Neurohypophysial Hormones Research Articles

Arginine vasopressin induces analgesic effects and inhibits pyramidal cells in the anterior cingulate cortex in spared nerve injured mice.

Neuropathic pain (NP) is a severe disease caused by a primary disease or lesion affecting the somatosensory nervous system. It is reported that NP is related to the increased activity of glutamatergic pyramidal cells and changed neural oscillations in the anterior cingulate cortex (ACC). Arginine vasopressin (AVP), a neurohypophyseal hormone, has been shown to cause pain-alleviating effects when applied to the peripheral system. However, the extent to which, and the mechanisms by which, AVP induces analgesic effects in the central nervous system remains unclear. In the present study, we observed that intranasal delivery of AVP inhibited mechanical pain, thermal pain, and spontaneous pain sensitivity in mice with spared nerve injury. Meanwhile, AVP application exclusively reduced the FOS expression in the pyramidal cells but not interneurons in the ACC. In vivo electrophysiological recording of the ACC further showed that AVP application not only inhibited the theta oscillation in local field potential analysis but also reduced the firing rate of spikes of pyramidal cells in the ACC in neuropathic pain mice. In summary, AVP induces analgesic effects by inhibiting neural theta oscillations and the spiking of pyramidal cells of the ACC in mice with neuropathic pain, which should provide new potential noninvasive methods for clinical treatment of chronic pain.NEW & NOTEWORTHY Following intranasal administration of arginine vasopressin (AVP), the pain thresholds for mechanical and thermal nociception significantly increased in the spared nerve injury (SNI) group; exogenous intranasal delivery of AVP improved the physical coordination of SNI mice, resulting in an analgesic effect; AVP treatment significantly reduced the increased firing rate of PYRACC of the SNI group; AVP treatment significantly inhibited the elevated theta oscillation in the anterior cingulate cortex (ACC) in SNI mice.

Sympathetic Innervation of Interscapular Brown Adipose Tissue Is Not a Predominant Mediator of Oxytocin-Induced Brown Adipose Tissue Thermogenesis in Female High Fat Diet-Fed Rats.

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (TIBAT) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate TIBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated TIBAT similarly between sham rats and denervated rats (p = NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 μg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N = 7-8/group). Chronic 4V OT reduced body weight gain (sham: -18.0 ± 4.9 g; denervation: -15.9 ± 3.7 g) and adiposity (sham: -13.9 ± 3.7 g; denervation: -13.6 ± 2.4 g) relative to vehicle treatment (p < 0.05) and these effects were similar between groups (p = NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 (p < 0.05) and 3 (p < 0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice (p < 0.05 vs. vehicle). Together, these findings suggest that (1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and (2) the effects of OT to reduce weight gain and adiposity translate to other female mouse models of diet-induced obesity (DIO).

Is Oxytocin a Contributor to Behavioral and Metabolic Features in Prader-Willi Syndrome?

Prader-Willi Syndrome (PWS) is a rare genetic disorder typically characterized by decreased social interaction, hyperphagia, poor behavioral control and temper tantrums, together with a high risk of morbid obesity unless food intake is controlled. The genetic defects that cause PWS include paternal 15q deletion (estimated in 60% of cases), chromosome 15 maternal uniparental disomy (UPD) (estimated in 35% of cases) and imprinting defects and translocations. Several studies indicate an oxytocin deficiency in PWS. Oxytocin is a hypothalamic nonapeptide with receptors located in the brain and in various other tissues in the body. It acts as a neuropeptide in several brain areas of great importance for behavioral and metabolic effects, as well as a neurohypophyseal hormone released into the circulation. Oxytocin in both rats and humans has strong and long-lasting behavioral and metabolic effects. Thus, an oxytocin deficiency might be involved in several of the behavioral and metabolic symptoms characterizing PWS. Treatment with oxytocin has, in some studies, shown improvement in psycho-social behavior and hyperphagia in individuals with PWS. This review focus on the behavioral and metabolic effects of oxytocin, the symptoms of a potential oxytocin deficiency in PWS and the effects of oxytocin treatment.

Intraperitoneal administration of arginine vasotocin (AVT) induces anorexigenic and anxiogenic actions via the brain V1a receptor-signaling pathway in the tiger puffer, Takifugu rubripes

Arginine vasotocin (AVT) is produced mainly in the hypothalamus and as a neurohypophyseal hormone peripherally regulates water-mineral balance in sub-mammals. In addition, AVT-containing neurons innervate several areas of the brain, and AVT also acts centrally as both an anorexigenic and anxiogenic factor in goldfish. However, it is unclear whether these central effects operate in fish in general. In the present study, therefore, we investigated AVT-like immunoreactivity in the brain of the tiger puffer, a cultured fish with a high market value in Japan and also a representative marine teleost species, focusing particularly on whether AVT affects food intake and psychomotor activity. AVT-like immunoreactivity was distributed higher in the ventral region of the telencephalon, the hypothalamus and midbrain. Intraperitoneal (IP) administration of AVT at 100 pmol g−1 body weight (BW) increased the immunoreactivity of phosphorylated ribosomal proteinS6 (RPS6), a neuronal activation marker, in the telencephalon and diencephalon, decreased food consumption and enhanced thigmotaxis. AVT-induced anorexigenic and anxiogenic actions were blocked by IP co-injection of a V1a receptor (V1aR) antagonist, Manning compound (MC) at 300 pmol g−1 BW. These results suggest that AVT acts as an anorexigenic and anxiogenic factor via the V1aR-signaling pathway in the tiger puffer brain.

Spatial transcriptomics reveal basal sex differences in supraoptic nucleus gene expression of adult rats related to cell signaling and ribosomal pathways

BackgroundThe supraoptic nucleus (SON) of the hypothalamus contains magnocellular neurosecretory cells that secrete the hormones vasopressin and oxytocin. Sex differences in SON gene expression have been relatively unexplored. Our study used spatially resolved transcriptomics to visualize gene expression profiles in the SON of adult male (n = 4) and female (n = 4) Sprague-Dawley rats using Visium Spatial Gene Expression (10x Genomics).MethodsBriefly, 10-μm coronal sections (~ 4 × 4 mm) containing the SON were collected from each rat and processed using Visium slides and recommended protocols. Data were analyzed using 10x Genomics’ Space Ranger and Loupe Browser applications and other bioinformatic tools. Two unique differential expression (DE) analysis methods, Loupe Browser and DESeq2, were used.ResultsLoupe Browser DE analysis of the SON identified 116 significant differentially expressed genes (DEGs) common to both sexes (e.g., Avp and Oxt), 31 significant DEGs unique to the males, and 73 significant DEGs unique to the females. DESeq2 analysis revealed 183 significant DEGs between the two groups. Gene Ontology (GO) enrichment and pathway analyses using significant genes identified via Loupe Browser revealed GO terms and pathways related to (1) neurohypophyseal hormone activity, regulation of peptide hormone secretion, and regulation of ion transport for the significant genes common to both males and females, (2) Gi signaling/G-protein mediated events for the significant genes unique to males, and (3) potassium ion transport/voltage-gated potassium channels for the significant genes unique to females, as some examples. GO/pathway analyses using significant genes identified via DESeq2 comparing female vs. male groups revealed GO terms/pathways related to ribosomal structure/function. Ingenuity Pathway Analysis (IPA) identified additional sex differences in canonical pathways (e.g., ‘Mitochondrial Dysfunction’, ‘Oxidative Phosphorylation’) and upstream regulators (e.g., CSF3, NFKB complex, TNF, GRIN3A).ConclusionThere was little overlap in the IPA results for the two different DE methods. These results suggest sex differences in SON gene expression that are associated with cell signaling and ribosomal pathways.

Lack of evidence for coevolution between oxytocin receptor N-terminal variants and monogamy in placental mammals

Oxytocin (OXT) is a neurohypophyseal hormone that influences a wide range of affiliative behaviors, such as pair-bonding and infant care, across mammals. The effects of OXT depend significantly on an adequate interaction with its receptor, OXTR. OXTR belongs to the G-protein coupled receptor family. The extracellular N-terminal domain of OXTR interacts with the linear C-terminal tail of OXT and is required for OXT binding. Across mammalian species there is a genetic diversity in OXTR terminal sequence. Previous work on primates has shown an association between OXTR phylogeny and monogamy. However, it is not clear whether this variation coevolved with either mating system (monogamy) or infant care behaviors (such as allomaternal care). Here, we take a phylogenetic comparative and evolutionary modeling approach across a wide range of placental mammals (n = 60) to test whether OXTR N-terminal variants co-evolved with either monogamy or allomaternal care behaviors. Our results indicate that the diversity in OXTR N-terminal region is unlikely to provide the underlying genetic bases for variation in mating system and/or allomaternal behavior as we find no evidence for co-evolution between protein sequence and affiliative behaviors. Hence, the role played by OXT in influencing affiliative behaviors is unlikely to be mediated by the genetic diversity of its receptor.

Effect of Neurohypophyseal Hormones on Excretion of Proteins by the Kidneys

Vasopressin (VP) is one of the main factors affecting intraglomerular hemodynamics, filtration pressure and the state of mesangial cells and contributing to the progression of proteinuria. The aim of this work was to study the effect of neurohypophyseal hormones (VP and oxytocin) on urinary protein excretion. Experiments were performed on Wistar rats, healthy and with microalbuminuria caused by minimal damage to the glomerular filter. Microalbuminuria was modeled by administration of D-nitroarginine methyl ester (D-NAME, 50 mg/kg, intraperitoneally). VP (0.05 and 1.5 nmol/kg) and oxytocin (0.15 nmol/kg) were administered to rats intramuscularly, V2-antagonist (15 nmol/kg) and V1a-antagonist (20 nmol/kg) intraperitoneally. To reduce the level of endogenous VP, animals were given water to drink (10 ml/kg), urine was collected for 2 h, and the levels of total protein, albumin, β2-microglobulin, and immunoglobulin G (IgG) were analyzed. In healthy rats, VP at a dose of 0.05 nmol/kg and oxytocin did not affect albumin excretion, but VP at a dose of 1.5 nmol/kg provoked microalbuminuria. In a model of impaired properties of the glomerular filter caused by the D-NAME administration, VP at a dose of 0.05 nmol/kg and oxytocin led to the normalization of albumin excretion, and VP at a dose of 1.5 nmol/kg caused pronounced proteinuria, albumin excretion increased by 100 times, IgG – by 10 times. Blockade of V2 receptors aggravated protein loss caused by D-NAME and VP (1.5 nmol/kg), while blockade of V1a receptors prevented it. Thus, at high concentrations in the blood, VP enhances protein filtration in the kidney. This effect is mediated by V1a receptors and, depending on the barrier properties of the glomerular filter, leads to the development of microalbuminuria or severe proteinuria. Oxytocin and VP at a dose at which it predominantly activates V2 receptors have an antiproteinuric effect. The revealed effects of neurohypophyseal hormones on albumin excretion open up new promising therapeutic targets for the correction of glomerular dysfunctions.

Effect of Neurohypophysial Hormones on Protein Excretion by the Kidneys

Effect of Neurohypophysial Hormones on Protein Excretion by the Kidneys

Neuropeptidergic control circuits in the spinal cord for male sexual behaviour: Oxytocin-gastrin-releasing peptide systems.

The neuropeptidergic mechanisms controlling socio-sexual behaviours consist of complex neuronal circuitry systems in widely distributed areas of the brain and spinal cord. At the organismal level, it is now becoming clear that "hormonal regulations" play an important role, in addition to the activation of neuronal circuits. The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord is an important component of the neural circuits that control penile reflexes in rats, circuits that are commonly referred to as the "spinal ejaculation generator (SEG)." Oxytocin, long known as a neurohypophyseal hormone, is now known to be involved in the regulation of socio-sexual behaviors in mammals, ranging from social bonding to empathy. However, the functional interaction between the SEG neurons and the hypothalamo-spinal oxytocin system remains unclear. Oxytocin is known to be synthesised mainly in hypothalamic neurons and released from the posterior pituitary into the circulation. Oxytocin is also released from the dendrites of the neurons into the hypothalamus where they have important roles in social behaviours via non-synaptic volume transmission. Because the most familiar functions of oxytocin are to regulate female reproductive functions including parturition, milk ejection, and maternal behaviour, oxytocin is often thought of as a "feminine" hormone. However, there is evidence that a group of parvocellular oxytocin neurons project to the lower spinal cord and control male sexual function in rats. In this report, we review the functional interaction between the SEG neurons and the hypothalamo-spinal oxytocin system and effects of these neuropeptides on male sexual behaviour. Furthermore, we discuss the finding of a recently identified, localised "volume transmission" role of oxytocin in the spinal cord. Findings from our studies suggest that the newly discovered "oxytocin-mediated spinal control of male sexual function" may be useful in the treatment of erectile and ejaculatory dysfunction.

Oxytocin Modulates Osteogenic Commitment in Human Adipose-Derived Stem Cells.

Human adipose-derived stem cells (hASCs) are commonly harvested in minimally invasive contexts with few ethical concerns, and exhibit self-renewal, multi-lineage differentiation, and trophic signaling that make them attractive candidates for cell therapy approaches. The identification of natural molecules that can modulate their biological properties is a challenge for many researchers. Oxytocin (OXT) is a neurohypophyseal hormone that plays a pivotal role in the regulation of mammalian behavior, and is involved in health and well-being processes. Here, we investigated the role of OXT on hASC proliferation, migratory ability, senescence, and autophagy after a treatment of 72 h; OXT did not affect hASC proliferation and migratory ability. Moreover, we observed an increase in SA-β-galactosidase activity, probably related to the promotion of the autophagic process. In addition, the effects of OXT were evaluated on the hASC differentiation ability; OXT promoted osteogenic differentiation in a dose-dependent manner, as demonstrated by Alizarin red staining and gene/protein expression analysis, while it did not affect or reduce adipogenic differentiation. We also observed an increase in the expression of autophagy marker genes at the beginning of the osteogenic process in OXT-treated hASCs, leading us to hypothesize that OXT could promote osteogenesis in hASCs by modulating the autophagic process.

Phylogenetic and functional properties of hagfish neurohypophysial hormone receptors distinct from their jawed vertebrate counterparts

Vertebrate neurohypophysial hormones, i.e., vasopressin- and oxytocin-family peptides, exert versatile physiological actions via distinct G protein-coupled receptors. The neurohypophysial hormone receptor (NHR) family was classically categorized into four subtypes (V1aR, V1bR, V2R and OTR), while recent studies have identified seven subtypes (V1aR, V1bR, V2aR, V2bR, V2cR, V2dR and OTR; V2aR corresponds to the conventional V2R). The vertebrate NHR family were diversified via multiple gene duplication events at different scales. Despite intensive research effort in non-osteichthyes vertebrates such as cartilaginous fish and lamprey, the molecular phylogeny of the NHR family has not been fully understood. In the present study, we focused on the inshore hagfish (Eptatretus burgeri), another group of cyclostomes, and Arctic lamprey (Lethenteron camtschaticum) for comparison. Two putative NHR homologs, which were previously identified only in silico, were cloned from the hagfish and designated as ebV1R and ebV2R. In vitro, ebV1R, as well as two out of five Arctic lamprey NHRs, increased intracellular Ca2+ in response to exogenous neurohypophysial hormones. None of the examined cyclostome NHRs altered intracellular cAMP levels. Transcripts of ebV1R were detected in multiple tissues including the brain and gill, with intense hybridization signals in the hypothalamus and adenohypophysis, while ebV2R was predominantly expressed in the systemic heart. Similarly, Arctic lamprey NHRs showed distinct expression patterns, underscoring the multifunctionality of VT in the cyclostomes as in the gnathostomes. These results and exhaustive gene synteny comparisons provide new insights into the molecular and functional evolution of the neurohypophysial hormone system in vertebrates.

Vasopressin V1a receptor and oxytocin receptor regulate murine sperm motility differently.

Specific receptors for the neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin, are present in the male reproductive organs. However, their exact roles remain unknown. To elucidate the physiological functions of pituitary hormones in male reproduction, this study first focused on the distribution and function of one of the AVP receptors, V1a. In situ hybridization analysis revealed high expression of the Avpr1a in Leydig cells of the testes and narrow/clear cells in the epididymis, with the expression pattern differing from that of the oxytocin receptor (OTR). Notably, persistent motility and highly proportional hyperactivation were observed in spermatozoa from V1a receptor-deficient mice. In contrast, OTR blocking by antagonist atosiban decreased hyperactivation rate. Furthermore, AVP stimulation could alter the extracellular pH mediated by the V1a receptor. The results highlight the crucial role of neurohypophyseal hormones in male reproductive physiology, with potential contradicting roles of V1a and OTR in sperm maturation. Our findings suggest that V1a receptor antagonists are potential therapeutic drugs for male infertility.

Structures of the arginine-vasopressin and oxytocin receptor signaling complexes.

Arginine-vasopressin (AVP) and oxytocin (OT) are neurohypophysial hormones which share a high sequence and structure homology. These are two cyclic C-terminally amidated nonapeptides with different residues at position 3 and 8. In mammals, AVP and OT exert their multiple biological functions through a specific G protein-coupled receptor family: four receptors are identified, the V1a, V1b, V2 receptors (V1aR, V1bR and V2R) and the OT receptor (OTR). The chemical structure of AVP and OT was elucidated in the early 1950s. Thanks to X-ray crystallography and cryo-electron microscopy, it took however 70 additional years to determine the three-dimensional structures of the OTR and the V2R in complex with their natural agonist ligands and with different signaling partners, G proteins and β-arrestins. Today, the comparison of the different AVP/OT receptor structures gives structural insights into their orthosteric ligand binding pocket, their molecular mechanisms of activation, and their interfaces with canonical Gs, Gq and β-arrestin proteins. It also paves the way to future rational drug design and therapeutic compound development. Indeed, agonist, antagonist, biased agonist, or pharmacological chaperone analogues of AVP and OT are promising candidates to regulate different physiological functions and treat several pathologies.

Localization of the Neuropeptide Arginine Vasotocin and Its Receptor in the Osmoregulatory Organs of Black Porgy, Acanthopagrus schlegelii: Gills, Kidneys, and Intestines.

The neurohypophysial hormone arginine vasotocin (avt) and its receptor (avtr) regulates ions in the osmoregulatory organs of euryhaline black porgy (Acanthopagrus schlegelii). The localization of avt and avtr transcripts in the osmoregulatory organs has yet to be demonstrated. Thus, in the present study, we performed an in situ hybridization analysis to determine the localization of avt and avtr in the gills, kidneys, and intestines of the black porgy. The avt and avtr transcripts were identified in the filament and lamellae region of the gills in the black porgy. However, the basal membrane of the filament contained more avt and avtr transcripts. Fluorescence double tagging analysis revealed that avt and avtr mRNAs were partially co-localized with α-Nka-ir cells in the gill filament. The proximal tubules, distal tubules, and collecting duct of the kidney all had positive hybridization signals for the avt and avtr transcripts. Unlike the α-Nka immunoreactive cells, the avt and avtr transcripts were found on the basolateral surface of the distal convoluted tubule and in the entire cells of the proximal convoluted tubules of the black porgy kidney. In the intestine, the avt and avtr transcripts were found in the basolateral membrane of the enterocytes. Collectively, this study provides a summary of evidence suggesting that the neuropeptides avt and avtr with α-Nka-ir cells may have functions in the gills, kidneys, and intestines via ionocytes.

Identification of neurohypophysial hormones and the role of VT in the parturition of pregnant seahorses (Hippocampus erectus).

Neurohypophysial hormones regulate the reproductive behavior of teleosts; however, their role in the gestation and parturition of ovoviviparous fishes with male pregnancy (syngnathids) remains to be demonstrated. In the present study, the complementary DNA (cDNA) sequences of arginine vasotocin (VT) and isotocin (IT) from the lined seahorse (Hippocampus erectus) were cloned and identified. We observed that the mature core peptides of seahorse VT and IT were conserved among teleosts. In the phylogenic tree, seahorse VT and IT were clustered independently with teleost VT and IT. The tissue distribution patterns of VT and IT were similar, and both were highly expressed in the brain, gills, and gonads. Interestingly, they were also expressed to some extent in the brood pouch. In situ hybridization revealed that VT and IT messenger RNA (mRNA) signals in the brain were mainly located in the preoptic area region of the hypothalamus. Intraperitoneal administration of the VT core peptide to pregnant seahorses induced premature parturition, stimulated gonadotropin release, increased serum estrogen levels, and decreased prolactin secretion. Moreover, VT injection upregulated the mRNA expression of the membrane estrogen receptor in the brood pouch. In summary, neurohypophysial hormones promote premature parturition by regulating estrogen synthesis through the hypothalamus–pituitary–gonad axis.

Circulating isotocin, not angiotensin II, is the major dipsogenic hormone in eels

Angiotensin II (AngII) is generally known as the most important dipsogenic hormone throughout vertebrates, while two other neurohypophysial hormones, vasopressin and oxytocin, are not dipsogenic in mammals. In this study, we found that systemic isotocin, but not vasotocin, is the potent dipsogenic hormone in eels. When injected intra-arterially into conscious eels, isotocin, vasotocin and AngII equally increased ventral aortic pressure dose dependently at 0.03-1.0 nmol kg-1, but only isotocin induced copious drinking. The dipsogenic effect was dose dependent and occurred significantly at as low as 0.1 nmol kg-1. By contrast, a sustained inhibition of drinking occurred after AngII injection, probably due to baroreflexogenic inhibition. No such inhibition was observed after isotocin injection despite similar concurrent hypertension. The baroreceptor may exist distal to the gill circulation because the vasopressor effect occurred at both ventral and dorsal aorta after AngII but only at ventral aorta after isotocin. By contrast, intra-cerebroventricular (i.c.v.) injection of isotocin had no effect on drinking or blood pressure, but AngII increased drinking and aortic pressure dose dependently at 0.03-0.3 nmol per eel. Lesioning of the area postrema (AP), a sensory circumventricular organ, abolished drinking induced by peripheral isotocin, but not i.c.v. AngII. Collectively, isotocin seems to be a major circulating hormone that induces swallowing through its action on the AP, while AngII may be an intrinsic brain peptide that induces drinking through its action on a different circumventricular site, possibly a recently identified blood-brain barrier-deficient structure in the antero-ventral third ventricle of eels, as shown in birds and mammals.

Effects of pituitary hormones deficiency from the specific pituitary lobes on learning, memory and survival behavior in the Wistar rat

The role of the different adenohypophyseal hormones (GH, PRL, ACTH, TSH, LH and FSH) and neurohypophyseal (AVP and OXY) hormones on animal behavior, memory and learning have been stablished, however the role of lobe‐specific hormones on these cerebral functions has been not completely dilucidated. Here we study the specific pituitary hormone deficiencies in hypophysectomized (HYPOX), with anterior lobectomized (AL) and neurointermediate lobectomized (NIL) rats, subject to novel object recognition (NOR), forced swim (FS) and prepulse inhibition (PPI) tests. For comparisons the intact control (IC) and sham operated (SHAM) groups were also included. The NOR test that evaluate different phases of learning and memory in rodents, showed that memory discrimination index (DI) significantly increased in the NIL group, indicating that AVP and OXY deficiency negatively affect the ability of short and medium‐term memory. The FS test assess survival and motivation behavior; results showed that AL, NIL and HYPOX groups induced a loss in motivation and will to survive (increased immobility time); these observations may be partially explained by: 1) the significant deficiency of metabolic hormones (GH, ACTH‐corticosterone, TSH‐thyroid hormones and LH‐FSH‐testosterone hormones) whose decrease also induced significant loss in both mass muscle and body weight in AL and HYPOX groups and, 2) the decreased survival and motivational behavior induced by the AVP and OXY deficiency (NIL‐induced), thus supporting the view of the motivational and survival role of these hormones. The IPP test evaluates the rat ability to respond to potentially harmful acoustic stimuli and long‐term memory; results showed that AL animals did not show any sign of learning (expressed as very low inhibition percentage), whereas, interestingly, the HYPOX group (without any pituitary hormones) the long‐term memory was not significantly affected. In conclusion these results support the important role of the several pituitary hormones mainly neurohypophyseal hormones (AVP and OXY) controlling important brain functions necessary for learning, memory, and survival. These experimental models will allow in the future to study specifically the role of each pituitary hormone on the different aspects of animal behavior such as memory, motivation, generosity, adaptation, among others.

Resemblance in Physiological Systems during Phylogeny and Ontogeny

Although it is not certain whether some characteristics of the mammalian fetus/embryo may repeat the adult stage of ancestral vertebrates, comparison of these two time‐dependent processes should provide new insight into the molecular and functional evolution and its significance. Here we discuss two important biological models: 1) Renin‐angiotensin system (RAS) and 2) Urine concentration mechanism.Renin is a hormone and substrate‐dependent enzyme secreted mostly by the juxtaglomerular (JG) cells of the afferent arteriole located at the vascular pole of the glomerulus. Renin acts on renin substrates and forms angiotensin (Ang) I which is subsequently converted to Ang II by Ang converting enzyme (ACE). Renin containing cells evolved early both in phylogeny and ontogeny, whereas, the macula densa (tubule component), and extracellular mesangium appeared at later stages.Renin containing cells are distributed more widely intrarenally and/or extrarenally in early stages during phylogeny and ontogeny. Granulated cells and renin expression become progressively restricted to JG areas with phylogenic and ontogenic advancement. Kidney renin activities tend to be higher in primitive fishes than in more advanced, while the relative level of extrarenal renin expression to that of the kidney is higher in embryos than in more mature chicken and mice. Extra renal renin is noted in primitive vertebrates. Also, in both the mammalian fetus and nonmammalian vertebrates, the vasopressor and vascular action of Ang II evolved early. A single application of ACE inhibitors decreases the basal level of blood pressure and increase plasma renin activity in conscious adult teleost fish. Ang II stimulates, whereas ACE inhibitors inhibit, arteriolar branching in zebrafish. Likewise, the RAS is important during early ontogeny of mammals in vascular growth and development.Distal tubules of freshwater trout show secondary active NaCl cotransport mechanism without accompaniment of water and act as the so‐called “diluting segment.” Teleost fish cannot concentrate urine because they lack structural and functional countercurrent mechanisms. Only birds and mammals can form urine clearly hyperosmotic to plasma and conserve body water. The structure and function of adult quail kidneys have similarities to those of developing rodents. Both have a loop of Henle, consisting of descending limb and thick ascending limb, but they lack the thin ascending limb. Countercurrent urine concentration of adult quail and developing rodents heavily depends on NaCl recycling without participation of urea transport. Moreover, in both adult quail and developing rodent kidneys, aquaporin 2 gene expression and protein are present in the apical membrane of the collecting tubules, but the water conservation effect of neurohypophysial hormones is smaller than that of adult rodent kidneys. Hence, comparing these two time‐dependent processes may provide new insights into the interpretation of existing findings and provide perspective for future investigations.

Peptide Hormones in Medicine: A 100-Year History

This review is devoted to the 100-year history of the investigation of peptide hormones and the creation of drugs on their basis, starting from the insulin discovery and its introduction into a medical practice in 1921. The basic groups of the peptide hormones are discussed: neurohypophyseal hormones, hypothalamic releasing hormones, incretins, insulin, adrenocorticotropic hormone (ACTH), and calcitonin. The first therapeutic agents based on the peptide hormones were created by a traditional approach that involved the isolation of peptides from animal tissues, their purification to individual compounds, determination of their primary structure, their chemical synthesis or their deep purification, and the creation of a pharmaceutical substance. A modern approach to creation of peptide hormone drugs is based on their consideration as ligands of the corresponding cellular receptors and the use of computer modeling, efficient synthesis methods, and high-throughput screening. The combination of these methods enabled the development of analogs which would be more active than the corresponding natural compounds, exhibit other activities in addition to the hormonal regulation, and be resistant to biodegradation. Such therapeutic agents have been designed on the basis of agonistic and antagonistic analogs of somatostatin and luliberin, and have found wide application in hormonal regulation and cancer treatment. Over the past two decades, the glucagon-like peptide (GLP-1) has been intensively investigated as a potential therapeutic agent. In our review, we describe modifications which resulted in the most highly effective long-acting drugs. Now, natural hormones and their analogs are widely present in the pharmaceutical market.

A tribute to Professor Sergio Adamo, Full Professor of Histology and Embryology at Sapienza University, Rome.

Sergio Adamo prematurely left us on January 7th 2022, just one year after his retirement, leaving his family, friends and colleagues deeply sad and grieving. Sergio was a full Professor of Histology and Embryology at the Sapienza University of Rome. Since the foundation of the Institute of Histology and Embryology more than 50 years ago, he dedicated himself to the institution, research, and teaching with integrity, generosity, and a great sense of teamwork. Sergio's main research interests have been the mechanisms of myogenesis, muscle homeostasis and regeneration under normal and pathological conditions. Most relevant results obtained by Sergio and his collaborators indicate novel functions for the neurohypophyseal hormones, vasopressin and oxytocin, upon striated muscle differentiation, trophism, and homeostasis. Here we like to give the proper tribute to a mentor, a colleague and a sincere friend. He left an indelible mark on the professional and personal lives of all of us and his absence provokes a profound sense of emptiness. “The trouble with the world is that the stupid are cocksure and the intelligent are full of doubt.” Bertrand Russell