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Aims: To discuss the role of autocrine/paracrine signaling of urothelial arginine vasopressin (AVP) on mammalian bladder capacities and micturition thresholds, impact of distension on water/urea reabsorption from the bladder, review of the literature to better characterize the central/peripheral effects of AVP, desmopressin (dAVP) toxicity, and urine biomarkers of nocturia. Methods: This review summarizes discussions during an International Consultation on Incontinence‐Research Society 2024 think tank with respect to the role of urothelial AVP in aged individuals with nocturnal polyuria, impact of solute and water reabsorption by the bladder on uninterrupted sleep, central effects of AVP, pharmacological basis of dAVP toxicity, and biomarkers in nocturia/lower urinary tract dysfunction (LUTD) with neurological diseases. Results: Consensus recognized AVP function and pathways in the central nervous system (CNS), pre‐proAVP localized using immunohistochemistry in bladder sections from adult/aged noncancerous human punch biopsies and rodent bladder sections is likely to accelerate the systemic uptake of water and urea from the bladder of anesthetized mice instilled with 3H‐water and 14C‐urea. Mechanisms for charged and uncharged solutes and water transport across the bladder, mechanism of dAVP toxicity, and utility of urine biomarkers in those with neurological diseases/nocturia were determined from literature reviews. Conclusion: Pre‐proAVP is present in human/rodent bladders and may be involved in water reabsorption from bladder that prevents the sensation of fullness for uninterrupted sleep in healthy adults. The mechanism of action of AVP in the CNS was discussed, as was electrolyte/water transport across the bladder, the basis for dAVP toxicity, and feasibility of urine biomarkers to identify nocturia/LUTD with neurological diseases. [ABSTRACT FROM AUTHOR]

Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to the suprachiasmatic nucleus is the retinohypothalamic tract, with additional inputs from the intergeniculate leaflet pathway, the serotonergic afferent from the raphe, and other hypothalamic regions. Within the suprachiasmatic nucleus, two of the major subtypes are vasoactive intestinal polypeptide (VIP)-positive neurons and arginine-vasopressin (AVP)-positive neurons. VIP neurons are important for light entrainment and synchronization of suprachiasmatic nucleus neurons, whereas AVP neurons are important for circadian period determination. Output targets of the suprachiasmatic nucleus include the hypothalamus (subparaventricular zone, paraventricular hypothalamic nucleus, preoptic area, and medial hypothalamus), the thalamus (paraventricular thalamic nuclei), and lateral septum. The suprachiasmatic nucleus also sends information through several brain regions to the pineal gland. The olfactory bulb is thought to be able to generate a circadian rhythm without the suprachiasmatic nucleus. Some reports indicate that circadian rhythms of the olfactory bulb and olfactory cortex exist in the absence of the suprachiasmatic nucleus, but another report claims the influence of the suprachiasmatic nucleus. The regulation of circadian rhythms by sensory inputs other than light stimuli, including olfaction, has not been well studied and further progress is expected. [ABSTRACT FROM AUTHOR]

Background: As an integral ingredient of human sociality, prosocial behavior requires learning what acts can benefit or harm others. However, it remains unknown how individuals adjust prosocial learning to avoid punishment or to pursue reward. Given that arginine vasopressin (AVP) is a neuropeptide that has been involved in modulating various social behaviors in mammals, it could be a crucial neurochemical facilitator that supports prosocial learning. Methods: In 50 placebo controls and 54 participants with AVP administration, we examined the modulation of AVP on the prosocial learning characterized by reward and punishment framework, as well as its underlying neurocomputational mechanisms combining computational modeling, event-related potentials and oscillations. Results: We found a self-bias that individuals learn to avoid punishment asymmetrically more severely than reward-seeking. Importantly, AVP increased behavioral performances and learning rates when making decisions to avoid losses for others and to obtain gains for self. These behavioral effects were underpinned by larger responses of stimulus-preceding negativity (SPN) to anticipation, as well as higher punishment-related feedback-related negativity (FRN) for prosocial learning and reward-related P300 for proself benefits, while FRN and P300 neural processes were integrated into theta (4–7 Hz) oscillation at the outcome evaluation stage. Conclusions: These results suggest that AVP context-dependently up-regulates altruism for concerning others' losses and reward-seeking for self-oriented benefits. Our findings provide insight into the selectively modulatory roles of AVP in prosocial behaviors depending on learning contexts between proself reward-seeking and prosocial punishment-avoidance. [ABSTRACT FROM AUTHOR]

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations. [ABSTRACT FROM AUTHOR]

Hyponatremia is frequently found in patients with congestive heart failure. A reduction in effective circulatory blood volume in a volume-expanded patient with decreased cardiac output is linked to a baroreceptor-mediated non-osmotic release of arginine vasopressin (AVP). The increased production of AVP and salt and water retention in the proximal and distal tubules of the kidney by humoral, hemodynamic, and neural mechanisms increase circulatory blood volume and contribute to hyponatremia. Recent studies have indicated that hyponatremia predicts the short-term and long-term prognosis of heart failure by increasing cardiac death and rehospitalization. In addition, the early development of hyponatremia in acute myocardial infarction also predicts the long-term prognosis of worsening heart failure. AVP V2 receptor antagonism may relieve water retention, but it is unknown whether the V2 receptor inhibitor, tolvaptan, improves the long-term prognosis of congestive heart failure. The newly identified natriuretic factor in renal salt wasting has the potential of improving clinical outcomes when combined with a distal diuretic. [ABSTRACT FROM AUTHOR]

During development, many aspects of behaviour, including partner preferences and sexual behaviour, are "organized" by neural aromatization of androgen and oestrogen. This study aimed to analyse these processes in the mandarin vole (Microtus mandarinus); this is a novel mammalian model exhibiting strong monogamous pair bonds. Male pups were treated daily with a sesame oil only (MC) or the oestrogen receptor blocker‐clomiphene citrate sesame oil mixture (MT) from prenatal day 14 to postnatal day 10. Female pups were treated daily with sesame oil only (FC). Partner preferences, sexual behaviour, and the expression of androgen receptor (AR) and arginine vasopressin (AVP) were examined when animals were 3 months old. The MT and FC groups exhibited male‐directed partner preferences and feminized behaviour. AR‐immunoreactive neurons (AR‐IRs) in the medial preoptic area (mPOA), bed nucleus of stria terminalis (BNST), and medial amygdaloid nucleus (MeA) were reduced in MT males compared to MC males, and there was no significant difference in the number of AR‐IRs between MT males and FC females. AVP‐immunoreactive neurons (AVP‐IRs) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were reduced in MT males compared to MC males, and there were no significant differences in the number of AVP‐IRs between MT males and FC females. The results indicate a significant role of hormone signalling in the development of male mate preference in the novel monogamous mammal model. [ABSTRACT FROM AUTHOR]

This paper presents an aptameric graphene nanosensor for rapid and sensitive measurement of arginine vasopressin (AVP) toward continuous monitoring of critical care patients. The nanosensor is a field-effect transistor (FET) with monolayer graphene as the conducting channel and is functionalized with a new custom-designed aptamer for specific AVP recognition. Binding between the aptamer and AVP induces a change in the carrier density in the graphene and resulting in measurable changes in FET characteristics for determination of the AVP concentration. The aptamer, based on the natural enantiomer D-deoxyribose, possess optimized kinetic binding properties and is attached at an internal position to the graphene for enhanced sensitivity to low concentrations of AVP. Experimental results show that this aptameric graphene nanosensor is highly sensitive (with a limit of detection of 0.3 pM and a resolution of 0.1 pM) to AVP, and rapidly responsive (within 90 s) to both increasing and decreasing AVP concentration changes. The device is also reversable (within 4%), repeatable (within 4%) and reproducible (within 5%) in AVP measurements.

This review examines the complex interactions between estrogen receptors α and β (ERα and ERβ) and arginine vasopressin (AVP), delving into their significant roles in modulating empathy, a critical psychological component in human social dynamics. Empathy, integrating affective and cognitive elements, is anchored in neural regions like the amygdala and prefrontal cortex. ERα and ERβ, pivotal in estrogen regulation, influence neurotransmitter dynamics and neural network activities, crucial for empathic development. AVP, key in regulating water balance, blood pressure, and social behaviors, interplays with these receptors, profoundly impacting empathic responses. The study highlights that ERα predominantly enhances empathy, especially affective empathy, by stimulating AVP synthesis and release. In contrast, ERβ may diminish empathy in certain contexts by suppressing AVP expression and activity. The intricate interplay, homeostatic balance, and mutual conversion between ERα and ERβ in AVP regulation are identified as challenging yet crucial areas for future research. These findings provide essential insights into the neurobiological underpinnings of empathy, offering new avenues for therapeutic interventions in social cognitive disorders and emotional dysregulation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations.

Exercise-associated hyponatremia (EAH) is a life-threatening dilutional hyponatremia that typically occurs during or immediately after exercise in endurance athletes. A 49-year-old actress experienced dizziness 15 min after a 2-h stage performance while drinking several bottles of water. Thirty minutes later, the patient fell unconscious and was hospitalized. On admission, she showed dilutional hyponatremia (117 mmol/L) with extremely elevated arginine vasopressin (11.3 pg/mL). After initial treatment with 3% saline, her sodium levels immediately increased, and she recovered consciousness without developing subsequent osmotic demyelination syndrome. This case emphasizes the need for caution against excessive fluid intake during and/or after exercise to avoid EAH, even in non-athletes.

Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to the suprachiasmatic nucleus is the retinohypothalamic tract, with additional inputs from the intergeniculate leaflet pathway, the serotonergic afferent from the raphe, and other hypothalamic regions. Within the suprachiasmatic nucleus, two of the major subtypes are vasoactive intestinal polypeptide (VIP)-positive neurons and arginine-vasopressin (AVP)-positive neurons. VIP neurons are important for light entrainment and synchronization of suprachiasmatic nucleus neurons, whereas AVP neurons are important for circadian period determination. Output targets of the suprachiasmatic nucleus include the hypothalamus (subparaventricular zone, paraventricular hypothalamic nucleus, preoptic area, and medial hypothalamus), the thalamus (paraventricular thalamic nuclei), and lateral septum. The suprachiasmatic nucleus also sends information through several brain regions to the pineal gland. The olfactory bulb is thought to be able to generate a circadian rhythm without the suprachiasmatic nucleus. Some reports indicate that circadian rhythms of the olfactory bulb and olfactory cortex exist in the absence of the suprachiasmatic nucleus, but another report claims the influence of the suprachiasmatic nucleus. The regulation of circadian rhythms by sensory inputs other than light stimuli, including olfaction, has not been well studied and further progress is expected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tsuno and Mieda.)

Desert rodents are faced with many challenges such as high dietary salt in their natural habitats and they have evolved abilities to conserve water and tolerate salt. However, the physiological and molecular mechanisms involved in water and salt balances in desert rodents are unknown. We hypothesized that desert rodents regulated water and salt balances by altering the expression of AQP2 and α-ENaC in the kidney. Mongolian gerbils (Meriones unguiculatus), a desert species, were acclimated to drinking water with different salt contents: (0, control; 4% NaCl, moderate salt, MS; 8% NaCl, high salt, HS) for 4 weeks. The gerbils drinking salty water had lower body mass, food intake, water intake, metabolic water production and urine volume. The HS gerbils increased the expression of arginine vasopressin (AVP) in the hypothalamus, and also enhanced the expression of AQP2 and cAMP/PKA/CREB signaling pathway in the kidney. In addition, these gerbils reduced serum aldosterone levels and α-ENaC expression in the kidney. Creatinine clearance was lower in the HS group than that in the control group, but serum and urine creatinine levels did not change. These data indicate that desert rodents rely on AVP-dependent upregulation of AQP2 and aldosterone-dependent downregulation of α-ENaC in the kidney to promote water reabsorption and sodium excretion under high salt intake. [ABSTRACT FROM AUTHOR]

• AVP improves theta synchrony and accurate theta-gamma coordination in hippocampus. • AVP upregulates NR2B and PSD-95 expressions partially via V1a receptor. • AVP alleviates the impairment of spatial learning and memory in 2VO rats. • Hippocampal oscillation is a potential network mechanism of AVP functional role. Chronic cerebral hypoperfusion (CCH) is associated with cognitive decline in aging, Alzheimer's disease and vascular dementia. Neural oscillations and their interactions support brain communication and involve in cognitive function. Although arginine vasopressin (AVP) has been linked to spatial learning and memory, the effects of AVP on CCH in terms of the hippocampal neural network is unknown. Here we investigated the dynamics of neural oscillations in the hippocampus in a rat model of permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2VO) under urethane-anesthesia. Hypertonic saline (5.3%) was injected intraperitoneally to induce the endogenous AVP, and SR49059 was used as V1a receptor (an AVP receptor) antagonist. The results showed that AVP partly changed CA3 Schaffer collateral (CA3-SC) power distribution in the rat model of 2VO via V1a receptor, increased theta synchrony between CA3-SC and CA1 areas, enhanced CA3-SC theta-middle gamma phase-phase coupling, and improved spatial learning and memory performance. Biochemical fractionation further confirmed the recovery effect on N-methyl-D-aspartate receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD-95) surface expressions after hypertonic saline injection, suggesting a possible molecular mechanism in the hippocampus. The findings shed light on a functional role of endogenous AVP from a neural network perspective that AVP improves theta synchronization and accurate coordination of theta-gamma coupling probably through upregulating NR2B and PSD-95 expressions, and further promotes neural communication in the hippocampus to some extent. As a result, the impairment of spatial learning and memory induced by CCH is significantly alleviated. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) has been associated with a multitude of hypothalamic pituitary abnormalities, although it is unknown which aberrations reflect disease causation and which are the consequences of severe malnutrition. Among these endocrinopathies, hypothalamic–posterior pituitary aberrations have been described, including disorders of osmoregulation. We report the case of an adolescent female with a history of severe AN, restricting subtype, treated aggressively with multiple hospitalizations. During hospitalization for severe weakness and lethargy, her course of medical stabilization was complicated by significant polyuria, ultimately diagnosed as central diabetes insipidus (DI). This is the first reported case, to our knowledge, of a severely malnourished adolescent with AN—restricting subtype developing central DI during the refeeding process for medical stabilization, thus adding to the small body of existing literature on disordered osmoregulation in this patient population. This case report raises the question as to whether the frequency of central DI during refeeding is greater than that previously recognized. Additional research should focus on how neuroendocrine dysregulation of water balance might impact the clinical course of AN and its treatment. [ABSTRACT FROM AUTHOR]

Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding −11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia.

Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family.

Our knowledge on sodium and water homeostasis and regulation continues to evolve. A considerable amount of new information in this area has emerged in recent years. This review summarizes existing and new literature and discusses complex multi‐organ effects of high‐salt and low‐water intake and role of arginine vasopressin in this process, as well as the potential clinical significance of non‐osmotic sodium storage pool and rhythmicity of urine sodium excretion. It has become clear that sodium and water dysregulation can exert profound effects on kidney and vascular health, far greater than previously recognized. Maladaptation to a combined high‐salt and low‐water intake can be linked to the growing epidemic of hypertension and chronic kidney disease. Summary at a Glance: • Na+ and water regulations are tightly connected, involving neurohumeral multi‐organ regulations of AVP, glucocorticoids, RAAS activation, muscle catabolism, urea generation and salt‐retention. • High‐salt and low‐water intake, common in the general population, is potentially pathogenic and linked to the genesis of hypertension and CKD. • The tissue (mainly skin and muscle) storage pool of Na+ likely participates in Na+ and water homeostasis; heavier tissue Na+ storage may be pathological and has been associated with resistant hypertension and left ventricular hypertrophy. • When appropriate, a modest increase (∼0.5 ‐1.5 L/day) in water intake and reduction in dietary salt to a recommended range can blunt AVP increase and will likely be beneficial. [ABSTRACT FROM AUTHOR]

Familial neurohypophysial diabetes insipidus (FNDI), characterized by progressive polyuria and loss of arginine vasopressin (AVP) neurons, is an autosomal dominant disorder caused by AVP gene mutations. Our previous studies with FNDI model mice demonstrated that mutant proteins accumulated in the endoplasmic reticulum (ER) of AVP neurons. Here, we examined therapeutic effects of the chemical chaperone 4-phenylbutylate (4-PBA) in FNDI mice. Treatment with 4-PBA reduced mutant protein accumulation in the ER of FNDI mice and increased AVP release, leading to reduced urine volumes. Furthermore, AVP neuron loss under salt loading was attenuated by 4-PBA treatment. These data suggest that 4-PBA ameliorated mutant protein accumulation in the ER of AVP neurons and thereby prevented FNDI phenotype progression. [ABSTRACT FROM AUTHOR]

Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15min of asphyxia), but some release was still ongoing even 90min after the end of the 45min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding -11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia. [ABSTRACT FROM AUTHOR]

Vocal learning from social partners is crucial for the successful development of communication in a wide range of species. Social interactions organize attention and enhance motivation to learn species-typical behaviour. However, the neurobiological mechanisms connecting social motivation and vocal learning are unknown. Using zebra finches (Taeniopygia guttata), a ubiquitous model for vocal learning, we show that manipulations of nonapeptide hormones in the vasopressin family (arginine vasotocin, AVT) early in development can promote or disrupt both song and social motivation. Young male zebra finches, like human infants, are socially gregarious and require interactive feedback from adult tutors to learn mature vocal forms. To investigate the role of social motivational mechanisms in song learning, in two studies, we injected hatchling males with AVT or Manning compound (MC, a nonapeptide receptor antagonist) on days 2-8 post-hatching and recorded song at maturity. In both studies, MC males produced a worse match to tutor song than controls. In study 2, which experimentally controlled for tutor and genetic factors, AVT males also learned song significantly better compared with controls. Furthermore, song similarity correlated with several measures of social motivation throughout development. These findings provide the first evidence that nonapeptides are critical to the development of vocal learning. [ABSTRACT FROM AUTHOR]

Background: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS. Results: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca2+ influxes through L-type Ca2+ channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene. Conclusions: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation. [ABSTRACT FROM AUTHOR]

Highlights: [•] Vasopressin 1a receptor binding is diffuse and widespread in the titi monkey brain. [•] Oxytocin receptor binding is much more limited, with the densest binding in the hippocampus. [•] There is considerable interspecies variation in neuropeptide receptor expression in primates. [•] ALS-II-69 is a selective antagonist for the titi monkey oxytocin receptor. [•] SR49059 is a selective antagonist for the titi monkey vasopressin 1a receptor. [Copyright &y& Elsevier]

Abstract: Free radicals are essential for the vasopressin (AVP) response to plasmatic hyperosmolarity. Noradrenergic afferents are the major projections on the supraoptic nucleus (SON) of the hypothalamus and stimulate the expression of AVP via a nitric oxide (NO) pathway. In this study, we investigated the mechanisms linking free radicals and noradrenaline (NA)-induced regulation of AVP. Analysis of Tg8 transgenic mice, invalidated for the monoamine oxidase-A gene and with consequently high levels of brain monoamines and AVP in the SON, showed that free radicals are more abundant in their SON than in that of wild-type mice (WT). Antioxidant superoxide dismutase 1 and 2 and catalase enzyme activities were also higher in these mice than in WT. This may explain the observed absence of cytotoxicity that would otherwise be associated with such high level of free radicals. Treatment of Tg8 mice with α-MPT, a blocking agent for NA synthesis, decreased both the production of free radicals and the AVP levels in the SON. Furthermore, incubation of ex vivo slices including the SON with NA increased the production of free radicals and AVP levels in wild-type mice. When NA was associated with α-lipoic acid, an antioxidant blocking the production of free radicals, AVP remained at its control level, indicating that free radicals are required for the effect of NA on the expression of AVP. In slices incubated with SNP, a producer of NO, free radicals and AVP levels increased. When NA was associated with L-NAME (a NO synthase blocker), the levels of free radicals and AVP were the same as in controls. Thus, the noradrenaline–NO pathway, which stimulates the expression of vasopressin, involves free radicals. This study provides further evidence of the physiological importance of free radicals, which should no longer be considered solely as cytotoxic factors. [Copyright &y& Elsevier]

Highlights: [•] No iNOS was expressed in the bladder or urethra following CYP administration. [•] CYP induces a transient downregulation of nNOS coincident with progressive eNOS upregulation. [•] Changes in contractility were not associated with NO synthesis. [•] Altered NO or free radical production mediated by constitutive NOS isoforms may contribute to CYP pathogenicity. [Copyright &y& Elsevier]

Highlights: [•] Blockade of arginine vasotocin (AVT) signaling reduces aggression in A. ocellaris. [•] Blockade of AVT signaling reduces winning dyadic contests in A. ocellaris. [•] Blockade of AVT signaling reduces c-Fos expression in the social decision network. [ABSTRACT FROM AUTHOR]

Highlights: [•] AVP increased the production of l-serine in both WKY/Izm and SHRSP/Izm astrocytes. [•] The production of l-serine was lower in SHRSP/Izm than in WKY/Izm. [•] In SHRpch1_18, the expression of Slc1a4 and Phgdh decreased during ischemic condition. [ABSTRACT FROM AUTHOR]

Highlights: [•] The distribution of VIP-ir neurons in the SCN is conserved among different species. [•] The localization of AVP-ir neurons in the SCN is central and dorsal, not dorsomedial as in rodents. [•] AVP-ir and VIP-ir fibers from the SCN exhibit varicosities at intervals and dilated terminal buttons. [•] AVP-ir and VIP-ir fibers coexist in the same hypothalamic receiving areas for the SCN. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS). Background: Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. Methods: We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year. Results: A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF (copeptin: 13.2% vs. 5.0%, p > 0.001; MR-proADM: 15.8% vs. 4.1%, p > 0.001; MR-proANP: 17.7% vs. 3.5%, p > 0.001) as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001). These biomarkers improved prognostic discrimination and patient reclassification for CV death or HF at 1 year (all categorical net reclassification improvement: <10%; p > 0.001) and maintained an independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus B-type natriuretic peptide, cardiac troponin I, ST2, pregnancy-associated plasma protein A, and myeloperoxidase (each p ≤ 0.01). Conclusions: Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788) [Copyright &y& Elsevier]

Highlights: [•] Presents a comparison of stress response studies in rodents and humans. [•] Reviews DNA methylation-dependent mechanisms of stress responses. [•] Highlights HPA axis epigenetics as potential biomarkers for stress in humans. [•] Discusses promising directions for future studies into the epigenetics of stress. [ABSTRACT FROM AUTHOR]

Abstract: The foundations of brain architecture are established early in life through a continuous series of dynamic interactions in which environmental conditions and personal experiences have a significant impact on how genetic predispositions are expressed. New scientific research shows that early social experiences can actually influence how genes are expressed. Thus, the old-school concepts that genes are “chiseled in stone” or that they alone determine development have been disproven. The discovery of the epigenome provides an explanation, at the molecular level, for why and how early positive and negative social experiences give rise to a biological memory that can have lifelong impacts. Signatures associated with the epigenome can be temporary or permanent, affect multiple organ systems, and increase the risk not only for poor physical and mental health outcomes but also for impairments in future learning capacity and behavior. Here, we focus on recent evidence for a role of epigenetic DNA modifications as a potential mechanism that explains how early social life experiences become embedded in the circuitry of the developing brain and are associated with lifelong consequences. This article is part of a Special Issue entitled: Epigenetics in Brain Function. [Copyright &y& Elsevier]

Highlights: [•] Puberty is a critical period of brain development. [•] Puberty is a time of greater risk for neuropsychiatric disease. [•] Epigenectic mechanisms are involved in normal maturational processes. [•] Therefore, epigenetic mechanisms are a likely target for environmental perturbation. [•] This review discusses epigenetic processes in pubertal brain maturation. [ABSTRACT FROM AUTHOR]

Highlights: [•] The HPA axis is a complex neuroendocrine loop that integrates stressor-related information. [•] Sex differences in the HPA axis arise through effects of gonadal steroid hormones. [•] Estrogen can alter HPA function though divergent actions mediated by ERalpha and ERbeta. [•] Androgens inhibit HPA function through actions at the androgen receptor or ERbeta. [ABSTRACT FROM AUTHOR]

Abstract: Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with complex symptoms and unclear, multi-factorial pathogenesis. Animal (rodent) models of ASD-like behavior are extensively used to study genetics, circuitry and molecular mechanisms of ASD. The evolutionarily conserved nature of social behavior and its molecular pathways suggests that alternative experimental models can be developed to complement and enhance the existing rodent ASD paradigms. The zebrafish (Danio rerio) is rapidly becoming a popular model organism in neuroscience and biological psychiatry to study brain function, model human brain disorders and explore their genetic or pharmacological modulation. Representing highly social animals, zebrafish emerge as a strong potential model organism to study normal and pathological social phenotypes, as well as several other ASD-like symptoms. Here, we discuss the developing utility of zebrafish in modeling ASD as a new emerging field in translational neuroscience and drug discovery. [Copyright &y& Elsevier]

Abstract: Low-dose dexamethasone has been widely used for the prevention of nausea and vomiting after chemotherapy and surgical procedures and to treat motion sickness due to its minimal adverse effects, but the mechanisms underlying its anti-motion sickness effects are poorly understood. Previous studies have demonstrated that the endocannabinoid system is suppressed by motion sickness but stimulated by dexamethasone. The aim of the present study was to determine whether dexamethasone has an anti-motion sickness effect in rats and to elucidate the mechanism of this action. We used HPLC–MS/MS to measure the plasma concentrations of anandamide and 2-arachidonoylglycerol+1-arachidonoylglycerol, and we employed real-time quantitative PCR (qRT-PCR) and/or Western blot analysis to assay the expression of N-acylphosphatidyl-ethanolamine hydrolyzing phospholipase D, sn-1-selective diacylglycerol lipase, fatty acid hydrolase, monoacylglycerol lipase and endocannabinoid CB1 receptor in the dorsal vagal complex and stomach of rats exposed to a motion sickness protocol. The results showed that dexamethasone lowered the motion sickness index and restored the levels of endogenous cannabinoids and the expression of the endocannabinoid CB1 receptor, which declined after the induction of motion sickness, in the dorsal vagal complex and stomach. [Copyright &y& Elsevier]

Abstract: In the review article presented here, we demonstrate that the connective tissue is more than just a matrix for cells and a passive scaffold to provide physical support. The extracellular matrix can be subdivided into proteins (collagen, elastin), glycoconjugates (structural glycoproteins, proteoglycans) and glycosaminoglycans (hyaluronan). Our main focus rests on the anionic biopolyelectrolytes of the perlecan/syndecan superfamily which belongs to extracellular matrix and cell membrane integral proteoglycans. Though the extracellular domain of the syndecans may well be performing a structural role within the extracellular matrix, a key function of this class of membrane intercalated proteoglycans may be to act as signal transducers across the plasma membrane and thus be more appropriately included in the group of cell surface receptors. Nevertheless, there is a continuum in functions of syndecans and perlecans, especially with respect to their structural role and biomedical significance. HS/CS proteoglycans are receptor sites for lipoprotein binding thus intervening directly in lipid metabolism. We could show that among all lipoproteins, HDL has the highest affinity to these proteoglycans and thus instals a feedforward forechecking loop against atherogenic apoB100 lipoprotein deposition on surface membranes and in subendothelial spaces. Therefore, HDL is not only responsible for VLDL/IDL/LDL cholesterol exit but also controls thoroughly the entry. This way, it inhibits arteriosclerotic nanoplaque formation. The ternary complex ‘lipoprotein receptor (HS/CS-PG) – lipoprotein (LDL, oxLDL, Lp(a)) – calcium’ may be interpreted as arteriosclerotic nanoplaque build-up on the molecular level before any cellular reactivity, possibly representing the arteriosclerotic primary lesion combined with endothelial dysfunction. With laser-based ellipsometry we could demonstrate that nanoplaque formation is a Ca2+-driven process. In an in vitro biosensor application of HS-PG coated silica surfaces we tested nanoplaque formation and size in clinical trials with cardiovascular high-risk patients who underwent treatment with ginkgo or fluvastatin. While ginkgo reduced nanoplaque formation (size) by 14.3% (23.4%) in the isolated apoB100 lipid fraction at a normal blood Ca2+ concentration, the effect of the statin with a reduction of 44.1% (25.4%) was more pronounced. In addition, ginkgo showed beneficial effects on several biomarkers of oxidative stress and inflammation. Besides acting as peripheral lipoprotein binding receptor, HS/CS-PG is crucially implicated in blood flow sensing. A sensor molecule has to fulfil certain mechanochemical and mechanoelectrical requirements. It should possess viscoelastic and cation binding properties capable of undergoing conformational changes caused both mechanically and electrostatically. Moreover, the latter should be ion-specific. Under no-flow conditions, the viscoelastic polyelectrolyte at the endothelium — blood interface assumes a random coil form. Blood flow causes a conformational change from the random coil state to the directed filament structure state. This conformational transition effects a protein unfurling and molecular elongation of the GAG side chains like in a ‘stretched’ spring. This configuration is therefore combined with an increase in binding sites for Na+ ions. Counterion migration of Na+ along the polysaccharide chain is followed by transmembrane Na+ influx into the endothelial cell and by endothelial cell membrane depolarization. The simultaneous Ca2+ influx releases NO and PGI2, vasodilatation is the consequence. Decrease in flow reverses the process. Binding of Ca2+ and/or apoB100 lipoproteins (nanoplaque formation) impairs the flow sensor function. The physicochemical and functional properties of proteoglycans are due to their amphiphilicity and anionic polyelectrolyte character. Thus, they potently interact with cations, albeit in a rather complex manner. Utilizing 23Na+ and 39 K+ NMR techniques, we could show that, both in HS-PG solutions and in native vascular connective tissue, the mode of interaction for monovalent cations is competition. Mg2+ and Ca2+ ions, however, induced a conformational change leading to an increased allosteric, cooperative K+ and Na+ binding, respectively. Since extracellular matrices and basement membranes form a tight-fitting sheath around the cell membrane of muscle and Schwann cells, in particular around sinus node cells of the heart, and underlie all epithelial and endothelial cell sheets and tubes, a release of cations from or an adsorption to these polyanionic macromolecules can transiently lead to fast and drastic activity changes in these tiny extracellular tissue compartments. The ionic currents underlying pacemaker and action potential of sinus node cells are fundamentally modulated. Therefore, these polyelectrolytic ion binding characteristics directly contribute to and intervene into heart rhythm. [Copyright &y& Elsevier]

Highlights: [•] The mouse SCN is composed of a heterogeneous population of neurons. [•] Both regularly and irregularly firing neurons are present in the mouse SCN in vivo. [•] The SCN neurons display different discharge profiles across wake–sleep states. [•] The SCN neurons have functional topographic organization within the nucleus. [•] The SCN may play a potential role in both circadian and sleep–wake regulation. [Copyright &y& Elsevier]

Highlights: [•] Role for central allopregnanolone in reduced neuroendocrine stress responses. [•] Allopregnanolone and oxytocin system interactions for minimising preterm birth risk. [•] Disrupted neurosteroidogenesis in compromised pregnancy and offspring outcomes. [•] Role for progesterone or allopregnanolone in correcting adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Sfmbt2-hosted miR-466a-3p and its close relatives are often among the most significantly up-regulated or down-regulated miRNAs in responses to numerous deleterious environmental stimuli. The exact roles of these miRNAs in cellular stress responses, however, are not clear. Here we showed that many Sfmbt2-hosted miRNAs were highly hypertonic stress responsive in vitro and in vivo. In renal medulla, water deprivation induced alterations in the expression of miR-466(a/b/c/e/p)-3p in a pattern similar to that of miR-200b-3p, a known regulator of osmoresponsive transcription factor Nfat5. Remarkably, exposure of mIMCD3 cells to an arginine vasopressin analog time-dependently down-regulated the expression of miR-466(a/b/c/e/p)-3p and miR-200b-3p, which provides a novel regulatory mechanism for these osmoresponsive miRNAs. In cultured mIMCD3 cells we further demonstrated that miR-466a-3p and miR-466g were capable of targeting Nfat5 by interacting with its 3′UTR. In transgenic mice overexpressing miR-466a-3p, significant down-regulation of Nfat5 and many other osmoregulation-related genes was observed in both the renal cortex and medulla. Moreover, sustained transgenic over-expression of miR-466a-3p was found to be associated with polydipsia, polyuria and disturbed ion homeostasis and kidney morphology. Since the mature sequence of miR-466a-3p is completely equivalent to that of miR-466e-3p and that the seed sequence of miR-466a-3p is completely equivalent to that of miR-297(a/b/c)-3p, miR-466d-3p, miR-467g and miR-669d-3p, and that miR-466a-3p differs from miR-466(b/c/p)-3p only in a 5′ nucleotide, we propose that miR-466a-3p and many of its close relatives are important epigenetic regulators of renal Nfat5 signaling, osmoregulation and urine concentration in mice. [Copyright &y& Elsevier]

Highlights: [•] A general overview of circadian rhythms research and the suprachasmatic nucleus (SCN) is provided. [•] The SCN sends direct efferent projections to multiple sexually dimorphic brain regions. [•] Gonadal steroid receptors are expressed at most targets sites receiving direct SCN input. [•] Sex differences exist in the circadian timing of reproduction, stress hormone rhythms, and sleep. [•] Several diseases with sex differences in incidence are associated with disruptions to circadian systems. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Available clinical data raise the possibility that stress-adaptive mechanisms differ by gender. However, this notion has not been rigorously tested in relation to cortisol-mediated negative feedback. Materials/Methods: Degree of ACTH inhibition during and recovery from an experimental cortisol clamp was tested in 20 healthy older subjects (age 60±2.2y). Volunteers received oral placebo or ketoconazole (KTCZ) to inhibit adrenal steroidogenesis along with i.v. infusions of saline or a low vs high physiological dose of cortisol in a prospectively randomized double-blind, placebo-controlled design. ACTH and cortisol concentrations were measured every 10min during the feedback-clamp phase and thereafter (recovery or escape phase). Corticosteroid-binding globulin (CBG) was measured, and free cortisol concentrations were calculated. Results: Gender did not determine mean ACTH concentrations during the saline or cortisol feedback-clamp phases per se. However, women had markedly impaired ACTH recovery after stopping both low- and high-dose cortisol infusions compared with men (P =0.005, KTCZ/low-dose cortisol arm; and P =0.006, KTCZ/high-dose cortisol arm). Decreased ACTH recovery in women was accompanied by lower total and free cortisol concentrations, pointing to heightened feedback inhibition of hypothalamo-pituitary drive of ACTH secretion as the main mechanism. Conclusions: In summary, gender or a factor related to gender, such as sex steroids or body composition, determines recovery of ACTH secretion from cortisol-enforced negative feedback. Attenuated ACTH recovery in post-menopausal women may have relevance to sex differences in stress-related adaptations. [Copyright &y& Elsevier]

Highlights: [•] AVP induces mTOR phosphorylation in A-10 cells cultured in high glucose concentration. [•] The mTOR phosphorylation is mediated by the PI3K/Akt pathway activation. [•] The AVP-induced mTOR phosphorylation inhibited autophagy and stimulated cell proliferation. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to analyze whether arginine vasopressin (AVP) may be considered a modulator of intestinal motility. In this view, we evaluated, in vitro, the effects induced by exogenous administration of AVP on the contractility of mouse distal colon, the subtype(s) of receptor(s) activated and the action mechanism. Isometric recordings were performed on longitudinal and circular muscle strips of mouse distal colon. AVP (0.001nM–100nM) caused concentration-dependent contractile effects only on the longitudinal muscle, antagonized by the V1 receptor antagonist, V-1880. AVP-induced effect was not modified by tetrodotoxin, atropine and indomethacin. Contractile response to AVP was reduced in Ca2+-free solution or in the presence of nifedipine, and it was abolished by depletion of calcium intracellular stores after repetitive addition of carbachol in calcium-free medium with addition of cyclopiazonic acid. U-73122, an inhibitor of the phospholipase C, effectively antagonized AVP effects, whilst it was not affected by an adenylyl cyclase inhibitor. Oxytocin induced an excitatory effect in the longitudinal muscle of distal colon at very high concentrations, effect antagonized by V-1880. The results of this study shown that AVP, via activation of V1 receptors, is able to modulate positively contractile activity of longitudinal muscle of mouse distal colon, independently by enteric nerve activation and prostaglandin synthesis. Contractile response is achieved by increase in cytoplasmatic Ca2+ concentration via extracellular Ca2+ influx from L-type Ca2+ channels and via Ca2+ release from intracellular stores through phospholipase C pathway. No modulation has been observed on the contractility of the circular muscle. [Copyright &y& Elsevier]

Highlights: [•] Plasticity is an essential property of the circadian system. [•] The circadian clock controls gene expression, physiology and behavior. [•] There are daily changes in the structure of a diverse array of neuronal circuits. [•] Depending on the environment, specific neurons become essential to rhythmicity. [Copyright &y& Elsevier]