalamic OXT and spinal GRP systems. Identification of the male-specific brain-spinal cord neural circuit that regulates male sexual behavior may provide new avenues for therapeutic approaches to masculine reproductive dysfunction, including erectile dysfunction and/or ejaculation disorder.
While the hypothalamus is now classified into more than ten compartments, uncharacterized areas remain. In this study, we show a new area in the anterior hypothalamus (AH) of mice, a triangular-shaped area between the paraventricular hypothalamic nucleus (PVN) and the fornix, which is enriched in chondroitin sulfate proteoglycans (CSPGs). We designated this region perifornical area of the AH (PeFAH) based on its anatomical location. In Nissl staining, the PeFAH was distinguishable as an area of relatively low density. Immunohistochemical and DNA microarray analyses indicated that PeFAH contains sparsely distributed calretinin-positive neurons and densely clustered enkephalin-positive neurons. Furthermore, the PeFAH was shown to have bidirectional neural connections with the lateral septum (LS). We confirmed enkephalinergic projections from PeFAH neurons to the LS, and inversely, calbindin-positive LS neurons as afferents to the PeFAH. Finally, c-Fos expression analysis revealed that the activity of PeFAH neurons tended to be increased by psychological stressors but not by homeostatic stressors. These findings of neuronal subtypes and projections suggest that the region of the densely clustered encephalin-positive neurons in the PeFAH is comparable with the perifornical nucleus previously identified in rats.
The hypothalamus-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response, activation of which leads to the production of glucocorticoid hormones. Glucocorticoids are steroid hormones that are secreted from the adrenal cortex, and have a variety of effects on the body, including modulation of the immune system, suppression of reproductive hormones, maintenance of blood glucose levels, and maintenance of blood pressure. Glutamate plays an important role in coordination of HPA axis output. There is strong evidence that glutamate drives HPA axis stress responses through excitatory signaling via ionotropic glutamate receptor signaling. However, glutamate signaling via kainate receptors and group I metabotropic receptors inhibit HPA drive, probably via presynaptic inhibitory mechanisms. Notably, kainate receptors are also localized in the median eminence, and appear to play an excitatory role in control of CRH release at the nerve terminals. Finally, glutamate innervation of the PVN undergoes neuroplastic changes under conditions of chronic stress, and may be involved in sensitization of HPA axis responses. Altogether, the data suggest that glutamate plays a complex role in excitation of CRH neurons, acting at multiple levels to both drive HPA axis responses and limit over-activation.
Recently, various hypothalamic neurons have been successfully engineered from pluripotent stem cells, including mouse and human embryonic stem cells. Because pluripotent cells need to undergo stepwise changes during organogenesis, developmental analyses on the hypothalamus have been inevitable for numerous transcription factors that determine specification, survival, and migration during the formation of specific neurons. Hypothalamic progenitor cells arise from the retina and anterior neural fold homeobox (Rax)+ ventral part of the ventricular zone at embryonic day 10.5 (E10.5), and orthopedia (Otp) and steroidgenic factor-1 (SF-1) respectively appear in the dorsal and ventral regions at E13.5, which subsequently produce specific transcription factors required for the final maturation of hypothalamic neurons. In the pluripotent stem cells, rostrodorsal hypothalamus-like progenitors expressing retina and anterior neural fold homeobox are generated from floating aggregates in serum-free conditions with minimized exogenous patterning signaling. A certain population of the Rax+ progenitors generate Otp+ neuronal precursors, which subsequently develop into various dorsal and lateral hypothalamic neurons, including arginine vasopressin (AVP) and oxytocin neurons. Alternatively, early exposure to sonic hedgehog (Shh) induces differentiation markers including SF-1, specific for rostral–ventral hypothalamic-like precursors that eventually produce neuropeptide Y (NPY) and pro-opio-melanocortin (POMC). In conclusion, it is now possible to induce most types of hypothalamic neurons from pluripotent stem cells. Application of these cells would have advantages for studies on specification, migration, drug development, and regenerative medicine.
Arginine vasopressin (AVP) is expressed in discrete regions of a mammalian brain, and is involved in various physiological functions including the maintenance of body fluid osmolality, regulation of the hypothalamic-pituitary-adrenal axis, and formation of the circadian rhythm. Three types of AVP-expressing neurons, among others, have been studied most extensively; these are magnocellular neuroendocrine neurons in the hypothalamic paraventricular and supraoptic nuclei, parvocellular neuroendocrine neurons in the hypothalamic paraventricular nucleus, and neurons in the suprachiasmatic nucleus. Molecular mechanisms, underlying the regulation of AVP gene expression, are different depending on the neuronal type, and different transcription factors play key roles in mediating activation of AVP gene transcription: for example, circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) may be indispensable in AVP gene expression in the suprachiasmatic nucleus. The activator protein 1 (AP1; Fos/Jun) and cyclic adenosine monophosphate response element-binding protein (CREB)-related transcription factors are regarded as major transcription factors in the parvocellular and magnocellular hypothalamic neurons, respectively. According to recent studies, CREB3-like protein 1 (CREB3L1), a transcription factor of the CREB/activating transcription factor family, may mediate the osmolality-dependent AVP gene transcription in the magnocellular neurons.
Adequate regulation of corticotropin releasing hormone (CRH) secretion and expression is essential for endocrine, autonomic and behavioral stress adaptation. Maintenance of messenger RNA levels for peptide synthesis requires rapid but limited activation of CRH gene transcription. Activation of CRH transcription depends on cyclic AMP/protein kinase A signaling and binding of phospho-CREB to a critical cyclic AMP response element (CRE) at -270 in the CRH promoter. DNA methylation of the CRE CpG reduces CREB binding to the promoter affecting CRH expression. CREB-dependent activation of CRH transcription requires recruitment of the CREB co-activator, Transducer Of Regulated CREB activity (TORC). Cyclic AMP activates TORC by inhibiting salt induced kinase (SIK) type 2 allowing TORC dephosphorylation and nuclear translocation. Termination of the transcriptional response is essential for preventing pathology associated with chronic elevations of CRH and HPA axis activity. Glucocorticoid feedback inhibition, mainly through modulation of afferent pathways to hypothalamic CRH neurons, plays an important role. In addition, intracellular feedback mechanisms involving, Inducible Cyclic AMP Early Repressor (ICER), and cAMP-induced SIK1 activation and consecutive TORC inactivation, contribute to limiting CRH transcription. Understanding the molecular mechanisms of regulation of CRH expression is essential for understanding the pathogenesis and developing new therapeutic approaches for stress related disorders.
We previously generated oxytocin (OXT)-deficient mice and oxytocin receptor (OXTR)-deficient mice. Impaired social behaviors were observed in these mice, so they may be useful as animal models for studying the regulatory mechanism of social behavior by the OXT/OXTR system in the brain. In the present review, we aimed to overview our previous works to unravel the mechanism(s) by which OXTR deficiency leads to the impairment of social behaviors; for example, abnormalities in maternal behavior and/or social memory observed in mice deficient in the OXTR will be presented. By analyzing the brain of the OXTR-modified yellow fluorescent protein knock-in mice histologically, OXTR-expressing neurons were observed conspicuously in brain regions that are related to social behaviors. We focus on the characteristics of the regions containing neurons with prominent Oxtr gene expression in the present manuscript and discuss on the mechanisms through which OXT exerts its effects on social behaviors.
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