Master of Science, University of Akron, 2013, Biology

Vasopressin (AVP) is a neurohormone that plays a major role in regulating social behavior. While AVP regulates a number of social behaviors, its importance in the formation of pair bonds and paternal care in highly social species, such as the prairie vole (Microtus ochrogaster) and human beings, has become a major research focus. The majority of studies on AVP and the regulation of social behavior have concentrated on the role of the AVP V1a receptor (AVPR1a) subtype within the brain. However, recent studies have shown that the AVP V1b receptor (AVPR1b) subtype, also plays a significant role in the expression of social behavior, including social aggression, social motivation and social memory. Therefore, the goals of this thesis to isolated prairie vole AVPR1b, analyze its amino acid composition, localize expression within the brain and finally to compare these against known sequences and expression from polygynous rodents. In order to do this, AVPR1b RNA was extracted from the pituitary, to cDNA and sequenced. The amino acid sequence was deduced from the cDNA sequence. AVPR1b was localized through in situ hybrization histochemistry using a DIG-labeled mRNA probe containing prairie vole AVPR1b. The receptor was highly conserved showing a 92% similarity in cDNA sequence with mouse (Mus domesticus) and rat (Rattus norvegicus). The amino acid composition of the receptor was also highly conserved, showing mostly neutral substitutions with only one non-neutral substitution that occurred within the transmembrane portion of the G-coupled protein receptor. AVPR1b expression differed from rats and mice. While AVPR1b was observed in all the regions in which it has been reported in rats and mice including, the hippocampus (all regions), piriform cortex, PVN and dentate gyrus, AVPR1b was also expressed in previously unreported regions, including the oculomotor nucleus, pontine nucleus, substantia nigra and the dorsal raphe nucleus. AVPR1b has been reported in all these (open full item for complete abstract)

Committee: Bruce Cushing Dr. (Advisor); Amy Milsted Dr. (Committee Member); Qin Liu Dr. (Committee Member) Subjects: Behavioral Sciences; Biology; Endocrinology; Molecular Biology; Neurobiology

PHD, Kent State University, 2023, College of Arts and Sciences / Department of Biological Sciences

Oxytocin (Oxt) and vasopressin (Avp) are nine amino acid peptides that typically are conserved at amino acid positions 2, 3, 4, 5, 7, and 9, with position 3 having the greatest variability. All vertebrate species possess Oxt- and Avp-like peptides, with placental mammals expressing Oxt and Avp. Oxt and Avp are critical neuromodulators of sex-specific social behavior. Previous work has demonstrated that disruptions to the Oxt and Avp system across the lifespan result in behavioral changes. Notably, mice with lifelong disruptions display social memory deficits, communication deficits, and changes in male aggressive behavior. Previous work from our lab has demonstrated that transient disruption of the receptors for these two systems results in similar behavioral effects as those mice with lifelong system disruptions. This suggests that the Oxt and Avp systems play critical roles in the development of contextually appropriate social behavior. The embryonic development of the Oxt and Avp systems is not well understood, nor are mechanisms underlying the development and organization of the social brain. This dissertation seeks to understand the role of the Oxt and Avp systems in the organization and development of the social brain. In Chapter 2, the functionality of both the Oxt and Avp systems receptors were determined. In Chapter 3, receptor distribution was assessed across the lifespan in a mouse without Oxt receptors (Oxtr). In Chapter 4, Oxt and Avp were examined for expression and cell-type specificity during embryonic life. These findings further support of the role of Oxt and Avp underscoring the development and organization of the social brain.

Committee: Heather Caldwell (Advisor); Eric Mintz (Committee Member); Julia Huyck (Committee Member); Lee Gilman (Committee Member); Woo-Yang Kim (Committee Member) Subjects: Biology; Endocrinology; Neurobiology; Neurosciences

PHD, Kent State University, 2021, College of Arts and Sciences / Department of Biological Sciences

Oxytocin (Oxt) and vasopressin (Avp) are structurally similar neuromodulators of sex-specific social behavior across mammalian species. Due to their structural similarities, behavioral effects, and presence in the brain from embryogenesis to adulthood, examining how they alter behavioral output can shed light on commonalities between mammalian species and how social behavior is modulated across the lifespan. Previous work in multiple rodent species found that manipulations of the Oxt receptor (Oxtr) just after birth results in sex-dependent changes in neuroanatomy and behavior in adulthood; in some cases altering the Avp system. Mice with lifelong dysfunctions in their Oxt or Avp systems have similar behavioral abnormalities that vary by sex, including deficits in social memory and communication, as well as changes to male aggressive behaviors. Together, these findings suggest the Oxt and Avp systems play an important role in development, perhaps contributing to the sex-specific development of brain circuitry that is important to the neural regulation of social behavior. However, to date, much of this work has focused solely on the Oxt system, and there has been no direct connection between the actions of the developing Oxt system and adult behavior. Moreover, while these neuropeptide systems are present during embryonic development, most studies have focused on the postnatal period, and largely in only one sex — males. Work from our lab has shown that while females produce Oxt mRNA by E14.5, males do not produce Oxt mRNA until after birth despite both sexes producing the Oxtr by E16.5, suggesting the that the Oxtr's sex-dependent actions may begin at this time. This dissertation focuses on the ways in which the embryonic Oxt and Avp systems differ between males and females, and what the consequences are for the expression of social behaviors later in life. In Chapter 2, the timecourse of expression for the embryonic Avp system in males and females was determined. (open full item for complete abstract)

Committee: Heather Caldwell (Advisor); Gemma Casadesus-Smith (Committee Member); Christine Dengler-Crish (Committee Member); Helen Piontkivska (Committee Member) Subjects: Developmental Biology; Neurosciences

PHD, Kent State University, 2018, College of Arts and Sciences / Department of Biological Sciences

Maternal behavior is an evolutionary innate behavior that supports the development and growth of the offspring. Caring for the young is not only critical for the survival of the species, the quality of maternal care directly influences the offspring's developing brain and social behaviors. In most mammals, maternal behavior is associated with dramatic changes in brain neurochemistry, physiology and behavior to ensure parental responsiveness. Rodent models are useful for studying the neural underpinnings of these behavioral shifts. The onset of maternal care in rodents occurs rapidly at the time of parturition and is mediated by numerous neurotransmitter systems. The synthesis of vasopressin (Avp), endocannabinoids (eCBs), and oxytocin (Oxt) rapidly increases at the time of parturition and all three neurotransmitter systems have been found to be important for regulating maternal behaviors. This dissertation set out to study the role of Avp, eCB and Oxt systems in the neural regulation of the onset of maternal behaviors.

Committee: Heather Caldwell (Advisor); Eric Mintz (Committee Member); John Johnson (Committee Member); MaryAnn Raghanti (Committee Member); Stephen Fountain (Committee Member) Subjects: Behavioral Sciences; Neurosciences

Doctor of Philosophy, The Ohio State University, 1980, Graduate School

Committee: Not Provided (Other) Subjects: Biology

PHD, Kent State University, 2016, College of Arts and Sciences / Department of Biological Sciences

Vasopressin and its sister peptide oxytocin are established modulators of social behavior. Vasopressin influences social memory and recognition, aggression, affiliation, vocalizations and social responses to predators. However, previous work on vasopressin and social behavior has focused on captive populations or laboratory strains of rodents. This dissertation focuses on the modulation of social behavior and vocalizations by vasopressin in Richardson's ground squirrels (Urocitellus richardsonii). Specifically, we examined the role of central vasopressin on ground squirrel behavior in the field, highlighting differences between males and females. We then examined oxytocin and vasopressin receptor distribution throughout the brain. We conclude that vasopressin influences behavior, and this is further modulated by sex, season, and receptor distribution.

Committee: Heather Caldwell (Advisor); James Hare (Committee Member); Eric Mintz (Committee Member); Sean Veney (Committee Member); Stephen Fountain (Committee Member) Subjects: Biology; Neurosciences; Physiology

Master of Arts, The Ohio State University, 2009, Psychology

In animal studies the nanopeptides oxytocin (OT) and vasopressin (AVP) have been associated with social bonding. In humans, OT plasma levels appear to covary with perceptions of relationship quality. To investigate the relationships between behavioral indicators of marital quality and OT and AVP plasma levels, 37 couples were admitted for a 24-hour visit at the research center. Couples participated in a structured social support interaction task and completed self-report questionnaires of marital quality. Plasma OT and AVP were assayed using enzyme immunoassays. Positive behaviors during the marital interaction task were positively related to OT plasma levels, while both observed and self-reported negative behaviors were negatively associated with AVP plasma levels. These results provide evidence that marital quality is positively related to both OT and AVP plasma levels in humans.

Committee: Janice Kiecolt-Glaser K (Advisor); Michael Vasey (Committee Chair); Jennifer Cheavens (Committee Member) Subjects: Psychology

Bachelor of Science, Miami University, 2011, College of Arts and Sciences - Zoology

In many socially monogamous species, pair-bonded males contribute substantially to the care of their offspring. Previous studies suggest that single genes may influence paternal behavior. For example, a microsatellite polymorphism in the avpr1a gene has been shown to influence aspects of paternal behavior in male prairie voles (Microtus ochrogaster), with males with longer avpr1a microsatellites groomed pups more than did males with shorter avpr1a microsatellites under laboratory conditions. I investigated the relationship between avpr1a microsatellite length and paternal behavior in prairie voles, using males selectively bred to decouple avpr1a from other genes, and selected to possess avpr1a microsatellites substantially longer or shorter than the population average. Maximizing differences in the length of avpr1a microsatellites among males should provide a rigorous test of the hypothesis that avpr1a microsatellite length is positively associated with amount of paternal care. If avpr1a microsatellite length affects paternal behavior, males with longer microsatellites should display an increased frequency of pup grooming, spend more time in the nest with pups, and retrieve their own pup more quickly when it is removed from the nest, relative to males with shorter avpr1a microsatellites. However, our results suggest that avpr1a microsatellite length does not influence paternal behavior in prairie voles after being decoupled from other genes that might affect it.

Committee: Nancy Solomon PhD (Advisor); Linda Marchant PhD (Committee Member); Brian Keane PhD (Committee Member) Subjects: Animals; Behavioral Sciences; Biology; Zoology

PHD, Kent State University, 2012, College of Arts and Sciences / School of Biomedical Sciences

Social behavior is essential to an animal's survival and has been widely studied in a variety of species. All are regulated by the central nervous system and modulated by neuropeptides. One neuropeptide that is known to play a role in the regulation of social behavior is arginine vasopressin (Avp). Most of Avp's effects on behavior have been attributed to its action via its 1a receptor (Avpr1a). However, there is compelling evidence from knockout studies that the Avp 1b receptor (Avpr1b) also plays a significant role in the modulation of social behavior. Avpr1b knockout (-/-) mice show deficits in social behaviors, such as reduced aggression and impaired social recognition. The Avpr1b is more discretely distributed than the Avpr1a being found primarily in the CA2 region of the hippocampus by in situ hybridization. The presence of the Avpr1b within the CA2 region is of particular interest because animals with lesions to the hippocampus that include the CA2 region show social behavior deficits similar to that of Avpr1b -/- mice. This dissertation set out to study the role of the Avpr1b within the CA2 region of the hippocampus in the neural regulation of social behaviors, including aggression, social memory, and social motivation.

Committee: Heather Caldwell PhD (Advisor) Subjects: Behavioral Sciences; Endocrinology; Neurosciences

MS, Kent State University, 2011, College of Arts and Sciences / School of Biomedical Sciences

The neuropeptide arginine vasopressin (Avp) plays an important role in the regulation of variety of social behaviors such as aggression, paternal care, social memory, and social motivation. Two types of receptors mediate these central effects: the vasopressin 1a receptor (Avpr1a) and the vasopressin 1b receptor (Avpr1b). Through the use of Avpr1b knockout mice (-/-) a critical role of the Avpr1b in the regulation of social behavior has been identified. Mice that lack the Avpr1b have impaired aggression, altered social recognition and reduced social motivation. In humans, Avp has also been implicated in several neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. One of the features of some neuropsychiatric disorders, such as schizophrenia, are deficits in sensorimotor gating, i.e., the ability to filter incoming sensory, cognitive and motor information. Deficits in sensorimotor gating can be modeled in animals by administering psychotomimetics and measuring prepulse inhibition (PPI) of the acoustic startle reflex. The objective of my thesis work was to examine the role of the Avpr1b in sensorimotor gating. PPI was assessed in male and female Avpr1b -/- and Avpr1b +/+ mice after injection of the following psychotomimetics: amphetamine, apomorphine and MK-801. We found that male Avpr1b -/- mice have significantly more disrupted PPI when treated with MK-801, which is a N-methyl-D-aspartate (NMDA) receptor antagonist, as compared to Avpr1b +/+ mice; no genotypic differences were found in females. These data suggest that Avpr1b's modulation of the PPI neurocircuitry is likely via the glutamatergic system. We also found that Avpr1b -/- male mice have increased expression of NMDAR2A subunit expression in the hippocampus as compared to Avpr1b +/+ mice. It is likely that this alteration in the composition of NMDA receptors might be contributing to the PPI deficits seen in Avpr1b -/- mice following administration of a NMDA receptor an (open full item for complete abstract)

Committee: Heather Caldwell PhD (Advisor); Eric Mintz PhD (Committee Member); John Johnson PhD (Committee Member) Subjects: Neurosciences

PHD, Kent State University, 2009, College of Arts and Sciences / Department of Biological Sciences

Timing of the mammalian circadian clock, the suprachiasmatic nucleus (SCN) is regulated by photic and nonphotic entraining inputs. Photic inputs reach the SCN from the retinohypothalamic tract (RHT) utilizing glutamate as neurotransmitter, which activates the retinorecipient cells of the SCN in part by release of gastrin releasing peptide (GRP). Nonphotic inputs reach the SCN from the raphe nuclei and the intergeniculate leaflet utilizing serotonin (5-HT) and neuropeptide Y (NPY) as neurotransmitters respectively. Efferent signaling of the SCN to target areas involves arginine vasopressin (AVP). Brief (~2 day) constant light exposure (LLb), significantly enhances phase resetting responses to 5-HT1A,7 agonist 8-OH-DPAT and other nonphotic stimuli. The present study was undertaken to determine if LLb exposure can amplify phase resetting responses to endogenous 5-HT and accelerate re-entrainment responses to large magnitude phase advance shifts of the light/dark (LD) cycle. Endogenous 5-HT activity was increased by systemic administration of 5-HT precursor L-tryptophan and reuptake inhibitor fluoxetine. In hamsters exposed to LLb phase shifting responses to stimulated endogenous 5-HT were significantly enhanced compared to those under LD. LLb exposure also had significant potentiating effect on rhythm re-entrainment response to 8-OH-DPAT. Hamsters exposed to LLb and 8-OH-DPAT re-entrained faster to a 10 hour phase advance shift of the LD cycle compared to the vehicle or LD controls. Further, analysis of distinct daily rhythms of the SCN peptidergic activity and effect of serotonergic activation on them was studied. Sensitive microdialysis-radioimmunoassay procedure was used to explore the regulatory role of 5-HT on AVP and GRP release from the SCN. In hamsters housed under 14:10 LD, AVP exhibited daily fluctuations of release with levels increasing during the morning to peak around mid subjective day. This pattern persists under constant darkness confirming the circadi (open full item for complete abstract)

Committee: J. David Glass PhD (Advisor); E.M Mintz PhD (Committee Member); S.L. Veney PhD (Committee Member); M.A. Raghanti PhD (Committee Member); S.B. Fountain PhD (Committee Member) Subjects: Behaviorial Sciences; Biology; Neurology

PHD, Kent State University, 2006, School of Biomedical Sciences

Altered oxytocin cell development and function are associated with several neuropsychiatric disorders, including autism and Prader-Willi Syndrome. However, the molecular control of oxytocin cell development is poorly understood. Zebrafish have been shown to be a powerful model for identifying and analyzing regulatory genes that control brain development. The objective of this dissertation was to establish the zebrafish as a model system to study the molecular genetic control of development of isotocin, homolog of oxytocin, producing cells. The central hypothesis of this proposal is that an evolutionarily conserved regulatory gene network consisting of Sim1, Otp, Arnt2 and Pou3f2, control the development of isotocin cells in the developing zebrafish hypothalamus. The following four specific aims were accomplished: Aim 1 characterized the zebrafish hypothalamo-neurohypophysial system (HNS) during development. This aim identified and characterized isotocin and vasotocin cells in the zebrafish hypothalamus. Aim 2 identified and characterized transcriptional regulatory genes controlling zebrafish isotocin cell development. Potential zebrafish orthologs of the mammalian oxytocin cell regulatory genes Sim1, Otp, Arnt2 and Pou3f2 were identified and screened for influencing isotocin cell development. Aim 3 confirmed the requirement of sim1 and otp in isotocin cell development and evaluated the genetic interactions between these genes. This study demonstrated sim1 and otp act in parallel pathways to control differentiation of isotocin cells. Aim 4 evaluated the role of two potential, equally related, homologs of mammalian Pou3f2 in zebrafish isotocin cell development, pou47 and brn1.2. Pou47 and brn1.2 were both found to be required for isotocin cell development and do not genetically interact to specify isotocin cellular identity. Aim 5 evaluated the genetic interaction of these Pou3f2 homologs with sim1 and otp in their control of zebrafish isotocin cell development. The d (open full item for complete abstract)

Committee: Eric Glasgow (Advisor) Subjects:

Master of Science (MS), Bowling Green State University, 2007, Biological Sciences

Several studies have shown that perinatal exposure to xenobiotic mixtures such as polychlorinated biphenyls (PCBs) can cause physiological and behavioral disruption. These studies demonstrate that PCB-exposed rats are a possible model for understanding motor and social deficits in childhood developmental disorders like autism spectrum disorder (ASD). The mixture PCB 47/77 at 0 ppm, 12.5 ppm, or 25 ppm (w/w) of the diet was fed to pregnant Sprague-Dawley rats impacting offspring both indirectly and directly from GD 1 to PND 21. Motor functioning of offspring was tested at PND 14-16, 28-32, and 60-64 with measures of general motor activity and stereotypic repetitive behavior. Subsequently, t-maze learning acquisition and reversal was tested in males 25-29 days old and circulating levels of the hormone vasopressin were measured at 29 days of age by enzyme immunoassay. Numerous motoric impairments were found in PCB-exposed rats compared to controls including: 1) altered rates of activity, 2) significant delay in the formation of grooming chain syntax, 3) a longer latency in pup righting reflex, and 4) depressed ability to complete the hang and negative geotaxis tests at various stages of development. PCB-exposed rats showed a significant delay in t-maze learning aquisition and reversal in a dose dependent manner relative to controls. These consequences likely stem from neuroendocrine disruption despite no change in systemic circulating vasopressin concentration. The different results in animals given 12.5 ppm and 25 ppm PCB suggest use of this animal model to reveal a range of motoric disruption similar to the broad autistic phenotype.

Committee: Lee Meserve (Advisor) Subjects: Biology, Neuroscience

MS, University of Cincinnati, 2012, Pharmacy: Pharmaceutical Sciences

Despite the long-established presence of glutamate NMDA receptors at extrasynaptic sites (eNMDARs), their functional roles remain poorly understood. Factors influencing the concentration and time course of glutamate in the extrasynaptic space, such as the topography of the neuronal–glial microenvironment, as well as glial glutamate transporters, are expected to affect eNMDAR-mediated signalling strength. In this study, we used in vitro and in vivo electrophysiological recordings to assess the properties, functional relevance and modulation of a persistent excitatory current mediated by activation of eNMDARs in hypothalamic supraoptic nucleus (SON) neurons. We found that extracellular glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic INMDA), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin a-aminodadipic acid, enhanced tonic INMDA and neuronal activity, supporting an astrocyte regulation of tonic INMDA strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodeling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic INMDA strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic INMDA activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge.

Committee: Gary Gudelsky PhD (Committee Chair); Karen Gregerson PhD (Committee Member); David Richards PhD (Committee Member) Subjects: Pharmaceuticals