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T R Insel

Publications and source records attributed to T R Insel.

At least 55 records · Page 3Linked to original sources
PubMed1997

Molecular aspects of monogamy.

Comparative studies of monogamous and nonmonogamous voles demonstrate species differences in the regional expression of oxytocin (OT) receptors in the brain. These species differences have not been observed with other neurotransmitter receptors (except vasopressin). Species differences for OT receptor distribution were also observed in other microtine and murine species selected as monogamous or promiscuous. These chemical neuroanatomic differences appear to be functionally relevant, as treatments with selective OT agonists and antagonists influence those behaviors that appear critical to pair bonding in the monogamous prairie vole. To investigate the mechanism controlling tissue-specific expression of OT receptors, we sequenced the OT receptor gene in both prairie voles and montane voles. The findings are inconclusive. Although both species differ markedly from rat and human in their regulatory (but not their coding) sequences, the species show very subtle differences from each other. Ongoing studies are investigating the consequences of these subtle differences between prairie and montane voles. At the same time, several transactivating factors that might influence OT receptor expression need to be explored. NOTE ADDED IN PROOF: The rat oxytocin receptor gene sequence, cited in FIGURES 4 and 5, was based on an error published in ref. 22. The corrected sequence has now been published (Rosen et al. 1996. Proc. Natl. Acad. Sci USA 93: 12501). The correct sequence shows greater homology with the vole oxytocin receptor gene sequences, but the remaining differences support the argument made herein for species differences in regional receptor expression.

Animals↗
PubMed1997

Vasopressin and oxytocin immunoreactive neurons and fibers in the forebrain of male and female common marmosets (Callithrix jacchus).

Vasopressin (AVP) and oxytocin (OT) immunoreactive (ir) neurons and fibers were examined in the forebrain of male and female common marmosets (Callithrix jacchus). As expected from previous studies of cell distribution in the rodent and primate brain, AVP-ir cells were most evident in the paraventricularis, supraopticus, and suprachiasmaticus of the hypothalamus. AVP-ir cells were also widely distributed in the lateral hypothalamus and the bed nucleus of the stria terminalis. A sexually dimorphic pattern of AVP-ir cells was found in the bed nucleus of the stria terminalis, in which males had more AVP-ir cells than females. OT-ir cells were found in the paraventricularis and supraopticus of the hypothalamus as well as in the bed nucleus of the stria terminalis and the medial amygdala. Male and female marmosets did not differ in the distribution of OT-ir cells. Fibers for both AVP and OT were evident outside of the hypothalamic-neurohypophyseal tract, but a plexus of AVP-ir fibers in the lateral septum or lateral habenular nucleus, as seen in the rat brain, could not be detected for either peptide.

Animals↗
PubMed1997

Gene targeting approaches to neuroendocrinology: oxytocin, maternal behavior, and affiliation.

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.

Animals↗
PubMed1997

Species differences in V1a receptor gene expression in monogamous and nonmonogamous voles: behavioral consequences.

Arginine vasopressin modulates a number of species-typical social behaviors, including social memory in rats, scent marking and aggressive behavior in hamsters, and partner preference formation and paternal behavior in monogamous rodents. The distribution of V1a receptor binding sites in the brain varies greatly among species. Using in situ hybridization in 2 species of voles with strikingly different patterns of V1a binding sites and social behaviors, the authors demonstrate that differences in V1a receptor binding sites are due to species differences in regional V1a receptor gene expression. It is then demonstrated that the differences in receptor gene expression are associated with species differences in behavioral response to centrally administered vasopressin. Together, these data suggest that the phylogenetic plasticity of central neurohypophyseal peptide receptor expression may contribute to the evolution of species-typical social behaviors.

Amino Acid Sequence↗
PubMed1997

Changes in oxytocin receptor mRNA in rat brain during pregnancy and the effects of estrogen and interleukin-6.

Changes in brain oxytocin receptor (OTR) binding sites during the course of pregnancy may influence the sudden onset of maternal behavior in female rats at parturition. In situ hybridization was used to identify changes in OTR messenger ribonucleic acid (mRNA) expression during pregnancy and parturition. Two patterns of mRNA regulation were observed. Relative to diestrus virgin control females, OTR mRNA was elevated in the lateral septum and medial preoptic area at days 13-15 of pregnancy but not on the morning of parturition. In the central nucleus of the amygdala and ventromedial nucleus of the hypothalamus (VMH), OTR mRNA was most abundant on the morning of parturition. Strong signals for OTR mRNA were detected in the bed nucleus of the stria terminalis, hypothalamic paraventricular nucleus, supraoptic nucleus and suprachiasmatic nucleus. However no group differences were detected in these areas. As estrogen and interleukin-6 have been suggested to modulate OTR gene expression and both are elevated at the time of parturition, their effects on OTR mRNA in the brain were examined. Estrogen and interleukin-6, given simultaneously, significantly elevated the concentration of OTR mRNA in the VMH, but not in the amygdala. The increase in the VMH was significantly greater than that produced by estrogen alone, and interleukin-6 alone had no effects. These results demonstrate that transcriptional regulation of OTR gene expression mediates changes in receptor density in the brain in a region specific manner during pregnancy and suggests a potential mechanism for some of these changes.

Animals↗
PubMed1997

A neurobiological basis of social attachment.

OBJECTIVE: Although an inability to form normal social attachments characterizes many forms of psychopathology, there has been little study of the neural basis of social bond formation. The primary purpose of this article is to describe a novel approach to the neurobiology of attachment. METHOD: The author reviews animal research on two closely related neuropeptides, oxytocin and vasopressin, implicated in the central mediation of attachment behaviors. These neuropeptides appear to be important for the initiation of pair bonds and parental behaviors as well as the infant's response to social separation. RESULTS: Both cellular and molecular studies have begun to reveal the mechanisms by which oxytocin and vasopressin neural pathways are regulated, leading to a preliminary understanding of how these hormones act within the brain to influence complex social behaviors. CONCLUSIONS: Although their function in the human brain has yet to be demonstrated, the available evidence suggests that oxytocin and vasopressin may prove to be important in the pathophysiology of clinical disorders, such as autism, characterized by an inability to form normal social attachments.

Animals↗
PubMed1997

Central oxytocin and reproductive behaviours.

Oxytocin is a neurohypophyseal hormone that has long been associated with uterine contraction during parturition and milk ejection during nursing. Recent studies have suggested that oxytocin is also a neurotransmitter that has central effects important for reproduction, including the initiation of parental and sexual behaviours. This review describes oxytocin pathways in the brain and examines their regulation by gonadal steroids. Brain oxytocin receptors are remarkable for their plasticity and for striking species differences in their distribution. The molecular characterization of this receptor has provided several clues to the regulation of its expression. Comparative and transgenic studies suggest that central oxytocin release may influence reproductive behaviours, but the importance of these central effects depends on the pattern of expression of the receptor--a pattern that is species-specific.

Animals↗
PubMed1996

Oxytocin is required for nursing but is not essential for parturition or reproductive behavior.

Oxytocin, a neurohypophyseal hormone, has been traditionally considered essential for mammalian reproduction. In addition to uterine contractions during labor and milk ejection during nursing, oxytocin has been implicated in anterior pituitary function, paracrine effects in the testis and ovary and the neural control of maternal and sexual behaviors. To determine the essential role(s) of oxytocin in mammalian reproductive function, mice deficient in oxytocin have been generated using embryonic stem cell technology. A deletion of exon 1 encoding the oxytocin peptide was generated in embryonic stem cells at a high frequency and was successfully transmitted in the germ line. Southern blot analysis of genomic DNA from homozygote offspring and in situ hybridization with an exonic probe 3' of the deletion failed to detect any oxytocin or neurophysin sequences, respectively, confirming that the mutation was a null mutation. Mice lacking oxytocin are both viable and fertile. Males do not have any reproductive behavioral or functional defects in the absence of oxytocin. Similarly, females lacking oxytocin have no obvious deficits in fertility or reproduction, including gestation and parturition. However, although oxytocin-deficient females demonstrate normal maternal behavior, all offspring die shortly after birth because of the dam's inability to nurse. Postpartum injections of oxytocin to the oxytocin deficient mothers restore milk ejection and rescue the offspring. Thus, despite the multiple reproductive activities that have been attributed to oxytocin, oxytocin plays an essential role only in milk ejection in the mouse.

Animals↗
PubMed1996

Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study.

The genus Microtus includes several closely related species of voles with diverse patterns of social organization. Comparative studies of these species have previously tested hypotheses related to the evolution of monogamy and affiliation. In earlier studies, monogamous voles have been reported to differ from closely related nonmonogamous voles in the neural distribution of oxytocin and vasopressin receptors. These receptors have also been implicated in the behavioral differences relevant to monogamy, as oxytocin and vasopressin influence pair-bond formation in the monogamous species. In the current study, two monogamous and two nonmonogamous vole species were compared for the distribution of oxytocin and vasopressin immunoreactivity. Contrary to our predictions, gender dimorphisms in vasopressin immunoreactivity were as evident in the monogamous as in the nonmonogamous species. Also, species differences in oxytocin and vasopressin staining were subtle relative to the profound species differences previously reported for receptor binding. These results are consistent with the hypothesis that neuroendocrine systems may evolve by changes in receptor distribution rather than by restructuring the presynaptic pathway.

Animals↗
PubMed1996

Species differences in central oxytocin receptor gene expression: comparative analysis of promoter sequences.

The distribution of oxytocin binding sites in the brain is highly variable among mammals. Using two species of microtine rodents (voles) with strikingly different patterns of oxytocin binding sites in the brain, we demonstrate that these differences are due to differences in region specific gene expression and not post-translational processing. The distribution of oxytocin receptor mRNA closely resembles the distribution of oxytocin receptor binding sites in both species. Analysis of the 5' flanking region of the oxytocin receptor gene from both species reveals few differences in potential regulatory elements which could explain the differences in gene expression. These data suggest that species differences in oxytocin receptor binding are due to species differences in: i) distant DNA sequences further upstream or downstream which may influence expression; ii) the distribution of regulatory proteins such as transcription factors in the brain or iii) epigenetic factors, such as prenatal and perinatal environment which may affect gene expression in the adult.

Amino Acid Sequence↗
PubMed1995

Mating in the monogamous male: behavioral consequences.

In monogamous mammals, males typically show selective affiliation with a single mate, high levels of paternal care, and aggression towards conspecifics to protect male and offspring. We have previously described how selective aggression and affiliation increase after mating in the male prairie vole, Microtus ochrogaster. The current studies further explored the behavioral changes that follow mating in the male of this species. The first set of experiments tested males on several behavioral measures after 24 h of either mating, social (but not sexual) exposure, or no social contact. After 24 h of mating, but not after the other two conditions, aggression and affiliation (partner preference) increased as previously reported. In addition, mated animals showed increased exploration of the open arms of a plus maze, consistent with decreased fearfulness. There were no group differences in paternal behavior (which was high in all three conditions) or analgesia (assessed by tail flick latency). To determine the minimum amount of mating necessary for the induction of aggression, males were tested in a resident-intruder paradigm after 1,6, or 24 h of mating. Although 1 h of mating was associated with a transient increase in the frequency of threats and attacks, the full spectrum of enduring aggression was observed only in the males given 24 h of mating. In a final experiment, the behavioral consequences of mating were studied in males of the closely related montane vole (Microtus montanus) which does not pair bond. Males of this nonmonogamous vole species did not show increased aggression, partner preference, or alterations in plus maze exploration following 24 h of mating. These results demonstrate the importance of prolonged mating for the induction of pair bonding in the monogamous male and they suggest that increases in aggression and affiliation are associated with decreased fearfulness in pair bonded males.

Aggression↗
PubMed1995

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

Previous studies have demonstrated that central administration of vasopressin but not oxytocin facilitates pair bonding in the monogamous male prairie vole. This study tested vasopressin and oxytocin in the formation of the female vole's preference for a particular male partner. Initial studies showed that in monogamous female prairie voles (but not in nonmonogamous congeners), mating was followed by a partner preference that endured for at least 2 weeks. Nonmating prairie vole females developed a partner preference following oxytocin infusions, but not after vasopressin or cerebrospinal fluid infusions. Females given a selective oxytocin antagonist showed normal mating behavior, yet failed to develop a partner preference. The vasopressin antagonist failed to block partner preference formation in mated females. These results suggest that oxytocin, released with mating, may be critical to formation of a partner preference in the female prairie vole; this contrasts to vasopressin, which appears to be more important for pair bonding in the male of this species.

Animals↗
PubMed1995

Increased accumulation of oxytocin messenger ribonucleic acid in the hypothalamus of the female rat: induction by long term estradiol and progesterone administration and subsequent progesterone withdrawal.

To examine a possible role for gonadal steroid hormones in the enhanced accumulation of hypothalamic oxytocin (OT) messenger RNA (mRNA) and peptide in late pregnancy, we used an established model (22) in which sequential administration of estradiol (E2) and progesterone (P) SILASTIC capsules to ovariectomized rats is followed by removal of P. Long term and sustained E2 combined with abrupt P withdrawal mimics the gonadal steroid hormone pattern of late gestation in the rat (22). Using this paradigm, we demonstrate that OT mRNA is increased in the rat hypothalamus after long term P treatment, but only in the presence of E2 and only when P capsules are removed 48 h before killing. Furthermore, we show that P replacement in primiparous rats during late pregnancy blunts the increase in OT mRNA normally observed at the end of gestation. Our results support a role for E2 priming and P withdrawal in the enhanced accumulation of OT mRNA in the hypothalamus of the female rat.

Animals↗
PubMed1995

Effect of gonadal steroids upon hypothalamic oxytocin expression.

Oxytocin (OT) has been implicated in reproductive events. Gonadal steroids, which are also essential for reproduction, may in these instances influence the expression of the OT gene. The relationship between gonadal steroids and OT expression is incompletely understood. First, although estrogen (E) induces OT expression in heterologous in vitro systems and the OT gene contains an estrogen response element, evidence for a stimulatory effect of E upon OT mRNA in vivo as in the rat hypothalamus has been lacking. Second, an enhanced and coordinated expression of OT and vasopressin (AVP), mRNA during late pregnancy and lactation is not expected. This is especially true in lactation, during which suckling selectively activates OT, not AVP, neurons. We now report that E does increase OT mRNA levels in the rat hypothalamus. Ovariectomized rats were implanted initially with E, followed by progesterone (P) 48 hrs later; both were sustained for 12 days and the P implants were removed 48 hrs prior to sacrifice. By in situ and Northern blot hybridizations, OT, but not AVP, mRNA was increased in the hypothalamus of animals receiving this regimen compared to sham treated cohorts. A similar phenomenon associated with exposure to E and P followed by P withdrawal occurs in physiologic states such as day 21 of pregnancy, day 10-12 of lactation, and with interruption of the suckling stimulus for 48 hrs. If E was not administered or if P was not withdrawn prior to sacrifice, no increase was found in OT mRNA. Our data highlight the pivotal role of P withdrawal in the induction of the hypothalamic OT gene in the E-primed rat.

Animals↗