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M M McCarthy

Publications and source records attributed to M M McCarthy.

At least 37 records · Page 2Linked to original sources
PubMed2000

Developmental switch in the expression of GABA(A) receptor subunits alpha(1) and alpha(2) in the hypothalamus and limbic system of the rat.

The GABA(A) receptor is a pentameric ligand gated ion channel complex assembled from a family of at least 17 different subunits encoded by distinct genes. Two subunits, alpha(1) and alpha(2), exhibit age dependent expression throughout several areas of the brain. In general, the density of immunoreactive product for alpha(1) is greatest in the adult brain, while alpha(2) is highest in younger tissue. Since the developmental switch in alpha(1) and alpha(2) coincides with the end of the sensitive period for steroid-mediated sexual differentiation of the brain, we hypothesized that GABA(A) receptor subunit expression may be involved in this process. We have examined the age-dependent expression of alpha(1) and alpha(2) in discrete regions of the hypothalamus and limbic system of males and females. While we did not detect any dramatic sex differences in alpha(1) or alpha(2) immunoreactive density, each region exhibited a unique developmental profile. In the ventromedial nucleus of neonatal animals immunoreactivity is highest for alpha(1), while in the adult the signal for alpha(2) is greater; the opposite of that observed in the ventrolateral thalamus. There is no age dependent change for alpha(1) in the preoptic area, while alpha(2) shows a small, but significant increase. Immunoreactive densities for both subunits increase in the arcuate nucleus and the hippocampus, but decrease in the lateral amygdala. We conclude that these regional differences in subunit expression across development determine individual characteristics of brain areas and may play a role in establishing unique physiological responses to GABA.

Aging↗
PubMed2000

Antisense oligodeoxynucleotides as a tool in developmental neuroendocrinology.

Antisense oligodeoxynucleotides have been highly successful agents at modulating gene expression in the adult brain and widely exploited in the field of neuroendocrinology. We have also used this technique in the developing brain to explore the role of select proteins during sensitive periods of development, particularly those influenced by steroid hormones. Presented here are the technical details of using antisense oligodeoxynucleotides in the neonatal brain, as well as a review of some of our successes and failures. Our goal is to illustrate the relative ease of use of this technique in neonates and demonstrate the power such an approach offers so that other investigators will also begin to take advantage of this useful tool.

Animals↗
PubMed2000

Calbindin-D28k immunoreactivity is a marker for a subdivision of the sexually dimorphic nucleus of the preoptic area of the rat: developmental profile and gonadal steroid modulation.

Calbindin-D28k (calbindin) is a 28 kilodalton calcium binding protein which potentially plays a role in neuroprotection. We report here the normal development and gonadal steroid modulation of a sexually dimorphic group of calbindin immunoreactive cells within the sexually dimorphic nucleus of the preoptic area (SDN) which we call the calbindin-immunoreactive SDN or CALB-SDN. Beginning on PN2, a faintly immunoreactive CALB-SDN is present, however, the volume is not sexually dimorphic. On PN4, the staining of the CALB-SDN appears more robust but the volume is still not sexually dimorphic. By PN8 and extending through PN12 and PN26, the latest age analysed, the volume of the CALB-SDN is larger in males by two- to fourfold. Cresyl violet counterstain reveals a similar developmental profile of the SDN as well as clusters of darkly staining calbindin immunonegative cells which lie around the CALB-SDN. Castration of males on PN0 decreases the volume of the CALB-SDN by PN12 and administration on the day of birth and PN1 of either testosterone propionate or oestradiol benzoate, but not dihydrotestosterone propionate to females increases the volume of the CALB-SDN by PN12. By demonstrating the sexual dimorphism and gonadal steroid modulation of the CALB-SDN, we hereby establish that calbindin is a specific marker of a subdivision of the SDN and can be used as such in future studies.

Aging↗
PubMed2000

Decreasing GAD neonatally attenuates steroid-induced sexual differentiation of the rat brain.

During development, exposure to gonadal steroids results in brain sexual differentiation. Postnatally, hypothalamic gamma-aminobutyric acid (GABA) levels are almost double in males versus females. We hypothesized that increased GABA neonatally results in masculinization. Males, females, and androgenized females were infused intrahypothalamically with antisense oligonucleotides against glutamic acid decarboxylase (GAD) mRNA at birth to reduce GABA synthesis. GAD protein and GABA levels were reduced 24 hr later without obvious toxic effects, as determined by histological examination. As adults, neonatally antisense-treated, androgenized females showed reduced intromission-like behavior and lordosis quotients compared with vehicle and scrambled controls. Lordosis quotients were reduced about 50% in nonandrogenized females versus vehicle and scrambled controls. These data suggest that GABA is involved in mediating brain sex differentiation and may act in both males and females.

Adrenal Cortex Hormones↗
PubMed1999

Steroid-induced developmental plasticity in hypothalamic astrocytes: implications for synaptic patterning.

We have previously demonstrated that astrocytes in the developing arcuate nucleus of the rat hypothalamus exhibit a sexually dimorphic morphology as a result of differential exposure to gonadal steroids. Testosterone via its aromatized byproduct, estrogen, induces arcuate astrocytes to undergo differentiation during the first few days of life. These differentiated astrocytes exhibit a stellate morphology. Coincident with the steroid-induced increase in astrocyte differentiation is a reduction of dendritic spines on arcuate neurons. As a result, the arcuate nucleus of males has fewer axodendritic spine synapses than females and this dimorphism is retained throughout life. In the immediately adjacent ventromedial nucleus, neonatal astrocytes are immature and unresponsive to steroids. Neurons in this region show no change in dendritic spines in the first few days of life but do exhibit increased dendritic branching as a result of testosterone exposure. These findings illustrate the importance of distinct populations of astrocytes in restricted brain regions and their potential importance to the establishment of regionally specific synaptic patterning. Conflicting reports leave the site of steroid-mediated astrocyte responsiveness in the arcuate nucleus unresolved: Are gonadal steroids acting directly on astrocytes or are steroid-concentrating neurons mediating astrocytic responsiveness? In this review, we discuss the current understanding of astrocyte-neuron interactions and the possible mechanisms for steroid-mediated, astrocyte-directed synaptic patterning in the developing hypothalamus.

Animals↗
PubMed1999

Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner.

One of the more striking sexual dimorphisms in the adult brain is the synaptic patterning in some hypothalamic nuclei. In the arcuate nucleus (ARC) males have twice the number of axosomatic and one-half the number of axodendritic spine synapses as females. The opposite pattern is observed in the immediately adjacent ventromedial nucleus (VMN). In both cases, early exposure to testosterone dictates adult dimorphism, but the exact timing, mechanism, and site of steroid action remain unknown. Astrocytes also exhibit sexual dimorphisms, and their role in mediating neuronal morphology is becoming increasingly evident. Using Golgi-Cox impregnation to examine neuronal morphology and glial fibrillary acidic protein immunoreactivity (GFAP-IR) to characterize astrocytic morphology, we compared structural differences in dendrites and astrocytes from the ARC and VMN in postnatal day 2 rat pups from four hormonally different groups. Consistent with previous observations, testosterone exposure induced a rapid and dramatic stellation response in ARC astrocytes. Coincident with this change in astrocytic morphology was a 37% reduction in the density of dendritic spines on ARC neurons. In contrast, astrocytes in the VMN were poorly differentiated and did not respond to testosterone exposure, nor were there any changes in neuronal dendrite spine density. However, VMN neurons exposed to testosterone had almost double the number of branches compared with that in controls. These data suggest that the degree of maturation and the differentiation of hypothalamic astrocytes in vivo are correlated with the ability of neurons to sprout branches or spines in response to steroid hormones and may underlie regionally specific differences in synaptic patterning.

Animals↗
PubMed1999

Developmental sex differences in amino acid neurotransmitter levels in hypothalamic and limbic areas of rat brain.

GABA, glutamate and aspartate are the predominant amino acid neurotransmitters in the mammalian brain. We have previously reported a developmental sex difference in messenger RNA levels of glutamate decarboxylase, the rate-limiting enzyme in GABA synthesis [Davis A. M. et al. (1996) Horm. Behav. 30, 538-552]. Males were found to have significantly higher levels of messenger RNA in many steroid-concentrating regions of the hypothalamus and limbic system on day 1 of life. Therefore, in this study, we have examined levels of amino acid neurotransmitters during early postnatal development in many of the same or related brain areas. We found that levels of all three transmitters change as animals age. While both GABA and aspartate concentrations increase, glutamate levels decrease. In addition, there are sex differences in neurotransmitter levels in several areas examined, including the ventromedial and arcuate nuclei of the hypothalamus, and the CA1 region of the hippocampus. Sex differences for GABA occur only on postnatal days 1 and 5. However, sex differences in aspartate occur later in development (postnatal day 20). The CA1 region of males has a significantly greater concentration of GABA, glutamate and aspartate than females on postnatal day 1. In addition, treatment of females with testosterone propionate on the day of birth results in increased GABA levels, suggesting that these sex differences may be the result of hormone exposure during development. We hypothesize that these hormonally mediated sex differences in amino acid transmitters early in development contribute to the establishment of sexually dimorphic neuronal architecture in the adult.

Aging↗
PubMed1999

Neurotoxic effects of endocrine disruptors.

Endocrine disrupting chemicals are a newly defined category of environmental contaminants that may affect animal and human populations by interfering with normal hormone action. There is substantial concern that these agents could have a range of subtle and long-lasting effects. Because of the sensitivity of the developing central nervous system to low levels of endogenous gonadal hormones during development, the central nervous system may be a target for the action of endocrine disrupting chemicals.

Animals↗
PubMed1999

The benefits of support group participation to lung cancer survivors--an evaluation.

It has been known for some time that participation in support groups is beneficial for most cancer survivors. Despite this, and even though lung cancer causes more deaths than breast, prostate, and colorectal cancers combined, the number of support groups formed for lung cancer survivors is surprisingly very small. In an effort to understand the lack of lung cancer specific support groups, the Alliance for Lung Cancer Advocacy, Support, and Education (ALCASE) conducted a survey of the facilitators of the lung cancer support groups then known to be in existence in the United States, in addition to a follow-up focus group with the facilitators via teleconference. The results of the survey and the focus group provide a very preliminary look at the value to lung cancer survivors of participating in support groups organized specifically for them. However, much more research is required, not only with the participants of these groups, but also with lung cancer survivors who do not participate, to fully gauge the effects of support group participation on the progress of their disease and on their quality of life.

Journal Article↗
PubMed1998

Effect of estrogen withdrawal on nitric oxide synthase expression and apoptosis in the rat vagina.

OBJECTIVES: The physiology of the female sexual response and its molecular mediators remain poorly understood. Nitric oxide (NO) is synthesized in neurons and is a potent relaxor of vascular and nonvascular smooth muscle. In this study, we hypothesize that vaginal atrophy and declining sexual function during menopause may be NO dependent. Using the rat as an experimental model, we examined the expression and topologic localization of vaginal NO synthase (NOS) and the concomitant induction of apoptosis under normal and estrogen-depleted conditions. METHODS: Thirty rats were categorized into six groups on the basis of phase of the estrous cycle or estrogen status after oophorectomy. The expression and cellular localization of NOS was examined in frozen sections using specific antibodies against neuronal (N-NOS) and endothelial NOS (E-NOS). Apoptotic cells were identified in situ using the terminal transferase technique (TUNEL). Trichome staining was performed in all specimens to determine smooth muscle/collagen ratios. RESULTS: N-NOS immunoreactivity was localized to nerve fibers supplying vaginal smooth muscle, perivascular nerve plexuses, and lamina propria. E-NOS was localized to vascular endothelium and perivascular smooth muscle fibers. Both E-NOS and N-NOS expression in intact cycling animals was highest during proestrous and lowest during metestrous. After oophorectomy, levels of both N-NOS and E-NOS declined substantially compared with those of intact animals, and there was a parallel induction of apoptosis. Estrogen withdrawal also resulted in increased vaginal atrophy, intramural collagen accumulation, and perivascular wall thickening, as identified by trichome staining. Estrogen replacement resulted in a significant increase in E-NOS and N-NOS expression, as well as diminished apoptosis and vaginal atrophy. CONCLUSIONS: This cellular distribution of NOS in the rat vagina suggests that NO may modulate both vaginal blood supply and vaginal smooth musculature. Estrogen appears to play a critical role in concomitantly regulating vaginal NOS expression and apoptosis in nerves, smooth muscle, vascular endothelium, and epithelium of the rat vagina. These findings may have significant clinical implications for the pathophysiology of postmenopausal female sexual dysfunction.

Animals↗
PubMed1997

Excitatory neurotransmission and sexual differentiation of the brain.

During normal development there is a perinatal sensitive period during which the male brain is exposed to high levels of gonadal steroids, resulting in permanent differentiation of neural substrates. The cellular mechanisms mediating hormonally induced sexual differentiation remain largely unknown. In the adult brain, steroids exert profound influences on the amino acid transmitters, GABA, and glutamate. We have found steroid regulation of amino acid neurotransmission during the perinatal sensitive period and propose this may be functionally related to sexual differentiation of the brain. Specifically, the mRNA coding for the rate-limiting enzyme in GABA synthesis, glutamic acid decarboxylase (GAD), is up to twice as high in some steroid-concentrating regions of the neonatal male brain compared to females, including the arcuate nucleus, dorsomedial nucleus, and the CA1 region of hippocampus. Sex differences in GABA tissue concentrations positively correlate with GAD mRNA differences in several brain regions. There are also sex differences in protein levels of GABA(A) receptor subunits. In parallel with these findings are significantly higher levels of binding to the non-NMDA glutamate receptor in steroid-concentrating regions of male brain. Given that GABA is an inhibitory transmitter and glutamate is an excitatory amino acid, these results initially appear paradoxical. However, in contrast to its inhibitory action in the adult brain, early in development GABA is actually excitatory and acts in a manner analogous to glutamate. Therefore, the combination of increased excitatory GABAergic and glutamatergic activity should result in substantially higher levels of neuronal excitation in the male brain. We speculate that an increased level of neuronal excitation is a potential mechanism mediating the permanent masculinization of the brain.

Aging↗
PubMed1997

Central nervous system actions of oxytocin and modulation of behavior in humans.

The posterior pituitary hormone oxytocin has modulatory effects on neural functioning that are significant to the regulation of behavior. Basic research in animals has established the importance of oxytocin in affiliation, including mating, pair bonding and parenting behaviors. It is also an important regulator of feeding, grooming and responses to stress. The actions of oxytocin in the brain are regulated by gonadal steroid hormones, particularly estrogen. Oxytocin might also influence normal behavior in humans, and dysfunctions in the oxytocin system might be involved in the etiology and expression of neuropsychiatric disorders.

Amino Acid Sequence↗
PubMed1997

Influence of maternal grooming, sex and age on Fos immunoreactivity in the preoptic area of neonatal rats: implications for sexual differentiation.

The medial preoptic area (mPOA) of the hypothalamus contains a sexually dimorphic nucleus (SDN-POA) that is 5-7 times larger in males than females and which contributes to the development and expression of male-specific sex behaviors in adulthood. Aside from a critical role for estrogen, the mechanisms that establish and maintain this sex difference are largely unknown. Differences in the size of the SDN-POA are thought to be related to estrogen-associated effects on programmed cell death (apoptosis) during early neonatal development. The expression of male sex behavior is also influenced by maternal behavior during development. During the postnatal period, the dam grooms the anogenital region of the pups to stimulate urination and defecation; however, male pups are groomed significantly more often than females and this maternal attention influences the expression of normal male sexual behavior in adulthood. Based on these observations, we hypothesized that different amounts of anogenital sensory stimulation might contribute to the sexually dimorphic development of the SDN-POA, specifically by providing for different levels of neuronal activation in the SDN-POA resulting in different degrees of cell death. Two experiments were conducted to test this hypothesis. In the first experiment, male and female rat pups on postnatal day 3 (PN 3) received simulated anogenital grooming with a stiff bristle paint brush. One hour later, the brains were removed and sections through the POA were cut and processed for the immunocytochemical detection of Fos-like immunoreactivity (IR) as an indicator of neuronal activation. In the second experiment, male and female littermates were killed on PN 3, 5, 7 and 12 and the number of Fos-immunoreactive cells and pyknotic cells detected in the SDN-POA were counted and compared. Our data demonstrate that anogenital stimulation on PN 3 results in a rapid induction of Fos-immunoreactive in the POA of both males and females. However, the majority of Fos-immunoreactive cells were located in the ventral POA and were distinctly lacking in the SDN-POA. In experiment 2, again no Fos-immunoreactive cells were detected in the SDN-POA of animals examined on PN 5-12. However, there was an increase in the number of pyknotic cells in the area surrounding and including the SDN-POA of females relative to males at PN 5, 7 and 12. Collectively, the data suggest that (1) anogenital grooming during early postnatal development induces a rapid activation of cells in the ventral mPOA, but not in the SDN-POA of rats, (2) there is a greater incidence of cell death in and around the SDN-POA of females vs. males during neonatal development, particularly toward the end of the hormone-sensitive critical period, and (3) Fos expression does not appear to be correlated with the sexually dimorphic development of, and/or programmed cell death within, the developing SDN-POA.

Aging↗
PubMed1996

GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase (GAD65 and GAD67) are reduced in the diagonal band of Broca during the afternoon of proestrus.

There is considerable evidence that GABAergic neurons play an important role in the regulation of gonadotropin-releasing hormone (GnRH) secretion, and that these neurons may mediate the feedback actions of gonadal steroids on GnRH neurons. The aim of the present study was to investigate whether endogenous changes in ovarian steroid secretion during the estrous cycle influenced GABAergic neuronal activity in the preoptic region of the hypothalamus, and in other steroid-sensitive brain regions. Intact, adult female rats were sacrificed at various times during the days of metestrus or proestrus. GABAergic neuronal activity was estimated by measuring the rate of accumulation of GABA in microdissected brain regions after pharmacological inhibition of GABA degradation. Concentrations of mRNA for both forms of glutamic acid decarboxylase (GAD65 and GAD67) were quantified in microdissected brain regions by a microlysate ribonuclease protection assay. In the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis (DBB(ovlt)), GABAergic neuronal activity was significantly reduced during the afternoon of proestrus compared with the morning of either proestrus or metestrus. In the lateral septal nucleus, GABAergic neuronal activity was significantly increased in the afternoon of proestrus compared with the morning. There were no significant effects of time of day or day of estrous cycle in the medial preoptic nucleus, median eminence, ventromedial nucleus, suprachiasmatic nucleus, medial septal nucleus, hippocampus (CA1 region), or cingulate cortex. In the DBB(ovlt), mRNA levels for both GAD65 and GAD67 were significantly reduced in the afternoon of proestrus compared with the afternoon of metestrus. By contrast, there was no change in GAD65 and GAD67 mRNA levels in the cingulate cortex at any of the times examined. These results demonstrate that GABAergic neuronal activity, and mRNA levels for both GAD65 and GAD67, are reduced in the DBB(ovlt) during the afternoon of proestrus. These results support the hypothesis that decreased GABAergic neuronal activity in this region plays a major permissive role in the generation and maintenance of the estrogen-induced LH surge.

Animals↗
PubMed1996

The medullary reticular formation is a site of muscle relaxant action of diazepam on deep back and neck muscles in the female rat.

We tested the hypothesis that the effect of systemic injections of diazepam (DZ, 125 mg/kg) to reduce the quality of the reproductive behavior, lordosis, and to reduce the EMG of lumbar back muscles involved in lordosis (Schwartz-Giblin et al., 1984) is exerted through a reticulospinal pathway with cells of origin in the nucleus gigantocellularis that excites lumbar motoneurons indirectly (Robbins et al., 1990, Robbins et al., 1992). In contrast, DZ facilitates lordosis behavior when infused into the midbrain central gray (McCarthy et al., 1995). Direct deposits of crystalline mixtures of DZ (20-80 ng) in dextrose were delivered to the medullary reticular formation (MRF) by diffusion from a cannula inserted through a guide to which a bipolar stimulating electrode was attached. The multiunit EMG response evoked by 20 (300 ms long) stimulus trains was recorded in back and neck muscles, lateral longissimus and splenius before and 5, 15, 30 and 60 min after local DZ deposits. There was a significant reduction in EMG response over this time period when stimulus intensities were within the range of 1.2-1.5 times threshold (Friedman two-way non-parametric test, P < 0.002). Large amplitude motor units that provide large tensions were the most sensitive to DZ-induced inhibition. Control deposits of dextrose had no significant effect. Systemic injections of progesterone (1 mg, i.p.) 60 min after DZ deposits, but not after dextrose deposits, further reduced the MRF-evoked EMG responses over the course of 1 h. As predicted, DZ infusions into the midbrain central gray did not reduce the reticulospinal-evoked axial muscle response, consistent with the facilitatory effect of midbrain central gray infusions of DZ on the lordosis quotient. The results suggest that benzodiazepine agonists (if endogenous) acting at sites in the MRF would be effective muscle relaxants during pregnancy, prior to the fall in progesterone that precedes labor.

Animals↗
PubMed1996

Sex differences in glutamic acid decarboxylase mRNA in neonatal rat brain: implications for sexual differentiation.

Sexual differentiation of rodent brain is dependent upon hormonal exposure during a "critical period" beginning in late gestation and ending in early neonatal life. Steroid hormone action at this time results in anatomical and physiological sexual dimorphisms in adult brain, but the mechanism mediating these changes is essentially unknown. The inhibitory neurotransmitter, GABA, is involved in regulation of sexually dimorphic patterns of behavior and gonadotropin secretion in the adult. Recent evidence suggests that during development GABA is excitatory and provides critical neurotrophic and neuromodulatory influences. We hypothesized that steroid-induced changes in GABAergic neurotransmission during this critical period are important mediators of sexual differentiation in brain. Therefore, we quantified levels of mRNA for GAD, the rate-limiting enzyme in GABA synthesis. On Postnatal Day 1, males had significantly higher levels of GAD mRNA in the dorsomedial nucleus, arcuate nucleus, and CA1 region of hippocampus. On Postnatal Day 15, after the critical period for sexual differentiation has ended, these differences were no longer present. We examined the role of gonadal steroids in regulating GAD by removing testes of males and administering testosterone to females at birth. Exposure to testosterone was correlated with increased GAD mRNA in the dorsomedial nucleus. A sex difference in GAD mRNA was also observed in the medial preoptic area, but the influence of testosterone was inconclusive. We conclude that sex differences in the GABAergic system during development are partially hormonally mediated, and that these differences may contribute to the development of sexually dimorphic characteristics in adult brain.

Animals↗
PubMed1996

Evidence for sexual differentiation of glia in rat brain.

It is well established that gonadal steroids mediate sexual differentiation of the brain via direct effects on neurons during a restricted critical period. In addition, estrogen can influence glial morphology in the adult brain, and in vitro studies suggest estrogen induces glial differentiation. However, there is a lack of in vivo evidence for steroid effects on glia during the critical period. We report here a hormone-mediated sexual differentiation of arcuate glia as early as Postnatal Day 1. Using glial fibrillary acidic protein immunoreactivity (GFAP-ir), we compared the responsiveness of astroglia in the rat arcuate nucleus among five hormonally different groups. The results indicate increased GFAP-ir cell surface area 24 hr after hormonal manipulation in castrate males compared to intact males, intact females (ANOVA; P < 0.01), and females injected with testosterone propionate (50 microg; ANOVA; P < 0.05). However, astroglia in intact males extended their processes significantly greater distances from the cell body compared to all other treatment groups (ANOVA; P < 0.01). The GFAP-ir cells were categorized into four distinct classes ranging from a simple bipolar to a fully stellate morphology. The frequency distribution of classes varied between groups with more stellate cells found in intact males. Finally, these sex differences in arcuate glia persisted into adulthood. We hypothesize that during the critical period, testosterone, or its metabolite estrogen, induce sexual differentiation of glia. We further hypothesize that in females glial cells remain partially undifferentiated and this may be important to glial plasticity seen in adult female arcuate.

Animals↗