The Role of Oxytocin and Vasopressin in Drug-Induced Reward-Implications for Social and Non-Social Factors.

Drug abuse is a worldwide problem that leads to negative physical, mental, and economic consequences. Although pharmacological strategies for drug addiction management have been widely studied, therapeutic options with high efficacy and a low side-effects profile are still limited. Recently, there has been a growing interest in oxytocin (OT) and vasopressin (AVP) systems as potential therapeutic targets for the treatment of drug abuse. OT and AVP are hypothalamic neuropeptides involved in numerous physiological processes. Additionally, studies show that these neurohormones are highly implicated in the modulation of a wide range of behaviors. Interestingly, ample evidence has shown that both, OT and AVP are able to decrease the consumption of different drugs of abuse, as well as to ameliorate their rewarding and reinforcing effects. Furthermore, OT and AVP have been strongly involved in prosocial effects and social reward. In particular, OT has been shown to be able to shift drug-induced reward into social-induced reward, mainly due to its interaction with the dopaminergic system. This phenomenon is also reflected in the results of clinical trials where intranasal OT shows promising efficacy in managing substance use disorder. Therefore, the aim of this review is to comprehensively characterize the involvement of OT and AVP in the rewarding and other behavioral effects of drugs of abuse in animal models, with a particular highlight on the impact of social factors on the observed effects. Understanding this relationship may contribute to higher drug development success rates, as a result of a more profound and deliberate studies design.

Psychoendocrinology: arginine vasopressin and resilience in patients with major depressive disorder.

BACKGROUND: There is a burgeoning body of evidence suggesting that arginine vasopressin (AVP) acts as a neuromodulator of the stress response. AVP stimulates the release of adrenocorticotropic hormone, synergistic to corticotropin-releasing hormone, which might explain AVP's role in resilience. Personal hardiness is the bedrock of resilience. Numerous studies have demonstrated elevated plasma levels of AVP in patients with major depressive disorder (MDD), suggesting an etiopathogenetic role as well as a novel therapeutic target. OBJECTIVE: The aim of this study was to examine the relationship between AVP and resilience in patients with MDD and to determine AVP levels in serum of patients with MDD. METHODS: Forty patients with MDD and 40 healthy control subjects were studied using the Dispositional Resilience (Hardiness) Scale by Barton, the Quality of Life Scale, the Social Readjustment Rating Scale, and the Beck Depression Inventory. Biochemical analysis of plasma levels of AVP, using the enzyme-linked immunosorbent assay (ELISA), was performed for all participants. RESULTS: Levels of AVP were statistically significantly elevated in patients with MDD compared with healthy controls. Psychological hardiness was decreased in patients with MDD compared with healthy controls, a finding also statistically significant. There was a negative correlation between plasma AVP level and psychological hardiness. CONCLUSION: AVP and psychological hardiness are negatively correlated, reflecting lower stress resilience. AVP levels are indeed higher in patients struggling with MDD.

Arginine vasopressin in the medial amygdala causes greater post-stress recruitment of hypothalamic vasopressin neurons.

Arginine vasopressin (AVP) is expressed in both hypothalamic and extra-hypothalamic neurons. The expression and role of AVP exhibit remarkable divergence between these two neuronal populations. Polysynaptic pathways enable these neuronal groups to regulate each other. AVP neurons in the paraventricular nucleus of the hypothalamus increase the production of adrenal stress hormones by stimulating the hypothalamic-pituitary-adrenal axis. Outside the hypothalamus, the medial amygdala also contains robust amounts of AVP. Contrary to the hypothalamic counterpart, the expression of extra-hypothalamic medial amygdala AVP is sexually dimorphic, in that it is preferentially transcribed in males in response to the continual presence of testosterone. Male gonadal hormones typically generate a negative feedback on the neuroendocrine stress axis. Here, we investigated whether testosterone-responsive medial amygdala AVP neurons provide negative feedback to hypothalamic AVP, thereby providing a feedback loop to suppress stress endocrine response during periods of high testosterone secretion. Contrary to our expectation, we found that AVP overexpression within the posterodorsal medial amygdala increased the recruitment of hypothalamic AVP neurons during stress, without affecting the total number of AVP neurons or the number of recently activated neurons following stress. These observations suggest that the effects of testosterone on extra-hypothalamic AVP facilitate stress responsiveness through permissive influence on the recruitment of hypothalamic AVP neurons.

Chemogenetic activation of endogenous arginine vasopressin exerts anorexigenic effects via central nesfatin-1/NucB2 pathway.

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300-370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.

Cardiovascular Neuroendocrinology: Emerging Role for Neurohypophyseal Hormones in Pathophysiology.

Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently receive more attention for their contributions to affiliative behavior, this mini-review discusses their roles in cardiovascular function broadly defined to include indirect effects that influence cardiovascular function. The traditional view is that neither AVP nor OXY contributes to basal cardiovascular function, although some recent studies suggest that this position might be re-evaluated. More evidence indicates that adaptations and neuroplasticity of AVP and OXY neurons contribute to cardiovascular pathophysiology.

Vasopressin regulates daily rhythms and circadian clock circuits in a manner influenced by sex.

Arginine vasopressin (AVP) is a neurohormone that alters cellular physiology through both endocrine and synaptic signaling. Circadian rhythms in AVP release and other biological processes are driven by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Loss of vasopressin signaling alters circadian behavior, but the basis of these effects remains unclear. Here we investigate the role of AVP signaling in circadian timekeeping by analyzing behavior and SCN function in a novel AVP-deficient mouse model. Consistent with previous work, loss of AVP signaling increases water consumption and accelerates recovery to simulated jetlag. We expand on these results to show that loss of AVP increases period, imprecision and plasticity of behavioral rhythms under constant darkness. Interestingly, the effect of AVP deficiency on circadian period was influenced by sex, with loss of AVP lengthening period in females but not males. Examining SCN function directly with ex vivo bioluminescence imaging of clock protein expression, we demonstrate that loss of AVP signaling modulates the period, precision, and phase relationships of SCN neurons in both sexes. This pattern of results suggests that there are likely sex differences in downstream targets of the SCN. Collectively, this work indicates that AVP signaling modulates circadian circuits in a manner influenced by sex, which provides new insight into sexual dimorphisms in the regulation of daily rhythms.

Acciones óseas de las hormonas de la neurohipófisis / Bone actions of neuro hypophyseal hormones

La oxitocina (OXT) como la arginina-vasopresina (AVP) son dos hormonas primitivas secretadas por la hipófisis posterior. Sus receptores están mucho más ampliamente distribuidos en el organismo de lo que se pensaba originalmente, incluido el hueso. En los estudios preclínicos, la OXT ha mostrado ser anabólica para el hueso, promoviendo la osteogénesis sobre la adipogénesis y favoreciendo la actividad osteoblástica sobre la osteoclástica. Tanto los osteoblastos como los osteoclastos tienen receptores para la OXT, y los efectos de los estrógenos sobre la masa ósea en ratones está mediada por lo menos en parte por la OXT. El mecanismo preciso por el cual la activación de los receptores de oxitocina (OXTR) se traduce en un incremento de la formación ósea permanece poco claro. La AVP también podría afectar el esqueleto en forma directa. Dos de los receptores de la AVP, V1a y V2 están expresados en osteoblastos y osteoclastos. La inyección de AVP en ratones de tipo salvaje aumenta la formación osteoclastos que producen resorción y reduce los osteoblastos formadores de hueso. En forma opuesta, la exposición de precursores osteoblásticos a antagonistas de los receptores V1a o V2, incrementan la osteoblastogénesis, como también lo hace la deleción genética del receptor V1a. (AU)

Both oxytocin (OXT) and argininevasopressin (AVP) are primitive hormones secreted by the posterior pituitary gland. OXT receptors are much more widely distributed in the body than originally thought, including in bone. In preclinical studies, OXT has been shown to be anabolic for bone, promoting osteogenesis over adipogenesis and favoring osteoblastic over osteoclastic activity. Both osteoblasts and osteoclasts have receptors for OXT, and the effects of estrogen on bone mass in mice is mediated at least in part by OXT. The precise mechanism by which the activation of oxytocin receptors (OXTRs) results in an increase in bone formation remains unclear. AVP could also have direct actions on the skeleton. The two AVP receptors, V1a and V2, are expressed in osteoblasts and osteoclasts. Injection of AVP in wild-type mice increases the formation of osteoclasts increasing bone resorption, and reduces bone-forming osteoblasts. On the contrary, the exposure of osteoblastic precursors to V1a and V2 antagonists increase osteoblastogenesis, the same as the genetic deletion of the V1a receptor. (AU)

Compromised regulation of the rat brain parenchymal arterioles in vasopressin-associated acute hyponatremia.

OBJECTIVE: In this study, we examined the effect of acute hyponatremia associated with vasopressin (AVP) on the responses of the isolated rat's MCAs and PAs to acidosis, nitric oxide donor (SNAP) and to endothelium-dependent vasodilator ATP. METHODS: The studies were performed on isolated, perfused and pressurized MCAs and PAs in control conditions and during AVP-associated hyponatremia. Hyponatremia was induced in vitro by lowering Na+ concentration from 144 to 121 mmol/L in intra- and extravascular fluid in the presence of AVP. RESULTS: Parenchymal arterioles showed greater response to an increase in H+ and K+ ions concentration and to ATP in comparison with MCAs in control normonatremic conditions. Both PAs and MCAs constricted in response to acute hyponatremia associated with AVP. Interestingly, disordered regulation of vascular tone was observed in PAs but not in MCAs. The abnormalities in the regulation comprised a significant reduction of PA response to acidosis and the absence of the response to the administration of SNAP or ATP. CONCLUSIONS: Arginine vasopressin-associated hyponatremia leads to constriction and dysregulation of PAs which may impair neurovascular coupling.

Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.

Involvement of ventral pallidal vasopressin in the sex-specific regulation of sociosexual motivation in rats.

The ventral pallidum (VP) is a critical node of the mesocorticolimbic reward circuit and is known to modulate social behaviors in rodents. Arginine vasopressin (AVP) signaling via the V1A receptor (V1AR) within the VP is necessary for the expression of socially motivated affiliative behaviors in monogamous voles. However, whether the VP-AVP system regulates socially motivated behaviors in non-monogamous species remains unknown. Here, we determined the extent of AVP fiber innervation in the VP as well as the involvement of the VP-AVP system in sociosexual motivation in adult male and female rats. We found that males have nearly twice the density of AVP-immunoreactive (AVP-ir) fibers in the VP compared to females, suggesting the possibility that males experience enhanced AVP signaling in the VP. We further found that this sex difference in VP-AVP-ir fiber density likely arises from an observed sex difference (males > females) in the percentage of VP-projecting AVP-ir cell bodies located in the bed nucleus of the stria terminalis and medial amygdala. To determine the behavioral implications of this sex difference, we next blocked AVP signaling in the VP by antagonizing VP-V1ARs in male and female rats and tested their preference to investigate an unfamiliar male rat or unfamiliar estrus female rat confined to corrals located on opposite ends of a three-chamber apparatus. Under vehicle conditions, males showed a significantly greater innate preference to investigate an opposite sex over same sex conspecific than estrus females. Interestingly, VP-V1AR antagonism significantly reduced males' opposite sex preference, while enhancing estrus females' opposite sex preference. Importantly, all subjects reliably discriminated between male and female stimulus rats regardless of drug treatment, demonstrating a change in motivational state rather than a perceptual impairment induced by VP-V1AR blockade. These results provide a novel functional link between a sex difference in ventral pallidal AVP fiber density and the sex-specific regulation of a sexually motivated behavior necessary for reproductive success.

Circadian Function in Multiple Cell Types Is Necessary for Proper Timing of the Preovulatory LH Surge.

The timing of the preovulatory surge of luteinizing hormone (LH), which occurs on the evening of proestrus in female mice, is determined by the circadian system. The identity of cells that control the phase of the LH surge is unclear: evidence supports a role of arginine vasopressin (AVP) cells of the suprachiasmatic nucleus (SCN), but it is not known whether vasopressinergic neurons are necessary or sufficient to account for circadian control of ovulation. Among other cell types, evidence also suggests important roles of circadian function of kisspeptin cells of the anteroventral periventricular nucleus (AvPV) and gonadotropin-releasing hormone (GnRH) neurons of the preoptic area (POA), whose discharge is immediately responsible for the discharge of LH from the anterior pituitary. The present studies used an ovariectomized, estradiol-treated preparation to determine critical cell types whose clock function is critical to the timing of LH secretion. As expected, the LH surge occurred at or shortly after ZT12 in control mice. In further confirmation of circadian control, the surge was advanced by 2 h in tau mutant animals. The timing of the surge was altered to varying degrees by conditional deletion of Bmal1 in AVPCre, KissCreBAC, and GnRHCreBAC mice. Excision of the mutant Cnsk1e (tau) allele in AVP neurons resulted in a reversion of the surge to the ZT12. Conditional deletion of Bmal1 in Kiss1 or GnRH neurons had no noticeable effect on locomotor rhythms, but targeting of AVP neurons produced variable effects on circadian period that did not always correspond to changes in the phase of LH secretion. The results indicate that circadian function in multiple cell types is necessary for proper timing of the LH surge.

Antidiuretic Hormone and Serum Osmolarity Physiology and Related Outcomes: What Is Old, What Is New, and What Is Unknown?

CONTEXT: Although the physiology of sodium, water, and arginine vasopressin (AVP), also known as antidiuretic hormone, has long been known, accumulating data suggest that this system operates as a more complex network than previously thought. EVIDENCE ACQUISITION: English-language basic science and clinical studies of AVP and osmolarity on the development of kidney and cardiovascular disease and overall outcomes. EVIDENCE SYNTHESIS: Apart from osmoreceptors and hypovolemia, AVP secretion is modified by novel factors such as tongue acid-sensing taste receptor cells and brain median preoptic nucleus neurons. Moreover, pharyngeal, esophageal, and/or gastric sensors and gut microbiota modulate AVP secretion. Evidence is accumulating that increased osmolarity, AVP, copeptin, and dehydration are all associated with worse outcomes in chronic disease states such as chronic kidney disease (CKD), diabetes, and heart failure. On the basis of these pathophysiological relationships, an AVP receptor 2 blocker is now licensed for CKD related to polycystic kidney disease. CONCLUSION: From a therapeutic perspective, fluid intake may be associated with increased AVP secretion if it is driven by loss of urine concentration capacity or with suppressed AVP if it is driven by voluntary fluid intake. In the current review, we summarize the literature on the relationship between elevated osmolarity, AVP, copeptin, and dehydration with renal and cardiovascular outcomes and underlying classical and novel pathophysiologic pathways. We also review recent unexpected and contrasting findings regarding AVP physiology in an attempt to explain and understand some of these relationships.

Neurohormonal, Endocrine, and Immune Dysregulation and Inflammation in Cardiorenal Syndrome.

"Organ crosstalk" is the complex physiological communication between different body systems, and it is necessary for the optimal equilibrium and functioning of the organism. In particular, heart and kidney function is tightly connected, and interplay between these two organs occurs through a vast array of dynamic and bidirectional mechanisms. The term cardiorenal syndrome (CRS) indicates an interaction between the heart and kidneys in acute and chronic disease settings. In all types of CRS, multiple pathophysiological processes are implicated in the initiation and progression of organ injury. In addition to hemodynamic parameters, endothelial injury, immunological imbalance, cell death, inflammatory cascades, oxidative stress, neutrophil migration, leukocyte trafficking, caspase-mediated apoptosis, extracellular vesicles, small noncoding RNAs, and epigenetics play pivotal roles in the development of CRS. In this review, we will focus on neurohormonal, endocrine, and immune dysregulation and inflammation as mechanisms involved in the pathogenesis of CRS.

It takes two! Exploring sex differences in parenting neurobiology and behaviour.

Parents lay the foundation for their children's socio-emotional experiences by sensitively responding to their needs. The hormonal and neurobiological changes that occur during the transition to parenthood importantly contribute to the parents' caregiving behaviour toward their children. Much research has emphasised the relationship between the mother, who is most often the primary caregiver, and her infant, with less focus on the role of fathers in child development. However, recent accounts have suggested that fathers also play an important role in promoting the health, development and psychosocial wellbeing of their children. Evidence from the behavioural literature has indicated that there are significant differences between typical mother-infant versus father-infant interactions. The current review aims to outline differences between maternal and paternal caregiving by discussing the differences in their biological mechanisms. First, we focus on the different hormones that are correlated with sensitive parenting behaviours in mothers and fathers. Next, we discuss the differences between neural bases of motherhood and fatherhood. Lastly, we discuss ways in which parental hormones, parental brain and parental exposure to infant cues interact to shape parental caregiving behaviour. In summary, this review highlights the distinct but complementary nature of maternal and paternal caregiving.

Oxytocin and vasopressin inhibit hyper-aggressive behaviour in socially isolated mice.

Despite the high prevalence of aggression across a wide range of disorders, there is a severe lack of pharmacological treatments. Recent rodent studies have shown both centrally and peripherally administered oxytocin is effective in reducing territorial aggression, an adaptive form of aggression not reflective of pathological hyper-aggression. The current study tested i.p. administered oxytocin and vasopressin in a model of non-territorial hyper-aggression and examined the involvement of oxytocin receptors (OXTR) and vasopressin V1a receptors (V1aR). Male Swiss mice (N = 160) were either socially isolated or group housed for 6 weeks prior to the commencement of testing; wherein two unfamiliar weight and condition matched mice were placed into a neutral context for 10 min. Socially isolated mice exhibited heightened aggression that was powerfully and dose-dependently inhibited by oxytocin and vasopressin and that was accompanied by dose-dependent increases in close social contact (huddling) and grooming. These anti-aggressive effects of oxytocin were blocked by pre-treatment with a higher dose of selective V1aR antagonist SR49059 (20 mg/kg i.p.), but not a lower dose of SR49059 (5 mg/kg i.p.) or selective OXTR antagonist L-368,899 (10 mg/kg i.p.). This is consistent with a growing number of studies linking a range of effects of exogenous oxytocin to actions at the V1a receptor. Interestingly, the highest dose of the OXTR agonist TGOT (10 mg/kg) also reduced isolation-induced aggression. These results suggest that while activation of the V1a receptor appears critical for the anti-aggressive effects of oxytocin, activation of the oxytocin receptor cannot be excluded. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity.'

Post-weaning social isolation exacerbates aggression in both sexes and affects the vasopressin and oxytocin system in a sex-specific manner.

Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors.

Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co-existing rhythms ("splitting"). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co-culturing slices with rhythmic neonatal wild-type SCNs. These co-culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co-culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.

Vasopressin and the Regulation of Thirst.

Recent experiments using optogenetic tools allow the identification and functional analysis of thirst neurons and vasopressin producing neurons. Two major advances provide a detailed anatomy of taste for water and arginine-vasopressin (AVP) release: (1) thirst and AVP release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. These anticipatory signals for thirst and vasopressin release converge on the same homeostatic neurons of circumventricular organs that monitor the composition of the blood; (2) acid-sensing taste receptor cells (which express polycystic kidney disease 2-like 1 protein) on the tongue that were previously suggested as the sour taste sensors also mediate taste responses to water. The tongue has a taste for water. The median preoptic nucleus (MnPO) of the hypothalamus could integrate multiple thirst-generating stimuli including cardiopulmonary signals, osmolality, angiotensin II, oropharyngeal and gastric signals, the latter possibly representing anticipatory signals. Dehydration is aversive and MnPO neuron activity is proportional to the intensity of this aversive state.

Asymmetric vasopressin signaling spatially organizes the master circadian clock.

The suprachiasmatic nucleus (SCN) is the neural network that drives daily rhythms in behavior and physiology. The SCN encodes environmental changes through the phasing of cellular rhythms across its anteroposterior axis, but it remains unknown what signaling mechanisms regulate clock function along this axis. Here we demonstrate that arginine vasopressin (AVP) signaling organizes the SCN into distinct anteroposterior domains. Spatial mapping of SCN gene expression using in situ hybridization delineated anterior and posterior domains for AVP signaling components, including complementary patterns of V1a and V1b expression that suggest different roles for these two AVP receptors. Similarly, anteroposterior patterning of transcripts involved in Vasoactive Intestinal Polypeptide- and Prokineticin2 signaling was evident across the SCN. Using bioluminescence imaging, we then revealed that inhibiting V1A and V1B signaling alters period and phase differentially along the anteroposterior SCN. V1 antagonism lengthened period the most in the anterior SCN, whereas changes in phase were largest in the posterior SCN. Further, separately antagonizing V1A and V1B signaling modulated SCN function in a manner that mapped onto anteroposterior expression patterns. Lastly, V1 antagonism influenced SCN period and phase along the dorsoventral axis, complementing effects on the anteroposterior axis. Together, these results indicate that AVP signaling modulates SCN period and phase in a spatially specific manner, which is expected to influence how the master clock interacts with downstream tissues and responds to environmental changes. More generally, we reveal anteroposterior asymmetry in neuropeptide signaling as a recurrent organizational motif that likely influences neural computations in the SCN clock network.

Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease.

Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM) that can lead to ductopenia, cirrhosis, and even malignant transformation. In this review, we examine cholestatic liver diseases characterized by extensive biliary fibrosis such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), polycystic liver disease (PLD), and MDR2-/- and BDL mouse models. Following biliary injury, cholangiocytes, the epithelial cells that line the bile ducts, become reactive and adopt a neuroendocrine phenotype in which they secrete and respond to neurohormones and neuropeptides in an autocrine and paracrine fashion. Emerging evidence indicates that cholangiocytes influence and respond to changes in the ECM and stromal cells in the microenvironment. For example, activated myofibroblasts and hepatic stellate cells are major drivers of collagen deposition and biliary fibrosis. Additionally, the liver is richly innervated with adrenergic, cholinergic, and peptidergic fibers that release neurohormones and peptides to maintain homeostasis and can be deranged in disease states. This review summarizes how cholangiocytes interact with their surrounding environment, with particular focus on how autonomic and sensory regulation affects fibrotic pathophysiology.