Prolactin, central nervous system and behavior: a critical review.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D W Pfaff
Publications and source records attributed to D W Pfaff.
Infusion of antisense oligodeoxynucleotides to the oxytocin receptor in the ventromedial hypothalamus reduces estrogen-induced sexual receptivity and oxytocin receptor binding in the female rat.
Exogenous administration of the neuropeptide oxytocin reliably facilitates sexual behavior in the female rat and exposure to estrogen increases oxytocin receptor (OTR) binding in the ventromedial nucleus (VMN) of the hypothalamus. We have used a novel approach to investigate the role of hypothalamic OTR in controlling behavior by infusing antisense oligodeoxynucleotides (oligo) to the 5'-region of the human OTR mRNA into the VMN of hormonally primed rats. Control infusions consisted of a scrambled-sequence oligo that had little or no homology to known mRNAs. OTR antisense oligo infusion significantly reduced lordosis frequency and intensity in females primed with estrogen. There was also a significantly greater number of rejection behaviors exhibited by antisense-oligo-infused estrogen-treated females versus controls and no evidence of decreased locomotion by either treatment. In contrast to the effects in estrogen-primed-females, when females were primed to be sexually receptive with estrogen plus progesterone, OTR antisense-oligo infusion had no effect on sexual behavior. The lack of effectiveness of OTR antisense oligo in females primed with progesterone may be the result of the action of this steroid on other neurotransmitter systems that also facilitate lordosis and thereby override a deficit in oxytocin binding. Alternatively, via previously described mechanisms, progesterone may enhance the effectiveness of oxytocin binding at its receptor. In vitro receptor autoradiography in estrogen-primed females indicated a 31% reduction in VMN OTR binding in the vicinity of the cannula tip in antisense-oligo-infused females compared to controls. There was no significant difference in the level of OTR binding in the central nucleus of the amygdala.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Sexual stimulation induces Fos immunoreactivity within GnRH neurons of the female rat preoptic area: interaction with steroid hormones.
We have shown previously that sexual stimulation (copulation with intromission or vaginocervical stimulation) induces c-fos mRNA and Fos-like immunoreactivity (IR) within estrogen-concentrating and nonconcentrating regions of the female rat forebrain, including regions that contain gonadotropin-releasing hormone (GnRH) neurons in septum and anterior preoptic area. The overall induction of Fos-like IR within these regions was specific to afferent sensory stimulation and did not require treatment with estrogen and progesterone. Because vaginocervical stimulation facilitates lordosis and increases the release of luteinizing hormone, the present study examined whether hormone treatment that promotes sexual receptivity, with or without sexual stimulation, increases Fos-like IR specifically within GnRH-containing neurons. Sexually experienced ovariectomized rats were administered estradiol benzoate (10 micrograms) 48 h and progesterone (500 micrograms) 4 h before either 1 h of paced copulation with a sexually vigorous male, 50 vaginocervical stimulations with a glass rod distributed over 1 h, or no stimulation. Control rats received injections of the oil vehicle. Fos-like IR was found within a significant number of GnRH-positive neurons in the anterior preoptic area caudal to the organum vasculosum following copulation with intromission or vaginocervical stimulation as compared with no stimulation. Although few GnRH cells coexpressed Fos following hormone treatment alone, this treatment enhanced the number of GnRH neurons that coexpressed Fos following vaginocervical stimulation as compared with the effect of vaginocervical stimulation in oil-treated rats. Together, these data indicate that estrogen and progesterone can augment the responsiveness of certain GnRH neurons to vaginocervical stimulation, consistent with the effects of sexual activity on GnRH release.
Animals↗
Inflammatory effects of gene transfer into the CNS with defective HSV-1 vectors.
The use of viral vectors which infect and express genes in post-mitotic neurons is a potential strategy for the treatment of disorders affecting the central nervous system (CNS). However, the inflammatory consequences of such strategies have yet to be systematically examined. Preparations of non-replicating defective herpes simplex virus type 1 (HSV-1) amplicon vectors containing the lacZ gene were obtained by standard methods and stereotaxically injected into the adult rat dentate gyrus (DG). The consequent gene expression and inflammatory effects following microinjection were investigated. beta-Galactosidase activity was detected in neurons of the DG from 24 h to at least 12 days after vector injection. A strong inflammatory response developed within 2 days, characterized by diffuse up-regulation of major histocompatibility complex (MHC) class I antigens and the activation of microglia. After 4 days the recruitment of MHC class II+ cells, activated T lymphocytes and macrophages was detected. These features persisted for at least 31 days. Of importance was the finding of beta-galactosidase activity in a bilateral group of neurons in the supramammillary nuclei (SMN) of the posterior hypothalamus, known to send afferent projections to the DG. The onset of inflammation at this secondary site was delayed, but its cellular characteristics resembled those found at the primary site of injection. Thus, the use of preparations of defective HSV-1 vectors for gene transfer in the CNS has immunological implications both at primary and secondary sites within the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Luteinizing hormone-releasing hormone (LHRH) and neural cell adhesion molecule (NCAM)-immunoreactivity in development of the forebrain and reproductive system.
The origin and migration of LHRH neurons (detected by immunocytochemical procedures) is preceded by a migration of NCAM-immunoreactive cells from the olfactory epithelium, and the formation of an NCAM-immunoreactive cellular aggregate between the olfactory epithelium and the developing forebrain. The central processes of the olfactory nerves grow into the lateral parts of this aggregate and the terminal and vomeronasal nerves grow into the medial parts. No nerve fibers of the main or accessory olfactory systems grow directly into the forebrain. The LHRH neurons, following the course of the terminal and vomeronasal nerves, traverse the medial edge of the NCAM-immunoreactive cellular aggregate before they enter the medial forebrain caudal to the developing olfactory bulbs. The LHRH neurons do not migrate through the olfactory bulbs. After formation of the olfactory bulbs, the cellular aggregate disappears and is replaced by the olfactory nerve layer of the olfactory bulb. The NCAM and LHRH-immunoreactive cells on the medial side appear to the retained in the ganglion terminale of the terminal nerve. The fate of the NCAM-immunoreactive cells that formed the aggregate could not be determined by the methods used in these studies. The early-appearing NCAM-immunoreactive cells may function to separate and direct axons of the olfactory, vomeronasal and terminal nerves (and the LHRH neurons) to their respective targets in the forebrain. The development and migration of neurons from both the lateral and medial parts of the olfactory placode appears to be essential for the normal development of the forebrain and reproductive system.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of intrahypothalamic administration of antisense DNA for progesterone receptor mRNA on reproductive behavior and progesterone receptor immunoreactivity in female rat.
Since reproductive behaviors of female rats can be correlated with estrogen-induced increases in progestin binding by hypothalamic neurons, we hypothesized that specific progesterone receptor (PR) antisense DNA sequences might decrease these behaviors. Antisense oligonucleotides (15 bases), spanning the translation start site of rabbit PR mRNA, were microinjected directly among ventromedial hypothalamic neurons, and their behavioral effects were compared to control oligonucleotides composed of the same nucleotide bases in scrambled order. When applied 12 but not 24 hr after estradiol, the PR antisense treatment significantly reduced iordosis behavior, measured either as a reflex or in a mating behavior test. Notably, proceptive behaviors, which are strongly progesterone dependent, were greatly reduced in their occurrence (80% decrease). To see if PR protein was also reduced, antisense DNA was administered near the ventromedial hypothalamus on one side of the brain, while the other side received the scrambled control sequence or vehicle. The total number of PR-immunoreactive cells on the antisense side was significantly lower in the ventromedial nucleus, but not in control measurements from the medial preoptic area. Interrupting gene expression for PR, a transcription factor, in hypothalamic neurons, can have behavioral and immunocytochemical effects.
Animals↗
B-50/GAP-43 expression via a defective herpes simplex virus vector results in persistent morphological changes in non-neuronal cells.
Explore the source record for details and available documents.
Animals↗
Immunological consequences of HSV-1-mediated gene transfer into the CNS.
Defective HSV-1 viral vectors were prepared using amplicon methods. The amplicon contained the cytomegalovirus immediate-early promoter and the lacZ gene as a reporter in addition to the HSV elements required for replication and packaging in vitro. Viral vectors were stereotaxically injected into the rat dentate gyrus and the resulting expression and immune response were investigated. Beta-galactosidase activity was detected in several thousand neurons from as early as 24 hours to as late as 10 days after injection. A significant immune response to the vector inoculation developed, which was characterised by diffuse MHC class I up-regulation from 48 hours and the infiltration of MHC class II+ cells and activated T lymphocytes and macrophages from day 4. These features persisted for at least 31 days. Of particular interest was a small group of neurons in the posterior hypothalamus which were found bilaterally to express beta-galactosidase. The immune response at this distant uninjected site was delayed in onset but its features were similar to that found at the primary site of inoculation.
Animals↗
Increase in c-erbA alpha 2 mRNA in the parvocellular region of the paraventricular nucleus of the hypothalamus following thyroidectomy in the adult male rat.
To examine thyroid hormone regulation of c-erbA alpha 2 mRNA expression in the parvo-cellular region of the paraventricular nucleus of the rat hypothalamus (pPVN), quantitative in situ hybridization was performed using 3H-labeled probe complementary to c-erbA alpha 2 mRNA. Thyroidectomy induced a significant increase in the number of silver grains overlying the cytoplasm in the pPVN relative to sham-operated controls. This effect was prevented by daily injection of thyroxine. These results indicate that hypothyroidism induced an increase in cellular c-erbA alpha 2 mRNA level in the pPVN.
Animals↗
Sexual stimulation activates c-fos within estrogen-concentrating regions of the female rat forebrain.
Regions of the brain that concentrate estrogen and progesterone are thought to regulate female sexual behavior by altering gene expression and neural sensitivity to afferent stimulation. We used immunocytochemistry and in situ hybridization to examine c-fos gene expression within estrogen-concentrating regions of the forebrain following various types of sexual stimulation with or without hormone treatment. Ovariectomized rats received injections of estradiol benzoate 48 h and progesterone 4 h before testing. Control rats that had been ovariectomized at least 5 months before testing did not receive hormone treatment. Rats were then either placed into bilevel testing chambers with sexually vigorous males, received manual stimulation of the flanks, received vaginocervical stimulation with a glass rod, or were left in their home cages. Copulation with intromission and ejaculation in hormone-treated rats, or stimulation of the vaginal cervix in both hormone-treated and control rats, produced a dramatic induction of c-fos mRNA and Fos-like immunoreactivity in estrogen-concentrating regions, such as the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus, ventromedial hypothalamus, lateral habenula, and medial amygdala, in addition to regions that do not readily concentrate estrogen, such as the neocortex, thalamus, and striatum. Mechanical stimulation of the flanks produced a smaller induction of Fos in these rats, whereas hormone treatment alone had no effect. These data demonstrate that afferent sensory stimulation, but not estrogen or progesterone, regulates c-fos gene expression within different estrogen-concentrating and non-concentrating regions of the female rat forebrain.
Animals↗
Arginine vasopressin levels after daily infusions of antisense oligonucleotides into the supraoptic nucleus.
Explore the source record for details and available documents.
Animals↗
Nerve growth factor affects defense-related behaviors, but not lordosis, in ovariectomized, estrogen-treated rats.
Effects of NGF and anti-NGF on estrogen-sensitive behaviors were examined in ovariectomized, estrogen-treated rats. Intracerebroventricular (i.c.v.) administration of NGF resulted in a significant decrease in body weight. Daily treatment with low levels of estradiol resulted in a steady increase in lordosis behavior as reflected by average lordosis quotient and lordosis score. No effects of NGF or anti-NGF on lordosis behavior were detected. Estrogen treatment also resulted in a significant increase in the number of vocalizations elicited from female controls by male contact during sex behavior. NGF-treatment enhanced this effect, resulting in significantly more vocalizations elicited earlier in the course of estrogen treatment than were elicited from non-NGF-treated controls. These effects were blocked by progesterone. An increase in the number of rejections elicited by male contact during sex behavior was also observed in NGF-treated animals relative to controls. In addition, i.c.v. infusions of anti-NGF prevented the estrogen-mediated increase in elicited vocalizations, suggesting that NGF may have a physiological role in regulating this behavior. These data implicate NGF in the regulation of specific defense-related behaviors in estrogen-treated rats. Effects of NGF and anti-NGF on immunocytochemical staining for p75NGFR-, and ChAT-like immunoreactivity were also analyzed and are discussed.
Aggression↗
The oxytocin receptor: a target for steroid hormones.
Explore the source record for details and available documents.
Animals↗
Novel approaches to the study of oxytocin neurotransmission in the rat brain.
Explore the source record for details and available documents.
Animals↗
Alpha 1 adrenergic regulation of estrogen-induced increases in luteinizing hormone-releasing hormone mRNA levels and release.
Prazosin, an alpha 1 adrenergic antagonist, was used to examine the relationship between adrenergic inputs and the stimulatory effects of estrogen on LHRH mRNA and release. Bilateral cannulae were implanted just dorsal to the preoptic area (POA). Estrous cycles were monitored daily by vaginal smears. On the morning of diestrus, each rat was ovariectomized and assigned to one of three treatment groups: Control--injected with sesame oil (n = 5); Surge--injected with estradiol benzoate (EB, 10 micrograms) to produce an LH surge (n = 5); or, Surge+Prazosin--injected with EB and a prazosin-filled inner cannula was put into the POA (n = 6). Between 4-6 pm of the following day, rats were anesthetized, decapitated, trunk blood collected, and brains were stored in liquid nitrogen. In situ hybridization was performed using a 32P end-labelled 59-mer complementary to LHRH mRNA. Reduced silver grains, proportional to LHRH mRNA content, were quantified. Treatment with estrogen alone resulted in an LH surge and a 50% increase (P < 0.05) in numbers of cells expressing LHRH. This estrogen-induced increase and the LH surge were completely blocked (P < 0.01) by prazosin. Prazosin also decreased (P < 0.01) the median number of grains per cell from 81 (Surge) to 65 grains per cell (Surge+Prazosin). When the number of grains in LHRH-expressing neurons were totalled, EB increased (P < 0.05) LHRH gene expression by 53%, and local administration of prazosin completely blocked (P < 0.01) this increase.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cell-specific expression of preproenkephalin intronic heteronuclear RNA in the rat forebrain.
Using in situ hybridization with multiple probes to the rat preproenkephalin gene, we have identified a novel population of cells in the reticular thalamic nucleus and basal forebrain which express RNA derived from the preproenkephalin gene. These cells contain nuclear RNA from downstream of an alternate transcription start site in intron A of the preproenkephalin gene (Kilpatrick et al., Mol. Cell Biol., 10 (1990) 3717-3726), while in the same cells preproenkephalin exon 2 RNA is undetectable. The results suggest that in this population of cells, preproenkephalin gene transcription initiates from the intron A initiation site, and is regulated by an additional mechanism which results in the accumulation of nuclear preproenkephalin intron A-derived heteronuclear RNA. The anatomical distribution of these cells indicates that they may be involved in the control of cerebral cortical function.
Animals↗
In situ hybridization for creatine kinase-B messenger RNA in rat uterus and brain.
Creatine kinase-B (CKB) is present in both uterus and brain, and in uterus its synthesis (protein and mRNA) is regulated by estrogen. In the present study we have used in situ hybridization to detect CKB mRNA in uterus and brain, and to determine whether there is cell type specific induction of CKB by estrogen in these tissues. Tissue was taken from ovariectomized (ovx) rats that had been injected with either estrogen (17 beta-estradiol-3-benzoate and/or 17 beta-estradiol) or vehicle alone, 2, 8, 24 and 72 h previously. The brains and uteri were removed, frozen, cryostat-sectioned, and processed for in situ hybridization histochemistry. The uterine and brain sections were incubated with a tritiated DNA probe complementary to a 3' fragment of CKB mRNA, or a control sense probe to the same 3' fragment. In uterine smooth muscle cells, a 2.5- and 3.5-fold induction of CKB mRNA was observed 2 and 24 h after estrogen administration, respectively, and levels approached ovx controls at 72 h. A smaller induction (1.9-fold, 2 h) was observed in uterine epithelium, with little induction of CKB mRNA in stroma. In the brain CKB mRNA was detected in neurons, but not in clearly identified glia, and only occasionally in ependymal cells. In brain regions containing estrogen receptors there was no evidence of a significant estrogen effect on CKB mRNA levels. Some brain regions had higher neuronal expression than others (e.g. medial septum vs. preoptic area), but expression was widespread and not limited to neuroendocrine sites.
Animals↗
Catalepsy induced by muscimol infused into the hypothalamus can be sensitized and is modulated by ovarian steroids.
Muscimol (25 ng), but not saline, infused into the region of the zona incerta and lateral hypothalamus induced significant catalepsy in female rats. Daily administration of muscimol for 5 days resulted in a sensitization of the cataleptic response such that there was a significantly greater response to the same dose of muscimol beginning on Day 3 and continuing to increase up to Day 5. It was determined that the increase in catalepsy across days was not the result of conditioning after an initial exposure to muscimol. The endocrine condition of the female affected the degree of catalepsy induced by the first exposure to intrahypothalamic muscimol. Ovariectomized rats pretreated with estradiol benzoate (EB) exhibited significantly greater catalepsy than did females untreated or treated with progesterone or combined EB and progesterone. Weekly administration of muscimol also produced significant sensitization of the behavioral response, and the degree of sensitization was again affected by endocrine condition. Specifically, although females treated with EB for 2 days before muscimol infusion showed a significantly greater catalepsy after the first infusion than did ovariectomized females, they failed to show any increase in catalepsy scores across the 4 weeks of treatment. The greater catalepsy induced by muscimol infusion in EB-treated females may be related to changes in dopaminergic transmission. In contrast, females pretreated with progesterone 4 hr before muscimol infusion (with or without prior EB) exhibited highly significant increases in cataleptic response across the 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗