Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation

doi:10.1006/hbeh.1997.1377

Hormones and Behavior

Volume 31, Issue 3, June 1997, Pages 221-231

https://doi.org/10.1006/hbeh.1997.1377 Get rights and content

Abstract

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.

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Maternal affiliation by infants is the first social behavior of mammalian animals. We report here that elimination of the Tph2 gene essential for serotonin synthesis in the brain reduced affiliation in mice, rats, and monkeys. Calcium imaging and c-fos immunostaining showed maternal odors activation of serotonergic neurons in the raphe nuclei (RNs) and oxytocinergic neurons in the paraventricular nucleus (PVN). Genetic elimination of oxytocin (OXT) or its receptor reduced maternal preference. OXT rescued maternal preference in mouse and monkey infants lacking serotonin. Tph2 elimination from RN serotonergic neurons innervating PVN reduced maternal preference. Reduced maternal preference after inhibiting serotonergic neurons was rescued by oxytocinergic neuronal activation. Our genetic studies reveal a role for serotonin in affiliation conserved from mice and rats to monkeys, while electrophysiological, pharmacological, chemogenetic, and optogenetic studies uncover OXT downstream of serotonin. We suggest serotonin as the master regulator upstream of neuropeptides in mammalian social behaviors.
Acute intranasal oxytocin dose enhances social preference for parents over peers in male but not female peri-adolescent California mice (Peromyscus californicus)
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Peri-adolescence is a critical developmental stage marked by profound changes in the valence of social interactions with parents and peers. We hypothesized that the oxytocin (OXT) and vasopressin (AVP) systems, known for influencing social behavior, would be involved in the maintenance and breaking of bonding behavior expressed by very early peri-adolescent males and females. In rodents, OXT is associated with mother–pup bonding and may promote social attachment to members of the natal territory. AVP, on the other hand, can act in contrasting ways to OXT and has been associated with aggression and territoriality. Specifically, we predicted that in peri-adolescent male and female juveniles of the biparental and territorial California mouse (Peromyscus californicus), a) OXT would increase the social preferences for the parents over unfamiliar age-matched peers (one male and one female), and b) AVP would break the parent-offspring bond and either increase time in the neutral chamber and/or approach to their unfamiliar and novel peers. We examined anxiety and exploratory behavior using an elevated plus maze and a novel object task as a control. Peri-adolescent mice were administered an acute intranasal (IN) treatment of 0.5 IU/kg IN AVP, 0.5 IU/kg IN OXT, or saline control; five minutes later, the behavioral tests were conducted. As predicted, we found that IN OXT enhanced social preference for parents; however, this was only in male and not female peri-adolescent mice. IN AVP did not influence social preference in either sex. These effects appear specific to social behavior and not anxiety, as neither IN OXT nor AVP influenced behavior during the elevated plus maze or novel object tasks. To our knowledge, this is the first evidence indicating that OXT may play a role in promoting peri-adolescent social preferences for parents and delaying weaning in males.
Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors
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Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.
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Oxytocin is a peptide hormone synthesized and released from the hypothalamus for regulation of maternal behaviors, social cognition, and other physiological processes. Oxytocin is part of a family of neurohypophysial nonapeptides, which are evolutionarily ancient and found in many vertebrate and invertebrate species. Oxytocin or oxytocin analogs have been shown to regulate forms of social behavior, particularly those related to reproduction and maternal care of offspring.
Classically, oxytocin supports two main functions: lactation and parturition. Oxytocin signaling in mammary glands is required for milk letdown and the milk ejection reflex, and is important for uterine contractions by acting on the myometrium (smooth muscle of the uterine walls). Oxytocin signaling occurs within the central nervous system, affecting maternal and paternal behaviors, pair bond formation, and social cognition or neural function in general.
This chapter describes the action of oxytocin within the body and brain. The first section provides a historical overview, discussing how methodological developments enabled discoveries of the structure and function of oxytocin, as well as the circuitry for oxytocin secretion and signaling. The organization of the hypothalamic oxytocin system is outlined and a number of physiological processes modulated by or requiring oxytocin are described in more detail. This includes several potentially important gender-specific differences in the mammalian oxytocin system, including those identified in humans. Some of the most important functions and gender differences of oxytocin relate to synaptic transmission and neuroplasticity involved in social cognition and maternal behavior, which to date have mainly been examined experimentally in rodents. Many aspects of oxytocin signaling remain unclear, and this chapter concludes with some speculation as to future directions for research into this important peptide system.
Investigation of an F-18 oxytocin receptor selective ligand via PET imaging
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The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague–Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus.
Mesotocin and maternal care of chicks in native Thai hens (Gallus domesticus)
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Oxytocin (OT) is known to induce and regulate maternal behaviors in mammals via the supraoptic nucleus and paraventricular nucleus (PVN), whereas the function of mesotocin (MT; the avian homolog of OT) is poorly understood in birds. To elucidate the association of MT and the regulation of maternal behaviors in birds, we studied changes in the number of MT-immunoreactive (ir) neurons in native Thai chickens using immunohistochemistry. We observed that MT-ir neurons and fibers appeared in discrete regions located close to the third ventricle from the level of the preoptic area through the anterior hypothalamus with an abundance observed in the nucleus supraopticus, pars ventralis (SOv), nucleus preopticus medialis (POM), and PVN. The number of MT-ir neurons was low in the SOv, POM, and PVN of non-laying hens, but it increased gradually when the hens entered the laying stage, and peaked in incubating and rearing hens. We compared the number of MT-ir neurons in the SOv, POM, and PVN of native Thai hens rearing chicks (R) with that of non-rearing chicks (NR). The number of MT-ir neurons was high in the R hens, but low in the NR hens in these nuclei. For the first time, these results indicate that the association between the MT neurons and the presence of chicks might, in part, play a role in the neuroendocrine reorganization to establish and maintain maternal behaviors in native Thai chickens. MTergic activity is likely related to the contribution of rearing behavior in this equatorial precocial species.

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^☆: E. KnobilJ. D. Neill, Eds.

¹: To whom correspondence should be addressed at Department of Psychiatry and Behavioral Sciences, P.O. Drawer AF, Emory University School of Medicine, Atlanta, GA 30322. Fax: (404) 727-3233. E-mail: [email protected].

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Regular ArticleGene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation☆

Abstract

Neuropeptides

Horm. Behav.

Mol. Brain Res.

Eur. J. Pharmocol.

Trends Pharmacol. Sci.

Horm. Behav.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Vasopressin and oxytocin receptors in the central nervous system

Crit. Rev. Neurobiol.

Oxytocin receptors and human parturition: A dual role for oxytocin in the initiation of labor

Science

Social organization of the prairie vole (Microtus ochrogaster

J. Mamm.

Oxytocin: A neuropeptide for affiliation—Evidence from behavioral, receptor autoradiographic, and comparative studies

Psychoneuroendocrinology

Regional changes in brain oxytocin receptor post-partum: Time-course and relationship to maternal behavior

J. Neuroendocrinol.

A gender-specific mechanism for pair bonding: Oxytocin and partner preference formation in monogamous voles

Behav. Neurosci.

Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles

Proc. Natl. Acad. Sci. USA

Gonadal steroids have paradoxical effects on brain oxytocin receptor

J. Neuroendocrinol.

Structure and comparison of the oxytocin and vasopressin genes from rat

Proc. Natl. Acad. Sci. USA

Regular Article
Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation☆