Posterior Pituitary Hormones

C H A P T E R

10 Posterior Pituitary Hormones Amanda P. Borrow, Sally A. Stover, Natalie J. Bales, Robert J. Handa Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, United States S SON V1aR, V1bR and V2R V1R V2R VMH VTA

Abbreviations AC ACTH AH ANP AQP2 ASD ATP AVP AVT BNST cAMP ceA CRF1 CRH CVO DAG eCFP GPCR H1 H2 hnRNA HPA I ICV IP3 LG LS LV M MDD meA MEC MPOA NO NTS OB OT OTR OVLT PAG PIP2 PKA PKC PLC PP PVN

adenylyl cyclase adrenocorticotropic hormone anterior hypothalamus atrial natriuretic peptide aquaporin-2 autism spectrum disorder adenosine triphosphate arginine vasopressin arginine vasotocin bed nucleus of the stria terminalis cyclic adenosine monophosphate central nuclei of the amygdala corticotropin-releasing hormone receptor 1 corticotropin-releasing hormone circumventricular organ diacylglycerol enhanced cyan fluorescent protein G proteinecoupled receptor hydrin 1 hydrin 2 heterologous nuclear RNA hypothalamic-pituitary-adrenal isotocin intracerebroventricular inositol triphosphate licking and grooming lateral septum lysine vasopressin mesotocin major depressive disorder medial amygdala myoepithelial cell medial preoptic area nitric oxide nucleus of the solitary tract olfactory bulb oxytocin oxytocin receptor organum vasculosum of the lamina terminalis periaqueductal gray phosphatidylinositol biphosphate protein kinase A protein kinase C phospholipase C phenypressin paraventricular nucleus

Hormonal Signaling in Biology and Medicine https://doi.org/10.1016/B978-0-12-813814-4.00010-9

seritocin supraoptic nucleus vasopressin receptors hepatic vasopressin receptor renal vasopressin receptor ventromedial hypothalamus ventral tegmental area

1. INTRODUCTION The posterior pituitary, or neurohypophysis, constitutes one lobe of the pituitary gland. The primary function of the posterior pituitary is the transmission of hormones originating from neurons located in hypothalamic brain regions such as the supraoptic nucleus (SON) and paraventricular nucleus (PVN) for secretion directly into peripheral circulation. Accordingly, the posterior pituitary is largely composed of axons and axon terminals. These terminals store oxytocin (OT), arginine vasopressin (AVP), and other neuropeptides within secretory granules (Gaddum, 1928; Silverman, 1976) (Fig. 10.1). While OT and AVP are the predominant hormones secreted by the posterior pituitary, others have also been identified, including somatostatin, which is received via projections from the PVN (Larsen et al., 1992), and endothelin, located within terminals of PVN and SON neurons (Yoshizawa et al., 1990). These hormones generally serve to regulate the synthesis, storage, and secretion of OT and AVP. The posterior pituitary includes two main structures: the posterior lobe, and the contiguous infundibular stalk and median eminence. In contrast to the anterior pituitary, which contains neuroendocrine epithelial cells, about 42% of the posterior pituitary is comprised of axons and axon terminals arising from hypothalamic neurons (Nordmann, 1977). These axon terminals are supported by glial cells known as pituicytes and contain neurosecretory granules storing OT and AVP. Unmyelinated axons originating from the hypothalamus project to

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Paraventricular nucleus Supraoptic nucleus

Hypothalamus

Optic chiasm

Oxytocin

Vasopressin

Posterior pituitary

Anterior pituitary

Oxytocin

Vasopressin

FIGURE 10.1 Diagrammatic representation of the neurohypophyseal control of oxytocin and vasopressin secretion into the general circulation. Oxytocin- and vasopressin-synthesizing neurons are located in the supraoptic and paraventricular nuclei of the hypothalamus. Axons from these neurons extend down the infundibular stalk to terminate along blood vessels within the posterior lobe of the pituitary. The neurosecretory products are stored in axon terminals of the posterior pituitary, where they are released into the circulation upon neural stimulation that activates soma in the hypothalamus.

the posterior lobe via the pars infundibularis of the infundibular stalk. The unmyelinated axons of the posterior pituitary contain Herring bodies, distinguishable axonal swellings housing neurosecretory granules (Yukitake et al., 1977). This chapter will focus on the principle components of these granules, the hormones OT and AVP.

2. EVOLUTION OF NEUROHYPOPHYSEAL HORMONES While OT and AVP are present in all placental mammals, related peptide analogs can be found throughout the animal kingdom. Furthermore, the precursor proteins for these hormones share an identical exon-intron organization across mammalian, fish, and invertebrate species. The existence of AVP- and OT-like neuropeptides in representatives of both Protostomia and Deuterostomia lineages has revealed a phylogenetically ancient origin for these hormones, which occurred sometime

before the split of these lineages some 640e760 million years ago (Stafflinger et al., 2008). Researchers have identified 16 nonapeptides to date in the vertebrates (Fig. 10.2), all sharing a high level of structural homology. These peptides can be categorized as members of either the basic or neutral nonapeptide family based on the amino acid at position 8. All vertebrates, with the exception of cyclostomes, have at least two of these peptides, with a minimum of one from each family. As cyclostomes possess a single nonapeptide, arginine vasotocin (AVT), AVT has been proposed to be the ancestral vertebrate nonapeptide through which all others have since been derived (Sawyer, 1977). AVT shares a ring structure with OT and a tail structure with AVP. The gene for AVT is believed to have duplicated at the base of the gnathostome lineage, resulting in two genes that formed the foundation of the basic and neutral families. The subsequent development of functionally distinct paralogs is thought to result from the occurrence of novel ligandereceptor interactions (Banerjee et al., 2017). The evolutionary history of AVP is fairly straightforward, as indicated by the presence of AVP in mammals and of AVT in cyclostomes and nonmammalian vertebrates. As AVT acts on both AVP and OT receptors, the existence of AVP in mammals can be explained as an increase in receptor selectivity (Acher, 1996). In contrast, the history of OT-like peptides is considerably more complex. This family includes OT, which is found in eutherian mammals, mesotocin, which is produced in birds, reptiles, marsupials, amphibians, and lungfishes, isotocin, which is found in bony fishes, and a variety of additional peptides within the family of cartilaginous fishes (Acher et al., 1997). OT/AVP homologs have also been identified in a number of invertebrate species (Banerjee et al., 2017). AVP-related peptides have been found in various insects, mollusks, and annelids, while OT-related peptides have also been observed in mollusks and annelids (Stafflinger et al., 2008; Oumi et al., 1994; Reich, 1992). Contrary to vertebrates, virtually all invertebrates possess a single nonapeptide, supporting the hypothesis that the presence of two nonapeptide families occurred early on in vertebrate evolution (Van Kesteren et al., 1995). However, two cephalopods, the cuttlefish and the octopus, contain two unique members of the OT/AVP superfamily, suggesting that a separate gene duplication event occurred independently for invertebrates. While AVP and OT share a similar origin, the same may not be said with certainty for their receptors. Four receptors attributed to the OT/AVP family have been reported in the mammals: three for AVP (V1aR, V1bR, and V2R) and one for OT (OTR). Nonapeptide receptors have been cloned and characterized in a variety of nonmammalian species. Two additional V2R subtypes,

2. EVOLUTION OF NEUROHYPOPHYSEAL HORMONES

Logomorphes Rodentia Primates Cetacea Artiodactyla Perissodactyla Didelphidae

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AVP AVP AVP AVP AVP,LV AVP

Placental Mammals

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Peramelidae Macropodidae Phalangeridae Dasyuridae

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Prototheria

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Aves

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Ophidia Lacertillia

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Anura

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Crossopterygii Neopterygii Cyclostomata

M I

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Marsupial Mammals

AT,H1,H2 Amphibia AVT AVT

Bony Fish

AVT

Cyclostomes

FIGURE 10.2 The evolutionary lineage of bony vertebrate nonapeptides. Diagram showing the phylogenetic relationship of different forms of arginine vasopressin (AVP) and oxytocin (OT) in vertebrates. AVP, arginine vasopressin; AVT, arginine vasotocin; H1, hydrin 1; H2, hydrin 2; LV, lysine vasopressin; I, isotocin; M, mesotocin; OT, oxytocin; PP, phenypressin; S, seritocin. Adapted from Acher, R., 1996. Molecular evolution of fish neurohypophysial hormones: neutral and selective evolutionary mechanisms. Gen. Comp. Endocrinol. 102 (2), 157e172.

named V2B, identified in teleost fishes and birds (Daza et al., 2012), and V2C, found in the sea lamprey (Mayasich and Clarke, 2016), have been reported, leading to the hypothesis that at least six receptor subtypes were present in the gnathostome ancestor. The absence of V2B in mammals and V2R (or V2A) in birds indicates reciprocal losses in multiple lineages. While receptor characterization in the invertebrate has received considerably less attention to date, current findings have been illuminating with respect to the origin of AVP and OT receptors. A G proteinecoupled receptor (GPCR) for the OT/AVP-like peptide inotocin has been cloned in the red flour beetle and the parasitic wasp Nasonia vitripennis (Stafflinger et al., 2008). This receptor is structurally similar to the insect adipokinetic hormone, crustacean cardioprotective, and corazonin receptors, suggesting a common origin. An overlap of hormonal systems resulting from gene duplications and subsequent mutations of GPCRs and their associated ligands may have led to the abandonment of OT/AVP-like hormonal systems in certain insect species. This hypothesis would explain the limited expression of these peptides in holometabolous insects (Stafflinger et al., 2008). In addition to conservation of hormone structure across species, conservation of function has also been described for OT- and AVP-like peptides. AVP and AVT are both antidiuretic hormones, with a

demonstrated role in osmoregulation identified in mammals, nonmammalian tetrapods, birds, amphibians, reptiles, and fishes (Acher, 1996; Balment et al., 2006). AVP and AVT are also implicated in male sexual behavior in species ranging from birds (Jurkevich et al., 1996) to mollusks (Van Kesteren et al., 1995). OT and OT-like peptides show a more diverse range of functions; while they are primarily associated with reproduction (Parry et al., 1996), they also appear to mediate smooth muscle contractions in processes including gut contractility (Oumi et al., 1994) and contribute to osmoregulation in the amphibian (Akhundova et al., 1996) and in annelids (Oumi et al., 1994). Finally, the functional similarities across phyla are further supported by similarities in the location of peptide synthesis and of associated receptors. The synthesis of nonapeptides within a preoptic brain area and subsequent axonal transport into a neurohypophysis appears across vertebral species (Banerjee et al., 2017). Research in organisms including the mollusk (Van Kesteren et al., 1995), the cricket (Musiol et al., 1990), and the earthworm (Takahama et al., 1998) has found that OT- and AVP-like peptides are neurohormones produced within even the most rudimentary of nervous systems. The location of nonapeptide receptors belies their roles in reproduction and fluid homeostasis, with receptors localized in many organs involved in these processes.

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In summary, OT and AVP share a well-described, phylogenetically ancient origin. These peptides and their associated receptors are ubiquitously expressed across the animal kingdom in both chordates and nonchordates. While many insects have abandoned the usage of OT- or AVP-like hormones, the persistence of nonapeptides across animal species underscores their critical importance, particularly with regard to their roles in fluid homeostasis and reproduction.

3. THE STRUCTURE AND SYNTHESIS OF NEUROHYPOPHYSEAL HORMONES In addition to their conserved evolutionary history, the neuropeptides OT and AVP share many similarities in peptide and gene structure, mechanisms of synthesis, and even the location of the neurons that produce these hormones. Nonetheless, critical differences in the structure of the two ligands and their selective interactions with receptors and coupling to second messenger pathways allow cellular and system specificity when considering the diverse array of functions controlled by OT and AVP.

(A)

3.1 Peptide Structure In mammals, the structure of mature AVP and OT is very similar, in that both are nonapeptides containing two cysteine residues in the 1 and 6 positions. The cysteine residues form a disulfide bridge resulting in a cyclic core of six amino acids with a flexible amidated tail consisting of the remaining amino acids (amino acids 7e9). The two peptides differ in their amino acid identity at the 3 and 8 positions, resulting in a molecular weight of 1007 for OT and 1084 for AVP (see Fig. 10.3A). A difference in polarity at amino acid 8, where OTrelated peptides contain a neutral residue and AVP peptides have a basic amino acid, confers selectivity for the molecule’s interaction with its receptor. However, because of their common structure, both can bind and act on multiple members of the receptor family (see below). The disulfide bond does not appear to be implicated in binding to the OTR, although reductions in the ring size through disulfide engineering can abolish OTR activity (Muttenthaler et al., 2010), and improved stability and selectivity can be achieved by substituting dibromo-xylene analogs (Beard et al., 2018). Differences in the amino acid sequence of OT and AVP in various species have been discussed in the previous section.

Oxytocin

Vasopressin Gly

Gly

Gln

Gln Asn

Ile

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Leu

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Composite Hormone Response Element

(C)

Exon 1

Arg

Cys

Pro

S Cys S

Exon 1

Asn

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Enhancer Elements Exon 3

Pro

S Cys S

Exon 3

Vasopressin Gene Exon 1

Exon 2

Intergenic Region

Exon 2

Signal

OT

Neurophysin II

Signal

AVP

Neurophysin I

Exon 3

Copeptin

Gly-Lys-Arg

FIGURE 10.3 Diagrammatic representation of the amino acid sequence and structure of mammalian oxytocin (OT) and arginine vasopressin (AVP) (panel A) and the overlapping structure of the OT and AVP genes (panel B) and preprohormones (panel C). The components of the OT gene are shown in blue whereas those of the AVP gene are shown in green. Panel B shows the tail-to-tail alignment of the OT and AVP genes. Panel C shows the protein product derived from the three exons. The gly-lys-arg site is used for processing and for amidation of the mature peptide. A glycosylated (shown as yellow) carboxy fragment termed copeptin is characteristic of the AVP preprohormone, but is not found in the OT preprohormone. AVP, vasopressin; OT, oxytocin.

3. THE STRUCTURE AND SYNTHESIS OF NEUROHYPOPHYSEAL HORMONES

3.2 Gene Structure Both OT and AVP are predominantly synthesized by magnocellular neurons found in the SON and PVN of the hypothalamus, although they can also be synthesized in several other brain regions, as well as in peripheral tissues. The OT and AVP genes are both located on chromosome 20 and are organized in a tail-to-tail manner, separated by a short intergenic region. The two genes are consequently transcribed in opposite directions (Fig. 10.3B) (Gainer, 2012). Both the AVP and OT genes are composed of three exons and two introns, with the first intron and second exon being extremely homologous. Both are synthesized as preprohormones with a carboxy-terminal neurophysin. The prohormone of vasopressin is glycosylated at the carboxy-terminus, which gives rise to a glycopeptide (copeptin) of little known function. The length of the intergenic region differs by species.

3.3 Synthesis of Vasopressin As discussed before, AVP molecules are found in all known vertebrates. Although almost all mammals synthesize AVP, some, such as the pig, express a lysine-vasopressin variant. Invertebrate OT- and AVPlike molecules have also been identified in arthropods, and it is believed that the OT/AVP signaling system dates back more than 600 million years, having evolved from an ancestral vasotocin molecule (Gruber, 2014). The AVP preprohormone consists of a 19 amino acid signal peptide followed by the sequence coding for mature AVP. Separating the AVP carboxy-terminus from the adjacent neurophysin II is a processing and amidation site (Gly-Lys-Arg) sequence. A 39 amino acid glycopeptide (copeptin) is found on the carboxyterminus of the gene and is separated from neurophysin II by an arginine residue (Brownstein, 1983) (Fig. 10.3C). An important enhancer region is found in the intergenic region downstream of the AVP gene, which is responsible for cell-specific expression of AVP and OT. Glucocorticoid response elements, cyclic AMP (cAMP) response elements and AP-1/2 regulatory elements are found in an upstream promoter region of the AVP gene (Hyodo, 2015). The greatest concentration of AVP is found in magnocellular neurons of the SON and PVN. Within magnocellular neurons, AVP is synthesized on ribosomes as part of the preprohormone precursor. Following cleavage of the signal sequence, the prohormone is glycosylated in the rough endoplasmic reticulum and disulfide bond formation in the AVP molecule, as well as between cysteine residues in neurophysin II. The glycosylation of proteins is thought to be an important step in the transfer of material from the rough endoplasmic

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reticulum to the Golgi complex. Further processing of the prohormone happens in the Golgi apparatus where enzymatic cleavage to AVP, neurophysin II, and copeptin occurs. This cleavage also takes place in neurosecretory vesicles as the peptides are transported to axon terminals residing in the posterior pituitary (Castel et al., 1984). A more complete description of the intracellular processing of AVP can be found in Morris et al. (1987).

3.4 Synthesis of Oxytocin Although the synthesis of OT is comparable to that of AVP, it is transcribed in the opposite direction. Similar enhancer elements exist in the intergenic region between the two genes, and a composite hormone response element is found in the promoter region upstream of the OT start site. This composite response element is comprised of many different motifs, allowing potential interactions with estrogen receptors, glucocorticoid receptors, thyroid hormone receptors, retinoic acid receptors, and orphan receptors such as COUP-TF1 (see Fig. 10.3B) (Gainer, 2012). Other regulatory regions containing an SP-1 element are also found in upstream regulatory regions (Hiroi et al., 2013). Unlike AVP, the OT preprohormone is not glycosylated (Tasso et al., 1977). After the signal peptide is cleaved off, the remaining prohormone is packaged into neurosecretory granules for transport to the posterior pituitary. Of importance, the OT prohormone does not contain copeptin, but rather a small nonglycosylated adduct is found at the carboxy-terminal end. The mature peptide, OT, and its carrier molecular, neurophysin I, are stored in axon terminals until release is elicited by neural inputs.

3.5 Distribution of Oxytocin- and VasopressinSynthesizing Neurons in the Brain OT and AVP are synthesized predominantly by two groups of magnocellular neurons found in the SON and PVN of the hypothalamus. The axons of these cells are unmyelinated and form the hypothalamohypophyseal tract that transports OT and AVP to be stored, along with their respective neurophysin, in terminals within the posterior pituitary. Magnocellular OT neurons have also been described in a series of accessory nuclei that are scattered between the PVN and SON in mammals (Knobloch and Grinevich, 2014). Magnocellular OT neurons, particularly those in the SON, provide the OT that is released into the general circulation by the posterior pituitary. Of importance, magnocellular OT neurons, particularly from the PVN, also innervate forebrain structures including the nucleus accumbens the medial (meA) and central (ceA) nuclei of the amygdala,

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bed nucleus of the stria terminalis (BNST), lateral septum (LS), and other limbic areas (Knobloch et al., 2012). These fibers are thought to account for the varied effects of OT on specific behaviors. Parvocellular OT neurons of the PVN are distinct from magnocellular neurons based on size, shape, location, and involvement in different OT-dependent circuitries. Parvocellular OT neurons have been shown to project to specific brainstem nuclei and spinal cord regions. There, OT release can regulate autonomic functions including cardiovascular, breathing, feeding behavior, and nociception (Petersson, 2002; Conde´sLara et al., 2003; Mack et al., 2007; Atasoy et al., 2012). To date, it is not known how parvocellular OT neurons interact with magnocellular OT neurons, although recent evidence suggests that this can occur through direct release of OT onto spinal cord neurons to inhibit their activity and through descending connections from PVN OT neurons to the magnocellular OT neurons of the SON to modify OT release (Eliava et al., 2016). Magnocellular neurons that synthesize AVP are also found in the PVN and SON. Although earlier studies suggested that the expression of AVP and OT occurred in a nonoverlapping fashion (Sokol and Valtin, 1967), more recent studies in the SON indicate that there is overlap in OT and AVP expression, with some cells preferentially expressing OT, others that preferentially express AVP, and a third type that express both in near equivalent amounts (Glasgow et al., 1999). In any case, it appears that SON AVP neurons extend axons to the posterior pituitary for secretion of their product to the general circulation following action potentials generated in magnocellular AVP neurons. AVP neurons are also found in many other brain areas including the BNST. These neurons exhibit a robust sex difference in their expression, where the number of AVP-expressing neurons in males is twofold greater than in females. These AVP neurons project, in a similar sexually dimorphic fashion, to behaviorally relevant brain areas such as the LS and lateral habenula (De Vries et al., 1994). In addition, the PVN also contains a group of parvocellular neurons that express AVP and secrete into the hypothalamo-hypophyseal portal blood where AVP synergizes with cosecreted corticotropin-releasing hormone (CRH) to augment the actions of CRH on adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (Pei et al., 2014). Moreover, pharmacological activation of PVN AVP neurons acutely blunts food intake, suggesting that PVN AVP can have a number of different actions aside from those occurring following secretion by the posterior pituitary gland into peripheral circulation.

4. THE OXYTOCIN/VASOPRESSIN RECEPTOR FAMILY In vertebrates, receptors for OT and AVP are placed into a subfamily of GPCRs that mediate a vast array of functions. These include the regulation of blood pressure and water balance, parturition and lactation, social behaviors, neuroendocrine stress and autonomic responses, feeding, and mood and anxiety-like behaviors. Currently, four members of this family have been identified in mammals and include the OTR that is activated by OT and the V1aR, V1bR (also known as V3), and V2R that respond to AVP (Fig. 10.4).

4.1 Oxytocin Receptor The OTR interacts with the cyclic part of OT through interactions with transmembrane domains 3, 4, and 6 (Zingg, 2002), whereas the carboxy-terminal end of the OT molecule associates with transmembrane domains 2 and 3 and the first extracellular loop connecting these domains. The OTR is predominant in uterine myometrium, epithelium, and decidua (Arrowsmith and Wray, 2014), but it has also been shown to be expressed in mammary gland, testes, adrenal gland, and in select brain areas. Like all members of the AVP receptor subfamily, it is a GPCR linked to G-alpha(q) and upon activation leads to a rise in cytosolic calcium through release from intracellular stores and from extracellular influx. The OTR is also linked to Galpha(i) that inhibits increases in cAMP. Activation of the OTR has been shown to lead to stimulation of prostaglandin F2a. It has been proposed that phospholipase A2 can act as an intermediary to activate the mitogenactivated protein kinase pathway that is coupled to prostaglandin E2 synthesis in uterine decidual cells (Viero et al., 2010). AVP is a partial agonist of the OTR, suggesting that differences in OT and AVP responses are due to differences in amplitude of the functional response (Chini et al., 1996). Evidence for OTR function can be gleaned from studies of OTR knockout mice that show aberrant behaviors, obesity, and impaired thermoregulation (Nishimori et al., 2008).

4.2 Vasopressin Receptors The original nomenclature for AVP receptors was based on the finding that AVP triggered rises in cytosolic free calcium and increases in phosphatidylinositol breakdown leading to activation of protein kinase C (PKC) in hepatic tissues, whereas AVP activated adenylate cyclase and increased cAMP within the kidney. Hence, the

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4. THE OXYTOCIN/VASOPRESSIN RECEPTOR FAMILY

V1aR

PLC

αq

PLC

OTR

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αq

αq

β γ

AVP

β γ

β γ

V2R

αs

β γ ATP

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IP3 + DAG

IP3R Ca2+

AC

AVP

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PLC

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cAMP PKC

PKA AQP2 PAQP2

H 2O PAQP2

FIGURE 10.4 Diagrammatic representation of the actions of the different members of the AVP subfamily of GPCRs. The OTR, V1aR, and V1bR are G proteinecoupled receptors linked to G-alpha(q). These receptors regulate intracellular Ca2þ levels through the IP3 receptor located on the sarcoplasmic reticulum in smooth muscle cells or the endoplasmic reticulum of pituitary corticotrophs (V1bR) and other cells such as neurons. The right panel represents a kidney tubule cell where the V2R activation regulates cAMP levels through G-alpha(s). This results in the insertion of aquaporin-2 into the apical membrane of the cell, thereby allowing water to flow into the cell and out of the kidney tubule. AC, adenylyl cyclase; AQP2, aquaporin-2; ATP, adenosine triphosphate; AVP, arginine vasopressin; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol triphosphate; OT, oxytocin; PIP2, phosphatidylinositol biphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

hepatic receptor was termed V1R, whereas the renal receptor was termed V2R (Michell et al., 1979). Subsequently, a novel receptor was identified in the anterior pituitary gland that possessed a different pharmacological profile than that of the V1 receptor and was labeled V1bR, whereas the original hepatic-like receptor was designated V1aR (Jard et al., 1986). The anterior pituitary V1bR was found exclusively in corticotrophs and additionally was shown to potentiate the actions of CRH to increase secretion of ACTH following costimulation of the CRF1 receptor (Antoni, 1993), which can occur whether the V1bR is activated by AVP (Tanoue et al., 2004) or OT (Schlosser et al., 1994). V1aR was subsequently cloned from rat liver (Morel et al., 1992) and from a human liver cDNA library (Thibonnier et al., 1994). The human and rat receptors share approximately 72% sequence identity. V1aR is a seven transmembrane GPCR coupled to G-alpha(q), whereby it increases cytosolic free calcium and the activity of PKC. It is widely distributed throughout the body (liver, smooth muscle, adrenal gland, testes, and bladder) and the brain (cortex, brainstem, hippocampus, hypothalamus, and striatum) (Ostrowski et al., 1992). OT can also bind the V1aR but with lower affinity and potency (Chini et al., 2008). V1bR was cloned from a human pituitary cDNA library (Sugimoto et al., 1994). It has been shown to be

expressed at highest levels in the anterior pituitary, and in pancreatic b-cells, but also in other areas besides the anterior pituitary (Saito et al., 1995) including the brain, heart, small intestine, lung, liver, and kidney. Similar to the V1aR subtype, V1bR is coupled to Galpha(q) to increase production of inositol triphosphate (IP3) and diacylglycerol, resulting in increases in cytosolic free calcium and PKC upon activation. V1bR has also been shown to activate adenylyl cyclase through G-alpha(s) activation, but with lower potency than that for G-alpha(q). Structural analogs of AVP have helped delineate the binding characteristics of V1bR, which differ from V1aR and V2R. The renal AVP receptor, or V2R, is predominantly expressed by the principal cells of the renal collecting duct and is responsible for the antidiuretic actions of AVP. It was originally cloned from rat kidney and human renal cDNA libraries (Lolait et al., 1992). V2R mutations are responsible for congenital diabetes insipidus, characterized by renal resistance to AVP and the failure to concentrate urine, leading to polyuria. The V2R is unique from the other members of the subfamily in that it is primarily coupled to G-alpha(s), resulting in activation of adenylyl cyclase and increases in cAMP. V2R can be secondarily coupled to G-alpha(q) which can, albeit with low potency, increase cytosolic free calcium.

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5. PHYSIOLOGIC FUNCTIONS AND BEHAVIOR 5.1 Oxytocin While OT is implicated in a diverse group of physiologic functions, it is primarily responsible for smooth muscle contraction, in regulating affiliative and reproductive behaviors, and in mediating stress responsivity via the hypothalamicepituitaryeadrenal (HPA) axis. The primary functions of OT in mammalian physiology are described below. 5.1.1 Oxytocin in Reproduction OT plays a critical role in both male and female reproduction and contributes to both sexual arousal and orgasm (Borrow and Cameron, 2012). OTRs are richly expressed in reproductive tissues. OTR activation facilitates uterine contractions during the follicular phase of the menstrual cycle and during orgasm in women, while epididymal OTRs facilitate contractions during ejaculation and contribute to the emission of semen in men. Plasma OT levels increase during sexual arousal in both men and women, with levels returning to baseline shortly after orgasm. Several reports have also suggested that intranasal OT may increase sexual arousal and sexual satisfaction. While the effects of intranasal OT treatment on sexual arousal may be limited to men (Kruger et al., 2018), intranasal OT did increase sexual contentment and the ability for healthy women to have an orgasm (Zhang et al., 2015), and male partners of women with hypoactive sexual disorder reported an increase in their partners’ sexual performance following treatment with intranasal OT (Muin et al., 2017). It is unclear whether intranasal OT influences sexual function by acting on peripheral OTRs in reproductive organs or if direct central activation of reproductive neurocircuitry occurs. OT has also been implicated in pregnancy. In the rodent, vaginocervical stimulation induces OT release, which in turn stimulates the secretion of prolactin, a hormone critical for the initiation and maintenance of pregnancy. OT may continue to regulate gestational prolactin pulses through suprachiasmatic nucleus input. Interestingly, while infusion of an OTR antagonist into the ventromedial nucleus of the hypothalamus inhibits the establishment of pregnancy in the rat (Northrop and Erskine, 2007), OT and OTR knockout mice are still capable of reproducing normally (Nishimori et al., 1996; Takayanagi et al., 2005). It is unclear whether findings from knockout models indicate that OT is not essential for the establishment and maintenance of pregnancy, or if these mutants develop compensatory mechanisms to ensure reproductive viability. Regardless, both OT and OTR knockout mice are incapable of lactation, and cross-fostering is required for offspring survival.

OT has historically been assumed to be the initiating factor of parturition; indeed, OT is named from the Greek words for “quick birth.” Elevated plasma OT and uterine OTR during parturition have been reported in all placental mammals studied to date, and synthetic OT reliably induces labor. In the rat, the concentration of OT within the posterior pituitary increases by approximately 50% during pregnancy, then decreases immediately postpartum. Cervical distention induces action potentials within the hypothalamus, resulting in a large pulse of OT coinciding with the expulsion of each pup, a phenomenon known as the Ferguson reflex. Interestingly, the hypothalamus is not the only source of OT during parturition. While transection of the neurohypophyseal stalk has prolonged labor in the mouse, women with posterior pituitary dysfunction are still capable of normal delivery. OT mRNA levels increase during parturition in the amnion, chorion, and decidua, purportedly via estrogenic mediation. The activation of OTR acts on the uterine myometrium to stimulate contractions and functions indirectly through prostaglandin formation in the decidua. The previously established view of OT as an essential component of parturition has recently been challenged by the demonstration that OT null mice retain the ability to deliver viable pups. However, infusion of OT at gestational day 15.5 affected the onset of labor in OTdeficient mice, suggesting that OT focuses the timing of labor onset (Imamura et al., 2000). OTR inhibition induces uterine quiescence in placental mammals and has been successfully used as a treatment for preterm labor, indicating that OTRs are likely essential for parturition (Blanks and Thornton, 2003). Although OT null mice are capable of delivering offspring, pups are not able to successfully suckle and die within 24 h without investigator intervention. As OT is essential for milk ejection in placental mammals, injection of OT or rescue with the rat OT gene is able to restore the milk ejection reflex in OT knockout dams in response to suckling (Young et al., 1998). During suckling, mechanoreceptors of sensory nerve terminals in the areolus send cholinergic afferents to the PVN and SON, stimulating the pulsatile secretion of OT. Interestingly, infant-related visual or auditory stimuli have a similar effect on OT secretion in lactating women. Circulating OT induces the contraction of myoepithelial cells (MECs) within the mammary gland. Milk is then expelled into the lactiferous sinuses and ducts that are shortened and widened by MEC contraction, ultimately leading to ejection of milk from the nipple (Truchet and Honvo-Houe´to, 2017). Finally, OT facilitates bonding in romantic and parentechild relationships. Extensive investigation of one of the few socially monogamous, biparental mammals, the prairie vole, has reinforced the critical role of

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OT in the formation and maintenance of pair bonding (Johnson and Young, 2015). OT is also essential for maternal behaviors in rats and mice. Far fewer studies have examined the influence of OT on human relationships. In humans, baseline levels and patterns of release of OT in plasma or saliva are associated with partner interactions and relationship survival in romantic relationships and with parentechild interactions and parental behaviors. A recent report found that lower maternal plasma OT during the perinatal period was a predictor of relationship dissolution by the time the child was a toddler (Sunahara et al., 2018). While studies investigating human bonding and peripheral levels of OT are largely correlative, they provide intriguing insight into the involvement of OT in human relationships. 5.1.2 Oxytocin in Cardiac Function OT is a cardioprotective agent with both direct and indirect effects on the cardiovascular system. It is highly active within the heart; in fact, OT content in the right atrium of the rat was reported to be comparable to levels found in the hypothalamus (Jankowski et al., 1998). The known cardiovascular actions of OT include regulating blood pressure and vasodilation, antioxidant and antiinflammatory activities, mediating cardiac glucose intake, inhibiting inotropic and chronotropic effects, and cardiomyogenesis (for review, see Gutkowska et al., 2014). OT’s effects on the cardiovascular system occur directly, as OTRs are found in both the heart and large vessels, as well as indirectly via autonomic nervous system actions. OT neurons project to brain stem autonomic regulatory centers of the cardiovascular system, and to the spinal cord, where OT acts to regulate sympathetic nerve activity (Pyner, 2009). Circulating OT binds to atrial OTRs, stimulating the secretion of atrial natriuretic peptide (ANP). In turn, ANP regulates vascular tone and electrolyte balance by inducing hypotension, natriuresis, and diuresis. OT also regulates nitric oxide (NO), an inhibitor of sympathetic nervous activity. NO augments the natriuretic effects of ANP and is implicated in several of OT’s known cardiovascular functions, including negative inotropic and chronotropic effects and regulation of cardiomyogenesis. 5.1.3 Oxytocin in Fluid Balance Plasma hypertonicity creates an osmotic gradient that draws fluid out of cells, causing an elevation in blood pressure and volume and subsequent activation of osmoreceptors. Alterations in fluid balance such as acute hypernatremia potentiate the secretion of OT into the periphery in humans and in the rodent (Steinwall et al., 1998). Research in the rodent has demonstrated that OT inhibits renin release and potentiates renal sodium excretion, ultimately restoring plasma

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sodium concentration (Bernal et al., 2015; Sjo¨quist et al., 1999). OT may also facilitate natriuresis indirectly by stimulating ANP secretion from atrial cardiomyocytes, resulting in sodium excretion through direct actions on the kidney and through indirect inhibitory effects on ACTH and corticosterone secretion (Chriguer et al., 2003). In addition to its effects on sodium excretion, OT also functions as an osmoregulator by influencing salt and water consumption in the rodent. OT’s influence on behaviors associated with fluid homeostasis is described in Section 5.6. 5.1.4 Oxytocin Neurocircuitry and Behavior To understand the means by which OT regulates mammalian behavior, it is essential to review the brain areas affected by OT. The neurocircuitry of OTmediated behaviors such as parental care and sexual behavior has been best described in the rodent; however, recent advances in neuroimaging coupled with experiments utilizing intranasal OT have highlighted parallels between humans and rodents. As discussed, OTRs are distributed throughout the brain, underscoring the wide range of functions mediated by OT. The OT system is fairly plastic, with changes reported in OTR expression and in firing patterns, cellular morphology, and afferent inputs of OT neurons following events such as pregnancy, lactation, and chronic stress. 5.1.4.1 Reproductive Behavior Studies using transgenic knockout models have shown that OT is not essential for mating but does influence sexual behaviors. Both OT knockout and OTR knockout mice are still capable of successfully reproducing (Nishimori et al., 1996; Takayanagi et al., 2005). While OT null males do not have any apparent functional or behavioral deficits during mating, sexual receptivity is decreased in females (Nishimori et al., 1996; Zimmermann-Peruzatto et al., 2017). Further support for OT’s role in rodent sexual behavior has been provided by pharmacological studies. Intracerebroventricular (ICV) injection of OT stimulates proceptive and receptive behavior in the female rat and increases erections and reduces ejaculation latency in the male rat. Conversely, ICV administration of OT antagonists inhibits female and male sexual behaviors and abolishes ejaculation. The effects of exogenous OT on female sexual behavior may be site-dependent, as infusion of OT into the lateral ventricle has been shown to inhibit sexual receptivity in the rat (Schulze and Gorzalka, 1992), while infusion into the third ventricle has been found to facilitate receptivity. In the female rodent, sexual receptivity is primarily defined by the lordosis reflex, a dorsiflexed posture generally accompanied by lateroflexion of the tail that

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permits intromission by the male during copulation. This hormone-dependent reflex is triggered by pressure applied to the female’s flanks by a mounting male or by an investigator’s hand. The female rodent’s pelvic organs contain OTR and receive OT fibers descending through the lumbosacral spinal cord. This OT-ergic regulation of pelvic organs has several copulationrelated functions, including the mediation of lubrication, pain suppression, and muscle contraction during mating. The neurocircuitry of the lordosis reflex is well characterized. Several of its neural componentsdthe PVN, the ventromedial hypothalamus (VMH), the medial preoptic area (MPOA), and the periaqueductal gray (PAG)dhave been found to be regulated by OT (for review, see Veening et al., 2015). Despite the apparent lack of effects of OT gene deletion on male copulatory behavior, OT is still a critical component of male sexual function. Sexual behavior or electrical stimulation of the glans penis or dorsal nerve of the penis activates OT neurons in the PVN and SON and increases OT release in the PVN and cerebrospinal fluid. It is thought that the activation of magnocellular OT neurons in the PVN leads to activation of nearby parvocellular OT neurons, which facilitate genital reflexes via the sacral parasympathetic neurons in the spinal cord. In addition, PVN OT neurons send collateral projections to the nucleus paragigantocellularis of the brainstem, which provides tonic inhibition of penile reflexes (Veening et al., 2015). 5.1.4.2 Parental Care Maternal behavior is impaired in mice lacking the OTR (Takayanagi et al., 2005). OTR expression in the rat increases during the peripartum period in regions associated with maternal care and maternal aggression, including the MPOA, LS, BNST, ceA, olfactory bulb (OB), and the ventral tegmental area (VTA) (Bosch and Neumann, 2012; Sabihi et al., 2014). Administration of OT to regions such as the MPOA, VTA, and OB can initiate maternal behavior in virgin females, while OTR antagonists applied to these regions inhibit maternal care in lactating dams. Research investigating maternal aggression in rodents has identified the ceA, BNST, and LS as sites through which OT mediates aggressive behaviors (Bosch and Neumann, 2012). Finally, OTR expression is believed to play an integral role in natural variations in maternal care in the rodent. Assessment of rat dams that are previously characterized as being Low or High providers of licking and grooming (LG) of offspring during the first week of life has revealed elevated OTR binding in the MPOA, BNST, LS, PVN, and ceA of High LG dams compared with Low LG females. Moreover, levels of LG received by female rodents during early life are predictive of the maternal care that

they themselves will provide their offspring in adulthood. Accordingly, OTR expression in regions associated with maternal care is programmed by the levels of LG received during early life (Bales and Perkeybile, 2012). 5.1.4.3 Social Behavior OT regulates human and rodent social behaviors, including juvenile play, social recognition, pair bonding, sociability, and aggression. ICV OT has been shown to reverse social defeat-induced social avoidance and also improve social recognition in male, but not female, rats. Furthermore, ICV administration of an OTR antagonist inhibited social recognition in both male and female mice. Research using transgenic mice has confirmed the importance of OT in social recognition, as OT and OTR knockout mice show impairments in this behavior (Dumais and Veenema, 2016). Conversely, OT administered to the LS induced juvenile play behavior in female rats but not males. While sex differences were not found in the quantity of OTimmunoreactive neurons in these regions in the rat brain (DiBenedictis et al., 2017), male rats have been found to have higher OTR binding densities in the LS, BNST, meA, and VMH, among other regions, when compared to female rats (Dumais et al., 2013). Collectively, these findings indicate that OT has sex-specific effects on the regulation of social behavior. 5.1.4.4 Stress Responsivity and Anxiety-Like Behavior OT is known to dampen stress reactivity and for associated decreases in anxiety-like behaviors. Central administration of OT decreases anxiety-like behavior in rats and mice, and OT knockout mice show more anxiety-like behavior and a greater physiologic response to stress than wildtype controls (Amico et al., 2004). OT regulates function of the HPA axis, the primary circuit for the mammalian stress response, in a site-specific manner. Acute stress stimulates the secretion of OT from both the PVN and SON (Neumann, 2007), likely via the activation of glucocorticoid receptors on or near OT neurons (Torner et al., 2017). Within the PVN, OT has been found to inhibit CRH, resulting in dampened HPA axis activity as indicated by attenuated ACTH and adrenal corticosterone release. In contrast, OT acts at the level of the pituitary to potentiate the actions of CRH (Schlosser et al., 1994), thereby increasing ACTH release. Finally, OT suppresses stress responsivity and decreases anxiety-like behavior through projections to limbic brain regions such as the meA, ceA, and LS (Neumann, 2007). 5.1.4.5 Osmoregulatory Behavior OT regulates consummatory behaviors associated with fluid homeostasis. Studies using OT knockout

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mice have reported an enhanced intake of sodium chloride solution under basal conditions or following dehydration, while central administration of OT inhibits salt intake (Amico et al., 2003). These findings suggest that OT typically suppresses salt consumption. OT administration has also been shown to enhance the consumption of water in rodents that were food deprived, fed a lowsodium diet, or administered polyethylene glycol (Bernal et al., 2015), indicating that OT selectively drives behaviors associated with the restoration of fluid homeostasis. Information about body fluid volume and electrolyte balance reaches the brain via the sensory circumventricular organs (CVOs) of the lamina terminalis, the area postrema, and the organum vasculosum of the lamina terminalis (OVLT). The OVLT has been shown to project information about changes in osmolality to OT and AVP neurons in the PVN and SON (Johnson and Gross, 1993). The dorsal raphe nucleus, the parabrachial nucleus, and the area postrema have all been implicated as regions regulating the response of OT neurons to osmotic challenge (Olszewski et al., 2010; Vivas et al., 2014). These neurons are activated in the mouse following isotonic blood volume expansion or the induction of acute hypernatremia (Ruginsk et al., 2007). In the rat, chronic salt loading increased OT mRNA and OTenhanced cyan fluorescent protein (eCFP) expression in the PVN and SON in a transgenic OT-eCFP reporter model (Katoh et al., 2010). The secretion of OT from the hypothalamus in response to osmotic stimuli has also been shown to be mediated by ANP, which colocalizes with PVN and SON OT neurons (Chriguer et al., 2003). While research has defined many of the key brain areas involved in osmoregulation, the downstream effects of OT secretion on consummatory behaviors related to the restoration of fluid balance have not been characterized. Interestingly, osmotic challenge also influences fear and anxiety behaviors, suggesting a link through OT. In the mouse, hypertonic saline injection has been shown to decrease anxiety-like behavior and stress responsivity (Smith et al., 2015). It is postulated that the murine behavioral response to hypertonia is due to an OT-mediated inhibition of CRH neurons within the PVN and the amygdala and from the axonal release of OT from PVN neurons into the BNST, thereby activating specific OT responsive populations of neurons within this brain area (Smith et al., 2015). The HPA axis also regulates the OT response to an osmotic stimulus, since pretreatment with the synthetic glucocorticoid, dexamethasone, reduces OT secretion and inhibits the activation of PVN and SON OT neurons (Ruginsk et al., 2007). This system may be dysregulated

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in patients with panic disorder and in a rat model of panic disorder, as injection of a hypertonic saline solution can increase symptoms of panic and anxietylike behavior, respectively (Jensen et al., 1991; Molosh et al., 2010). 5.1.4.6 Feeding Behavior Central OT has also been shown to mediate feeding behavior, with primarily anorexigenic actions. ICV injections of OT or OTR agonists suppress food intake in the rat, while OTR antagonists stimulate food consumption. Since only high-dose OT is capable of suppressing feeding when administered peripherally, OT’s hypophagic effects likely occur through central mechanisms. These findings are consistent with the observation that OT does not readily cross the bloodebrain barrier. The OT system is also believed to regulate homeostasis associated with feeding. OT responds to physiologic cues indicating fullness such as changes in gastric distention and alterations in plasma osmolarity (discussed in Section 5.1.4.5) resulting from food intake. OT also regulates feeding in a selective manner, as it is implicated in conditioned tasted aversion and in regulating carbohydrate consumption. Parvocellular OT neurons in the PVN have reciprocal projections to the area postrema, the nucleus of the solitary tract (NTS), and the dorsal motor nucleus of the vagus nerve, brainstem nuclei known to regulate feeding. OT has been found to facilitate the acquisition of conditioned taste aversion by activating the ceA (Olszewski et al., 2013) and suppressing sucrose intake via actions on the VTA (Mullis et al., 2013). Results from studies examining the distribution of OTR have led to hypothesized roles for OT neurotransmission in regulating food intake via reward, affect, and energy homeostasis neurocircuitry; however, the contribution of OT to feeding behavior mediated by these circuits has not been comprehensively evaluated (Olszewski et al., 2010).

5.2 Vasopressin AVP released from the posterior pituitary has two main sites of action. At the kidneys, it functions to regulate extracellular fluid volume, and on vascular smooth muscle, it causes vasoconstriction. 5.2.1 Vasopressin in Water Balance AVP maintains fluid homeostasis through its selective actions on the renal collecting duct. The AVP receptor V2R is found in the basolateral membrane of these cells and is activated upon AVP binding. Activation of V2R increases water permeability on the apical side of the

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kidney epithelial cells in the short term through increased trafficking of aquaporin-2 to the apical membrane and in the long term by increased aquaporin-2 gene expression (Fig. 10.4). Aquaporins are integral membrane proteins that play a critical role in regulating water content of cells by transferring water across the membrane. Aquaporin-2, the only aquaporin regulated by AVP, is found in the apical cell membrane of collecting ducts in the kidney. The primary function of AVP’s regulation of aquaporin-2 is to conserve the body’s water and to reduce the amount of water lost in urine. Under dehydrated conditions, reabsorption of water from the collecting duct rebalances fluid homeostasis by transporting solute-free water back into circulation, resulting in a decrease in plasma osmolarity and an increase in urine osmolarity. AVP restores homeostasis by decreasing the formation of urine, which in turn increases blood volume, arterial pressure, and cardiac output. 5.2.2 Vasopressin in Vasoregulation AVP plays a major role in blood pressure regulation through its actions as a potent vasoconstrictor. This occurs through the V1aR, which is found on vascular smooth muscle cells. Vasoconstriction is mediated by the IP3 and Rho-kinase signal transduction pathway and by the release of Ca2þ from the sarcoplasmic reticulum. AVP-mediated vasoconstriction is also dependent upon activation of PKC and L-type voltage-sensitive Ca2þ channels (Henderson and Byron, 2007). This ultimately increases arterial pressure as a result of increased systemic vascular resistance. Excess AVP can result in too much vascular constriction, which can lead to vasospasm and subarachnoid hemorrhage (Nishihashi et al., 2005). Both fluid resorption and blood vessel constriction are regulated by AVP originating from the hypothalamus and secreted by the posterior pituitary. In both cases, increased blood volume and vascular resistance cause elevations in arterial pressure. These two systems can work in tandem to maintain blood pressure and fluid balance. For example, dehydration or hemorrhage will cause a decrease in atrial pressure. In response, cardiopulmonary baroreceptors in the walls of the atrium decrease their firing rate under decreased pressure conditions. Normally, these atrial receptors project to and synapse within the NTS, causing increased ANP neurotransmission through efferent fibers that project to the SON to inhibit the release of AVP. During dehydration the baroreceptors decrease their firing rate, thereby decreasing the amount of ANP neurotransmission that usually inhibits AVP. This decrease in signaling results in increased AVP secretion until pressure returns to normal conditions.

An additional mechanism for blood pressure regulation has been identified that is specific to periods of dehydration. This mechanism utilizes hypothalamic osmoreceptors that detect the concentration of solutes in plasma. When the body is well hydrated, these osmoreceptors stay below threshold stimulation and AVP secretion is suppressed. With rising osmolarity, the osmoreceptors detect the increase and stimulate the secretion of AVP. AVP increases linearly with increasing plasma osmolarity, resulting in the retention of water. This process appears to be more sensitive than that of the baroreceptors. 5.2.3 Vasopressin Neurocircuitry and Behavior Several of the behaviors mediated by OT, including sexual behavior, social behavior, affective behavior, and parental care, have also been shown to be regulated by AVP. These hormones often assume oppositional functions and influence males and females differently. Many of the brain areas through which OT acts also contain AVP receptors and have been identified as key components of AVP behavioral neurocircuitry. AVP is involved in the processing of olfactory information from social contact, which, for the rodent, has important implications for several different types of behaviors. 5.2.3.1 Reproductive Behavior The effects of AVP on rodent reproductive behavior are particularly salient in males. Mating and matingrelated stimuli activate AVP neurons in brain areas such as the BNST and the meA of the male rat (Dass and Vyas, 2014; Ho et al., 2010), and administration of AVP reverses impairments in sexual behavior following castration. Conversely, ICV AVP has been shown to inhibit sexual behavior in the female rat (Zimmermann-Peruzatto et al., 2015). In the male prairie vole, 3 days of mating and social experience with a female will increase the number of AVP mRNA-labeled neurons in the BNST and has been shown to decrease the concentration of AVP-immunoreactive fibers in the LS. These changes were absent in female prairie voles. In the monogamous prairie vole, AVP appears to be critical for pair bonding behavior for males and, to a potentially lesser extent, females (Numan and Young, 2016). Thus, sex differences in the impact of AVP on reproductive behavior may be species- and behavior-specific. Moreover, this is consistent with the demonstration that there are profound sex differences in the number of AVP neurons in the brains of many rodents (Rood and De Vries, 2011; Wang et al., 1994; De Vries and AlShamma, 1990), with more AVP neurons in males relative to females.

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5.2.3.2 Parental Care AVP regulates both maternal and paternal care. The AVP system becomes activated during the perinatal period, with a reported increase in PVN AVP mRNA and elevated levels of AVP in the hippocampus and in plasma (Landgraf et al., 1991). AVP facilitates maternal behaviors in both rats and mice through its actions on the V1aR. Manipulation of V1aR in the MPOA has revealed an important role for these receptors in behaviors such as arched back nursing and pup retrieval that is specific to this brain area. AVP also regulates maternal aggression via V1aR in the ceA and BNST (Bosch and Neumann, 2012). While paternal behavior is not typically observed in the rodent, research conducted in the prairie vole, a species that displays biparental behavior, has provided insight into the influence of AVP on parental behavior in the male rodent. PVN and SON AVP mRNA increases in both male and female prairie voles during the postpartum period (Wang et al., 2000). Although pharmacological manipulation of V1aR in the LS has revealed that AVP acts on the LS to influence paternal behavior, the persistence of paternal care following castration, a manipulation that virtually abolishes AVP immunoreactivity within the LS, suggests that AVP signaling in this region is not essential for paternal behavior in the vole (Zimmermann-Peruzatto et al., 2015). 5.2.3.3 Social Behavior AVP and its receptors are found in many of the brain structures that comprise the social behavior neural network. The species-specific distribution of this hormone and its receptors is thought to contribute to the profound differences in social behavior between species (Albers, 2012). The formation of partner preference in both male and female prairie voles has been shown to occur through a V1aR-dependent mechanism, primarily via AVP signaling in the LS and the ventral pallidum. These two structures show differences in V1aR binding between monogamous and nonmonogamous vole species (Tickerhoof and Smith, 2017). AVP has been shown to regulate social recognition through its actions on the V1aR in the LS and OB in the rodent. AVP-mediated effects on social recognition have also been reported in the hippocampus and the meA. It has been proposed that AVP does not alter the salience of social stimuli, but instead facilitates the formation of memory, as social recognition can be affected by the administration of AVP or a V1aR antagonist after exposure to a social stimulus. AVP may be more critical for social recognition in male rodents, whereas it may only facilitate recognition in females (Gabor et al., 2012).

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AVP is also implicated in social aggression, although its effects may be mediated by prior social experience. In socially housed, unmanipulated rodents, AVP or a V1aR antagonist administered to the anterior hypothalamus (AH) facilitated and inhibited aggression, respectively. In addition, social isolation in hamsters and matinginduced pair bonding in prairie voles have been shown to increase aggressive behavior in males and concomitantly increase V1aR binding in the AH. Interestingly, voles with prior experience with aggressive interactions continued to show elevated levels of aggression following ICV administration of a V1aR antagonist (Winslow et al., 1993). Thus, activation of V1aR may not be required for the expression of aggressive behavior. A final AVP-mediated social behavior, communication, has been best described in the hamster. Flank marking is a form of scent marking through which social information, including social status, is transmitted. This behavior is mediated by V1a receptors in the MPOA/ AH (Albers, 2012), and it is also regulated by AVP signaling in extrahypothalamic regions such as the LS and the PAG (Terranova et al., 2017). While it was previously assumed that AVP regulates social behaviors solely through the V1aR, more recent research has indicated that V1bR also influence several social behaviors. V1bR knockout mice were shown to be less aggressive than wildtype controls, and to have mild deficits in social memory and in motivation to interact with social stimuli (Stevenson and Caldwell, 2012). Partial restoration of aggressive behavior has been shown following lentiviral-induced restoration of V1bR function within the hippocampus of knockout mice, suggesting that hippocampal V1bR are involved in the regulation of aggressive behavior (Pagani et al., 2015). 5.2.3.4 Stress Reactivity When considering AVP as a factor in regulating the neuroendocrine response to stressors, it is important to note that some parvocellular neurons in the PVN coexpress AVP and CRH. These neurons have axons that terminate in the external zone of the median eminence and release hormones into the hypophyseal portal vasculature. Significant evidence from rat studies have demonstrated that AVP and CRH are copackaged and coreleased by the same secretory granules and thereby work together to control the secretion of ACTH from the anterior pituitary corticotrophs (Whitnall et al., 1985). In this way, AVP has been shown to potentiate the actions of CRH through its binding to the V1bR. However, recent studies in mice indicate that the colocalization of AVP and CRH in PVN neurons could be

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much less than that reported for rats (<5%), suggesting that other mechanisms for interaction may be involved in various species (Biag et al., 2012). Nonetheless, studies have shown that AVP potentiation of CRHdriven ACTH secretion also renders corticotrophs resistant to the actions of glucocorticoids, resulting in a reduction of negative feedback (Lim et al., 2002; Antoni, 2012). This process may be mediated by the accumulation of very high levels of intracellular cAMP. The importance of central AVP neurons in the PVN for negative feedback regulation has also been explored. AVP synthesis and secretion is tightly controlled by glucocorticoids acting upon the AVP neurons in the PVN. Kova´cs et al. (2000) have demonstrated that AVP transcription is rapidly regulated following stress, where adrenalectomy advances the timing of the stress-induced rises in AVP heterologous nuclear RNA (hnRNA) (Kova´cs et al., 2000). At the level of the hypothalamus, AVP appears to reduce the stress-responsive increases in CRH activity, and correspondingly, neutralization of AVP enhances ACTH secretion. This is in contrast to the previously described potentiating actions of AVP at the level of the anterior pituitary. Importantly, it appears that parvocellular CRH/AVP neurons of the PVN are targets of rapid glucocorticoid feedback (Kova´cs et al., 2000), whereas this may not be the case for the AVP neurons projecting to the posterior pituitary. Dramatic increases in AVP expression have been reported following adrenalectomy in parvocellular but not magnocellular neurons (Kova´cs et al., 2000; Greenwood et al., 2015; Antoni, 1986), even though both contain glucocorticoid receptors (Kiss et al., 1988). Whether AVP can be directly released from the posterior pituitary in response to stress is still being debated. Increases in circulating AVP levels have not been consistently demonstrated following physical stressors such as immobilization, exposure to noxious fumes, hemorrhage, or insulin-induced hypoglycemia (Antoni, 1993). In humans, septic shock, myocardial infarction, stroke, and other severe physical stressors can increase circulating AVP levels, indicating the activation of posterior pituitary release. Recent studies argue that increases in AVP from the posterior pituitary should be accompanied by the corelease of copeptin, a more stable molecule that is easier to measure in the peripheral circulation (Urwyler et al., 2015). Correlations have been shown between serum copeptin levels and cortisol following social stress (Spanakis et al., 2016), at least in males. Nonetheless the relationship between AVP and copeptin does not always seem to be absolute and raises interesting questions regarding the processing of AVP and the involvement of the posterior pituitary in stressmediated changes in AVP (Spanakis et al., 2016; Tasevska et al., 2015).

6. DISEASE AND AGING 6.1 Neurohypophyseal Hormones and Disease Given the myriad organ systems regulated either directly or indirectly by OT and AVP, it is unsurprising that the dysregulation of secretion or aberrant function of these hormones has been implicated in a diverse range of diseases. While the efficacy of penetrance of these hormones into the central nervous system via intranasal administration remains hotly debated, it is nevertheless undeniable that both hormones show extraordinary therapeutic promise in treating disease of both central and peripheral origin. The following section will discuss some of the common disorders that are associated with changes in the peripheral or central regulation of OT and AVP.

6.2 Metabolic Disorders The OT system has a wide range of effects on feeding and metabolism. OT neurons are activated by food intake, resulting in an increase in plasma OT levels. Conversely, food restriction has been shown to decrease PVN OT mRNA levels in the rat. OT largely serves to suppress feeding behavior and inhibit obesity. Food consumption is elevated in rodents administered an OTR antagonist and in OTR-deficient mice. Similarly, patients with PradereWilli syndrome, a genetic disorder characterized by an OT neuron deficit, often show hyperphagia and obesity. It has been hypothesized that the OT’s hypophagic effects occur primarily via the potentiation of the anorexic neuropeptide cholecystokinin. However, OT directly regulates other hormones in the hypothalamicepituitaryeadipose axis, including leptin and insulin. OT has also been shown to suppress the rewarding properties of carbohydrates. OT knockout mice have an elevated preference for sucrose consumption and develop a prediabetic profile independent of food intake. In humans, OT may suppress caloric intake by activating brain regions involved in cognitive control such as the anterior cingulate cortex, supplementary motor area, and the ventrolateral prefrontal cortex (Spetter et al., 2018). Finally, as adipocytes contain OTR, OT may prevent obesity by targeting adipose tissue directly. Peripheral OT levels have been shown to be reduced in patients with obesity and type 2 diabetes. Furthermore, serum OT levels were negatively correlated with a number of metabolic disease-related markers, including glucose levels, total cholesterol, leptin, adiponectin, and body mass index (Akour et al., 2018; Qian et al., 2014). Thus, plasma OT may serve as a potential predictive or prognostic biomarker for metabolic disorders. OT may also have therapeutic potential for metabolic anomalies including glucose intolerance, insulin

6. DISEASE AND AGING

resistance, and obesity. Indeed, the intranasal administration of OT to obese patients or of OT or OT analogs in mouse models of diabetes has been shown to improve insulin sensitivity and blood lipid profiles, increase insulin secretion, and reduce body weight (Zhang et al., 2013). In response to these promising implications of OT as an appetite suppressant, investigation is currently underway to evaluate the potential benefits of intranasal OT on obesity. AVP has also been implicated in regulating metabolic function, with regulatory effects on glucose homeostasis believed to occur through all three AVP receptor subtypes. It is hypothesized that hepatic V1aR regulates insulin signaling, glucogenesis, and aldosterone secretion, while V1bR affects insulin signaling in adipose tissue and pancreatic glucagon secretion to control glucose tolerance (Nakamura et al., 2017). The involvement of V2R in glucose homeostasis is currently unknown. Dysregulation of the AVP system may play an important role in metabolic disease etiology. Elevated plasma levels of copeptin, a marker of AVP secretion, are associated with insulin resistance, hyperglycemia, increased triglyceride levels, low HDL cholesterol, obesity, metabolic syndrome, and type 2 diabetes. Strikingly, a community-based cohort study reported a 70%e100% increase in the odds of having metabolic syndrome when comparing participants with copeptin levels in the highest quartile versus the lowest quartile (Saleem et al., 2009). Preclinical models of metabolic syndrome and diabetes have demonstrated a similar pattern of AVP hypersecretion as indicated by elevated plasma AVP levels and hypertrophy of AVP neurons in the PVN and SON (Brooks et al., 1989). Treatment of obese Zucker rats, a rodent model of diabetes, with AVP has induced dose-dependent changes in metabolic function, with low-dose AVP decreasing hepatic steatosis, lipogenic gene expression, and triacylglycerol and cholesterol content, while high-dose AVP resulted in hyperinsulinemia and glucose intolerance. Administration of a V1aR antagonist decreased glucose intolerance, suggesting a potential target for pharmacotherapeutic intervention (Taveau et al., 2015). Currently, AVP is primarily being evaluated in clinical studies as a predictive and prognostic biomarker for diabetes.

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has also been reported to induce cardiomyogenesis. Research into the potential therapeutic benefits of OT in cardiovascular disease has been primarily limited to animal models. These findings suggest that exogenous OT may help regenerate cardiac tissue, limit myocardial ischemia, and decrease the extent of reperfusion injury. This hormone may also be particularly beneficial in the treatment of diabetic cardiomyopathy (Alizadeh and Mirzabeglo, 2013; Jankowski et al., 2016). AVP has also been shown to be critical for proper cardiac function by regulating blood pressure through actions directly on vascular smooth muscle cells, exerting potent vasoconstrictive effects, and on cardiac myocytes to increase cardiac contractility. AVP also indirectly influences the cardiovascular system by mediating blood volume and watereelectrolyte balance. Numerous reports have demonstrated elevated plasma AVP in patients with hypertension and with postinfarct cardiac failure. Furthermore, plasma levels of AVP or copeptin are correlated with severity and survival in heart disease, and are predictive of coronary artery disease, cardiac failure, and mortality, particularly in patients with diabetes (Enho¨rning et al., 2015; Lanfear et al., 2013). It is hypothesized that pathologic dysregulation of the interactions between AVP and the renin-angiotensin system, which serves to regulate blood pressure and volume, may contribute to hypertension and cardiovascular disease (Szczepanska-Sadowska et al., 2018). Previous efforts to utilize V2R antagonists for the treatment of patients with hyponatremia have been impeded by the resultant elevation in AVP levels and increased mortality due to worsening heart failure. Attention has since been turned to the V1aR as a target for heart disease prevention and treatment. Cardiac V1aR levels are elevated in late-stage human heart failure, and chronic blockade of V1aR in a rat model of hypertensive heart failure has ameliorated disease progression (Ikeda et al., 2015). Finally, coadministration of AVP with epinephrine has improved patient outcomes for cardiac arrest over epinephrine alone (Zhang et al., 2017). The impact of AVP on cardiac function and the encouraging results of current AVP-based interventions warrant continued investigation into AVP as a therapeutic target for cardiovascular disease.

6.4 Neurodevelopmental Disorders 6.3 Cardiovascular Disease OT has been identified as a cardiovascular hormone, with protective effects at the systemic and cellular level. The cardioprotective functions of OT include natriuresis, decreasing blood pressure, negative cardiac inotropy and chronotropy, vasodilation, antiinflammatory and antioxidant actions, and endothelial cell growth. OT

The importance of OT and AVP in the regulation of social and affiliative behavior has driven a recent surge of interest in the relationship between neuropeptides and neurodevelopmental disorders. Targeting these hormones or their receptors has led to behavioral improvements, particularly with regards to social interaction, for several disorders, including autism spectrum disorder

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(ASD), PradereWilli syndrome, Williams syndrome, and Fragile X syndrome. Currently, the primary focus of investigation into the utility of neuropeptides in neurodevelopmental disorders has been ASD. ASD is characterized by impaired social interaction and communication and restricted, repetitive behaviors (Association, 2013). A lack of consistency within current findings limits conclusions as to whether ASD is associated with abnormal levels of OT (Cochran et al., 2013). While much controversy also exists within the genetic literature, genetic variation in the receptors for OT and AVP has been definitively associated with ASD (Cataldo et al., 2018). A recent multidimensional neuropeptide biomarker analysis correctly predicted ASD disease status and symptom severity with a high degree of accuracy, with OTR and V1aR expression acting as the key determinants of group classification (Oztan et al., 2018). Thus, OTR and V1aR abnormalities may constitute an important component of ASD etiology. Presently approved pharmacological treatment for ASD has been limited to targeting behavioral symptoms of the disorder such as irritability, aggression, and selfinjury. Preliminary trials administering exogenous OT via intravenous or intranasal methods show improvement in social deficits and reductions in the occurrence of repetitive behaviors (Cochran et al., 2013), suggesting that OT or OTR may be a potential therapeutic target. Ongoing clinical trials are investigating the efficacy of intranasal OT and AVP and an oral V1aR antagonist in treating behavioral symptoms of ASD. By targeting these hormones and their receptors, the first therapeutics that address the core symptoms of ASD may be developed. Considerably less attention has been dedicated to the potential therapeutic utility of targeting AVP and OT in patients with the genetic disorders PradereWilli syndrome, Williams syndrome, and Fragile X syndrome. Evidence linking OT to each of these disorders suggests either aberrant OT activity and/or the potential for the therapeutic use of OT in treating the behavioral symptoms of these syndromes. Patients with PradereWilli syndrome reportedly have fewer PVN OT neurons and lower OT levels in cerebrospinal fluid and plasma (Johnson et al., 2016). Although one study has reported an increase in trust and a decrease in disruptive behaviors in patients with PradereWilli syndrome treated with intranasal OT (Tauber et al., 2011), another group saw no beneficial effects of intranasal OT on social behaviors (Einfeld et al., 2014). Patients with Williams syndrome, a disorder in which hypersociality and socially maladaptive behaviors are often present, have been shown to have significantly elevated OT levels in plasma. This same study also found that plasma OT levels were positively correlated with social approach behaviors and

demonstrated an abnormal response to acute stress (Dai et al., 2012). Finally, patients with Fragile X syndrome are often fearful of social interaction and demonstrate eye gaze avoidance, symptoms suggestive of deficits in OT neurotransmission. Moreover, intranasal OT administration results in increased eye contact and decreased salivary cortisol, suggesting a beneficial effect on social anxiety (Hall et al., 2012). Although AVP levels were not found to be significantly elevated in patients with Williams syndrome (Dai et al., 2012), it is unknown if any these disorders show underlying deficits in AVP activity or if targeting AVP in a manner similar to current clinical trials in ASD would result in any therapeutic benefit.

6.5 Neuropsychiatric Disorders Given the important role of OT and AVP in HPA axis regulation, it is not surprising that both hormones have been implicated in affective disorders such as generalized anxiety disorder, social anxiety disorder, major depressive disorder (MDD), and bipolar disorder. Preclinical research has reported potent effects of both AVP and OT on anxiety-like and depressive-like behavior, with frequently reported oppositional functions of these hormones on emotional regulation. In the rodent, central OT exhibits antidepressive and anxiolytic-like effects, while AVP typically increases negative affective behaviors (Neumann and Landgraf, 2012). These hormones are also implicated in the social “tend-and-befriend” response to psychological distress, which has been found to co-occur with altered PVN OT and AVP activity in a female-specific manner in the chronic variable stress model of affective disorders (Borrow et al., 2018). Synthesis of OT may be elevated in patients with depression. The number of PVN OT-immunoreactive neurons was found to be increased by 23% in postmortem tissue from patients with MDD or bipolar disorder (Purba et al., 1996). Similarly, PVN OT mRNA levels were elevated in melancholic depressive patients relative to nonmelancholic depressive patients, with a trend toward greater expression in melancholic depressive patients compared with control subjects (Meynen et al., 2007). Evaluation of plasma hormone levels has yielded conflicting results but suggests that patients with bipolar disorder may have elevated plasma OT levels, while patients with MDD may demonstrate a task-dependent dysregulation in OT release (Cochran et al., 2013). A small study in patients with treatment-resistant depression found that coadministration of intranasal OT with the antidepressant citalopram significantly reduced depressive symptoms (Scantamburlo et al., 2015). In contrast, women with postpartum depression did not

6. DISEASE AND AGING

show an improvement in mood following intranasal OT (Mah et al., 2013). Thus, intranasal OT may effectively treat symptoms of depression, but future studies in patients using larger sample sizes are needed to make definitive conclusions. In patients with anxiety disorders, plasma OT levels do not appear to differ from healthy controls. The therapeutic benefits of intranasal OT for anxiety disorders are currently unclear, as the limited number of available reports have provided conflicting evidence as to the nature of exogenous OT’s effects on anxiety. While intranasal OT has shown some benefit as an adjuvant treatment for patients with posttraumatic stress disorder when administered during exposure therapy (Flanagan et al., 2017), minimal effects were observed in patients with social anxiety disorder (Guastella et al., 2009). Interestingly, one study has reported an increase in anxiety in men with MDD treated with intranasal OT (MacDonald et al., 2013). While it is possible that these incongruous findings are the result of disorder-specific effects of exogenous OT, it is also likely that, as in the literature on depression, larger sample sizes are needed to fully understand the nature of intranasal OT’s effects on anxiety. Studies in rodents have identified largely anxiogenic, depressive effects of AVP (Neumann and Landgraf, 2012), yet a paucity of research investigating AVP in anxiety and depressive disorders has limited our understanding of AVP’s role in human affective disorders. While one study has observed a significant increase in AVP-immunoreactive neurons within the PVN of patients with MDD or bipolar disorder (Purba et al., 1996), levels of AVP in cerebrospinal fluid and of copeptin in plasma have not consistently differed between patients with depression and healthy controls. However, a positive correlation was recently reported between copeptin levels and the severity of anxiety and depression symptoms in a cohort of suicidal patients (Atescelik et al., 2017). Clinical trials with V1bR antagonists have shown a modest improvement in mood in patients with MDD, but no effect on generalized anxiety disorder (Griebel et al., 2012; Katz et al., 2017). Based on present findings, it appears that AVP may be weakly implicated in depression, but it likely does not contribute to anxiety disorder etiology. Another neuropsychological disorder, schizophrenia, is a debilitating disease characterized by positive and negative symptoms and cognitive impairments. Current medications treat the positive symptoms of this disorder such as hallucinations and delusions, but do not improve negative symptoms or cognitive deficits, both of which have been deemed the more important prognostic indicators for schizophrenia. A number of studies have reported that patients with schizophrenia may have reduced levels of plasma OT. Furthermore, an

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inverse relationship exists for plasma OT levels and symptom severity for all three categories of symptoms. Small clinical trials using intranasal OT have found this treatment to be encouragingly effective in reducing negative symptoms, metacognitive and social cognition deficits, and positive symptoms in patients with schizophrenia (Shilling and Feifel, 2016). While additional trials are needed to fully characterize the benefits of OT for patients with schizophrenia, such promising findings could indicate that intranasal OT may be an adjunctive treatment option for this disorder. Finally, neuropeptides have been implicated in drug addiction (Lee et al., 2016). Preclinical research has shown that OT and, to a lesser extent, AVP, are affected by drugs of abuse. The nature of these effects varies across drugs and is dependent upon the duration of exposure. Exogenous OT has been shown to reduce acute tolerance for drugs of abuse and, similarly, can reduce ethanol preference, while AVP has been shown to increase tolerance for ethanol. Unfortunately, the reduced tolerance observed for OT may require repeated administrations prior to exposure to cocaine or ethanol. In humans, intranasal OT has been shown to decrease ethanol withdrawal symptoms and reduce marijuana cravings in cannabis-dependent individuals. Thus, while the long-term effects of OT on addiction are unclear, intranasal OT may have some therapeutic benefits in treating symptoms of withdrawal. Recent investigation of V1bR antagonists has shown some promise in treating alcohol dependence and nicotine addiction, particularly for patients reporting high levels of stress (Ryan et al., 2017). The utility of V1bR antagonists as a treatment for alcoholism may be potentiated by coadministration with naltrexone (Zhou et al., 2018).

6.6 Neurodegenerative Disorders While OT and AVP may not be the underlying cause of neurodegenerative disorders such as Huntington disease and Parkinson disease, the pathogenesis of these disorders may have consequences for OT and AVP neurons. The therapeutic use of these hormones may also have benefits for some of the secondary symptoms of these disorders. Huntington disease is a devastating neurodegenerative disorder caused by a genetic mutation in the huntingtin gene. This disease is characterized by progressive psychiatric symptoms and cognitive and motor decline, but it commonly shows symptoms such as sleep disturbances and metabolic dysfunction. These secondary symptoms are likely the result of pathologic changes to the hypothalamus, with apparent consequences for the populations of OT- and AVPproducing neurons residing within this structure.

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Postmortem analysis has indicated a decrease in the number of OT and AVP neurons within the hypothalamus by 45% and 24%, respectively (Gabery et al., 2010). This finding has also been observed in a rodent model of Huntington disease (van Wamelen et al., 2013). A depletion of AVP-immunoreactive neurons without an alteration in AVP mRNA levels has been reported within the suprachiasmatic nucleus of the hypothalamus. As this structure serves as the body’s master regulator of circadian rhythms, dysfunctional AVP signaling within this nucleus may contribute to the disturbances in sleep and circadian rhythmicity observed in patients with Huntington disease (van Wamelen et al., 2013). Intranasal OT has been employed in one recent study to examine the effects of treatment on neural response to emotional and neutral faces. Administration of OT normalized a hypoactive neural response to faces showing disgust in Huntington disease gene carriers (Labuschagne et al., 2018). This finding suggests that OT may have some utility treating psychiatric symptoms such as apathy in Huntington disease. Targeting AVP may have additional benefit for symptoms such as sleep and circadian disturbances in this disorder. Parkinson disease is a progressive movement disorder associated with the degeneration of dopaminergic neurons. Patients with this disorder often show additional nonmotor symptoms, including neuropsychiatric symptoms, sleep disturbances, and symptoms related to autonomic dysfunction. A decrease in the number of PVN OT-immunoreactive neurons has been found in patients with this disorder (Purba et al., 1994). In a preclinical model of the nonmotor psychiatric symptoms of Parkinson disease, administration of a synthetic analog of OT decreased anxiety-like behavior and social avoidance (Mizuno et al., 2015). It is unknown what benefits, if any, would result from the administration of OT to a clinical population with Parkinson disease. Research is also very limited with regard to the role of AVP in this disorder. One study has reported that plasma AVP levels are decreased in patients with Parkinson disease (Sundquist et al., 1983), although it is unclear what the functional implications are for this decrease. While AVP has remained a largely unexplored avenue for symptomatic treatment of Parkinson disease, one potential use for AVP is treating nocturnal polyuria, a common symptom resulting from autonomic system dysfunction. A small study using desmopressin, a synthetic form of AVP, found a decrease in nocturnal voids in patients with Parkinson disease (Suchowersky et al., 1995).

6.7 Neurohypophyseal Hormones and Aging Aging can have dramatic effects on organismal function. The occurrence of senescence has been linked to changes in gene expression and the degradation of cellular function resulting from stress or prolonged replication (Weinert and Timiras, 2003). Age-associated changes in gonadal and neural function make neurohypophyseal hormones a likely target for similar alterations in activity and/or function. To date, very few studies have examined the effects of aging on the OT system in humans. However, research in the rodent, primarily conducted in the male rat, has demonstrated context-specific effects of aging on OT activity. Aging has been found to have no effect on basal hypothalamic OT levels (Melis et al., 1992), OT neuron morphology, or on the density of OT-immunoreactive fibers in the rat (Fliers et al., 1985a). However, aging does appear to decrease central OT-ergic activity, as indicated by a decrease in hippocampal and septal OT levels (Melis et al., 1992) and in the number of OTRs within the brain (Arsenijevic et al., 1995). Basal levels of OT within the posterior pituitary have been found to be increased in aged rats without basal changes in hypothalamic OT, suggesting that OT synthesis is unaffected by aging, but that the trafficking of OT is altered, with an increase in transport to the periphery (Bazhanova et al., 2000). Investigation of the OT response to acute stress has revealed an apparent decreased responsivity in aged rats (Keck et al., 2000). Interestingly, nucleolar volume, an indirect marker of peptide content, was found to be increased 3 days after acute stress in the PVN, SON, and anterior commissural nucleus of aged rats, indicating a delayed stress response in older rodents (Bazhanova et al., 2000). The effects of OT on social memory and depressive-like behavior are still preserved in aged rats following exogenous OT administration. Thus, the age-related decrease in central OT activity does not coincide with a degradation or alteration in the underlying circuitry of OT-mediated affective behavior and social memory (Arletti et al., 1995). In contrast to our understanding of basal and stressrelated OT activity in the aged rodent, research conducted in aging humans has been limited to postmortem analysis of OT neurons. Discrepant findings have reported either a decrease or no change in OT cell number in the aged human hypothalamus. In addition, no differences in the size of OT neurons have been found in aged humans relative to younger sex-matched controls (Ishunina and Swaab, 1999). Based on the

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limited amount of available data on human OT function in aging, it is difficult to conclude at present whether the robust effects of aging on OT in the rat are similarly found in humans. While the effects of aging on OT in humans are uncertain, OT may have unexpected therapeutic indications in aging adults. The regenerative capabilities of skeletal muscle and bone density are both diminished with age. Recent research has demonstrated that OT has regenerative effects on skeletal muscle (Elabd et al., 2014) and growth-promoting effects on bone (Elabd et al., 2007). Furthermore, OT may normalize body weight and the increase in intraabdominal fat adiposity associated with menopause (Beranger et al., 2014). As OT is a U.S. Food and Drug Administration approved drug, its administration may serve as a novel and safe method of preventing or treating age-related osteopenia, skeletal muscle loss, and hypoestrogenemia-associated weight gain and fat mass redistribution. AVP fiber density is decreased in a number of different brain areas in the aged male rat (Fliers et al., 1985b). Basal AVP secretion from the PVN is significantly elevated in aged rats (Keck et al., 2000), which corresponds with an elevation in AVP within the posterior pituitary (Bazhanova et al., 2000) and in plasma (Fliers and Swaab, 1983). In contrast, the intra-PVN release of AVP and the concentration of AVP within the median eminence in response to acute stress are blunted relative to younger animals (Bazhanova et al., 2000; Keck et al., 2000). One potential source for elevated basal AVP in aged animals is altered renal function. Indeed, urinary AVP concentration was found to be elevated in aged male rats, which correlated with urine volume and osmolality, which were increased and decreased, respectively, relative to younger controls (Goudsmit et al., 1988). As with OT, investigation of AVP activity in human aging has, to date, been limited. The number of AVP neurons was found to be increased in the human PVN in aged subjects (Van der Woude et al., 1995). AVP neuron size is increased in the PVN of aged women relative to young women. Finally, examination of neuronal activation via Golgi apparatus area has revealed an increase in AVP neuron activation within the SON of aged men and women (Lucassen et al., 1994). Thus, based on the currently available evidence, it appears that aging induces a global increase in human central AVP activity in parallel with reports in the rodent. Presently, there remains a need for research into the consequences of aging on OT and AVP signaling. Research in the male rat has demonstrated significant changes in both hormones, with differential effects on central versus peripheral function and on basal versus stress-related activity. Postmortem analysis of neural

tissue suggests changes within the PVN of elderly humans, with an elevation in AVP neuronal expression and an increase in neuronal size relative to younger controls. The impact of aging on human OT neurons is less understood. As gonadal hormones are altered with age and are potent regulators of OT and AVP expression, additional research that includes female subjects is required to better define the impact of senescence on neurohypophyseal hormones.

7. CONCLUSIONS AND FUTURE DIRECTIONS The myriad organ systems mediated by OT and AVP highlight the exciting therapeutic potential of these hormones in the treatment of a diverse number of human diseases ranging from cardiometabolic disorders to neuropsychiatric disorders to Huntington disease. While intranasal peptide administration has shown promise in reversing some of these pathologies in preliminary studies, it is likely that the future development of compounds that can more readily pass through the bloodebrain barrier will unlock promising new treatment options with substantial clinical benefit. In addition, plasma levels of OT and AVP or copeptin may function as valuable predictive and prognostic biomarkers for several diseases. Current limitations in evaluating plasma levels of these hormones have impeded progress in our understanding of the involvement of OT and AVP in human disease. Nonetheless, the future development of accessible, cost-effective methods for analysis of such biomarkers in plasma is vital for furthering our understanding of their function in disease.

Acknowledgments The authors thank Dr. Coni Stacher Hoerndli for her expert help with the illustrations. Research support for the authors’ lab comes from NIH R01 DK105826.

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