Neuronal networks. Vibrations in the memory.
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Cerebral Cortex↗
Biomedical subjects
K A Martin
Publications and source records attributed to K A Martin.
Mutations disrupting neuronal connectivity in the Drosophila visual system.
The photoreceptor neurons (R cells) of the Drosophila compound eye elaborate a precise array of neuronal connections in the brain. These projections exhibit target specificity and create topographic maps (retinotopy). We have screened histologically for mutations disrupting R cell connectivity in developing tissue. Eighty mutations were isolated from over 6000 ethylmethane sulfonate-mutagenized lines. Characterization of these mutations included genetic mosaic analysis to determine whether the gene is required in the retina or in the optic ganglia. Most mutations were found to affect connectivity indirectly by disrupting development more generally in the eye or brain. Genes were identified as candidates for playing direct roles in R cell connectivity by affecting axonal outgrowth (eddy), target recognition (limbo and nonstop), and retinotopy (limbo).
Animals↗
Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.
To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcycle gonadotropin surge in the human, the response of luteinizing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 micrograms/kg s.c. of the NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2,-D-Pal3,Arg5,D-4-p-met hoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH, where 2Nal is 2-naphthylalanine, 4ClPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylalanine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in all cycle phases (P < 0.0001). When this suppression was expressed as maximum percent inhibition, there was no difference in response during the early and late follicular and early luteal phases. However, at the midcycle surge, there was a leftward shift of the dose-response curve with significantly greater suppression of LH at the lower antagonist doses in comparison to the other cycle phases (P < 0.005), but no difference at the highest dose. Thus, we draw the following conclusions. (i) There is a consistently greater degree of LH inhibition by GnRH antagonism at the midcycle surge at submaximal degrees of GnRH receptor blockade than at other phases of the menstrual cycle in normal women. (ii) This leftward shift of the dose-response relationship to GnRH receptor blockade suggests that the overall amount of GnRH secreted at the midcycle surge is less than at other cycle stages. (iii) These data confirm the importance of pituitary augmentation of the GnRH signal at the time of the midcycle gonadotropin surge in the human.
Adolescent↗
The mouse creatine kinase paired E-box element confers muscle-specific expression to a heterologous promoter.
E-box elements, with the CANNTG sequence motif, occur in numerous promoters and enhancers. We evaluated the tissue-specific expression properties of the paired murine E-box element from the mouse muscle creatine kinase (MCK) enhancer in a minimal heterologous promoter construct. A 46-bp fragment containing the paired E-box element in its wild-type (wt) configuration conferred high levels of muscle-specific expression in transfected embryonic chicken cell cultures. The expression from this paired E-box element was similar to that of the simian virus 40 (SV40) promoter/enhancer, but a 21-bp fragment containing a single E-box was inactive. We conclude that the paired E-box element from the MCK enhancer is sufficient for high levels of muscle-specific expression when placed upstream from a non-muscle TATA element.
Actins↗
Synaptic output of physiologically identified spiny stellate neurons in cat visual cortex.
Spiny stellate neurons of area 17 of the cat's visual cortex were physiologically characterised and injected intracellularly with horseradish peroxidase. Six neurons from sublamina 4A were selected. Five had the S-type of simple receptive fields; one had a complex receptive field. Their axons formed boutons mainly in layers 3 and 4. An electron microscopic examination of 45 boutons showed that each bouton formed one asymmetric synapse on average. Spines were the most frequent synaptic target (74%); dendritic shafts formed the remainder (26%). On the basis of ultrastructural characteristics, 8% of the target dendrites were characterised as originating from smooth gamma-aminobutyrate-ergic (GABAergic) neurons. Thus the major output of spiny stellate neurons is to other spiny neurons, probably pyramidal neurons in layer 3 and spiny stellates in layer 4.
Animals↗
Map of the synapses formed with the dendrites of spiny stellate neurons of cat visual cortex.
The synaptic input of six spiny stellate neurons in sublamina 4A of cat area 17 was assessed by electron microscopy. The neurons were physiologically characterized and filled with horseradish peroxidase in vivo. After processing the neurons were reconstructed at the light microscopic level using computer-assisted methods and analyzed quantitatively. The extensive branching of the dendritic tree about 50 microns from the soma meant that the distal branches constituted five times the length of proximal dendrite. Proximal and distal portions of a single dendrite from each neuron were examined in series of ultrathin sections (1,456 sections) in the electron microscope. The majority (79%) of the 263 synapses examined were asymmetric; the remainder (21%) were symmetric. Symmetric synapses formed 35% of synapses sampled on proximal dendrites and were usually located on the shaft. They formed only 4% of synapses sampled on distal dendrites. Spines accounted for less than half of the total asymmetric synapses (45%); the remainder were on shafts. Symmetric synapses formed with four of 92 spines. Nine spines formed no synapses. Spiny stellate neurons in cat visual cortex appear to differ considerably from pyramidal neurons in having a significant asymmetric (excitatory) synaptic input to the dendritic shaft.
Animals↗
Polyneuronal innervation of spiny stellate neurons in cat visual cortex.
Our hypothesis was that spiny stellate neurons in layer 4 of cat visual cortex receive polyneuronal innervation. We characterised the synapses of four likely sources of innervation by three simple criteria: the type of synapse, the target (spine, dendritic shaft), and the area of the presynaptic bouton. The layer 6 pyramids had the smallest boutons and formed asymmetric synapses mainly with the dendritic shaft. The thalamic afferents had the largest boutons and formed asymmetric synapses mainly with spines. The spiny stellates had medium-sized boutons and formed asymmetric synapses mainly with spines. We used these to make a "template" to match against the boutons forming synapses with the spiny stellate dendrite. Of the asymmetric synapses, 45% could have come from layer 6 pyramidal neurons, 28% from spiny stellate neurons, and 6% from thalamic afferents. The remaining 21% of asymmetric synapses could not be accounted for without assuming some additional selectivity of the presynaptic axons. Additional asymmetric synapses may come from a variety of sources, including other cortical neurons and subcortical nuclei such as the claustrum. Of the symmetric synapses, 84% could have been provided by clutch cells, which form large boutons. The remainder, formed by small boutons, probably come from other smooth neurons in layer 4, e.g., neurogliaform and bitufted neurons. Our analysis supports the hypothesis that the spiny stellate receives polyneuronal innervation, perhaps from all the sources of boutons in layer 4. Although layer 4 is the major recipient of thalamic afferents, our results show that they form only a few percent of the synapses of layer 4 spiny stellate neurons.
Animals↗
David Whitteridge (1912-1994).
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England↗
Occurrence of chickenpox during pregnancy in women seropositive for varicella-zoster virus.
In a group of 21 women counseled after exposure to chickenpox during pregnancy, 4 developed varicella despite initial studies showing that preinfection sera were varicella-zoster virus (VZV)-seropositive by fluorescent anti-membrane antibody, latex agglutination, ELISA, and VZV glycoprotein immunoblot assay. Further investigations showed that 2 of the 4 had low-titer (1/100), low-avidity, VZV-reactive IgG3 antibodies by ELISAs of preinfection sera. After chickenpox, these women developed primary-like serologic responses to VZV. Two women with high-titer (1/1600, 1/3200), high-avidity, IgG1 antibodies showed anamnestic serologic responses after reinfection. The criteria of protective VZV immunity remain ill-defined.
Adult↗
Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site enzyme-linked immunosorbent assay.
The endocrine feedback role of dimeric inhibin on FSH secretion from the pituitary has been well established in many species; however, evidence that inhibin is an important endocrine regulator of FSH in the human is more tenuous. One potential explanation for the equivocal data may be that the inhibin immunoassay used most widely in the human is a heterologous assay with an antiserum that exclusively recognizes the inhibin alpha-subunit in both its monomeric form and in inhibin dimers. The aim of the present study was to quantify serum inhibin levels in a variety of fertile and infertile men and women using a new ultrasensitive enzyme-linked immunosorbent assay that is specific for the dimeric form (alpha/beta) only. The specificity of the present assay was demonstrated by the absence of significant cross-reactivity with Mullerian inhibiting substance, transforming growth factor-beta, activin, FSH, LH, hCG, TSH, and hCG alpha and with the alpha-subunit of inhibin. The assay was sensitive to 1 pg/mL, and serial dilutions of human male and female serum samples paralleled the recombinant 32-kilodalton (kDa) dimeric inhibin standard curve. Complete recovery of exogenous recombinant 32-kDa inhibin added to serum was obtained. Mean serum inhibin levels ranged from a low of 5.7 +/- 0.6 pg/mL in the early follicular phase to 49.0 +/- 11.2 pg/mL in the midluteal phase of the normal menstral cycle and were elevated during ovulation induction (1250 pg/mL) and pregnancy (500 pg/mL). Interestingly, mean levels of dimeric inhibin in women with polycystic ovarian syndrome (PCOS) were indistinguishable from normal follicular phase. The most striking observation was the extremely low mean inhibin levels (< 2 pg/mL) found in normal men, GnRH-deficient men before any pulsatile GnRH treatment, and men with Klinefelter's syndrome, all of which were indistinguishable from levels observed in postmenopausal women. These observations in the male raise the possibly that 1) some forms of circulating and bioactive inhibin in the human are not detected by this assay due to either their conformation or the presence of a unique binding protein for endogenous inhibin that does not bind to recombinant 32-kDa inhibin; or 2) dimeric inhibin is not a major endocrine regulator of FSH in the human male. In addition, the relatively high dimeric inhibin levels at midcycle and in the luteal phase of the normal menstrual cycle, after gonadotropin stimulation, and during pregnancy suggest that dimeric inhibin is predominantly produced by dominant follicles, corpora lutea, and placental tissues.
Adult↗
Potential for fertility with replacement of hypothalamic gonadotropin-releasing hormone in long term female survivors of cranial tumors.
Dysfunction of the hypothalamic-pituitary axis presenting as hypogonadotropic amenorrhea is a common sequelae of treatment for cranial tumors with surgery and/or radiation. We hypothesized that the site of the defect in this condition is hypothalamic, rather than pituitary, in the majority of patients. Nine women with acquired hypogonadotropic hypogonadism after treatment with transphenoidal pituitary surgery (n = 3), transphenoidal surgery plus conventional radiotherapy (XRT; n = 1), hypothalamic surgery plus XRT (n = 2), or XRT with or without noncentral nervous system surgery (n = 3) underwent assessment of endogenous pulsatile LH secretion and a standard GnRH test followed by iv administration of a physiological replacement regimen of exogenous GnRH. A total of 25 cycles were completed at doses of 75 or 100 ng/kg.bolus. Ovulation occurred in 78% of patients, with all ovulatory patients who desired fertility becoming pregnant. The hormonal responses in these cycles did not differ from the patterns of sex steroids and gonadotropins in normal women. The response to pulsatile GnRH was not influenced by GH deficiency or PRL abnormalities. Of the two patients who failed to ovulate, there was no evidence of folliculogenesis in one, whereas the second consistently developed follicles, but proved incapable of mounting a LH surge despite adequate preovulatory estradiol levels. Both patients had a history of pituitary radiation and surgery. There was no consistent relationship between the results of GnRH testing and the pattern of pulsatile LH secretion. However, the only patient who failed to achieve folliculogenesis was the only patient without a FSH response to GnRH testing and an apulsatile baseline study. Hypothalamic GnRH deficiency is the etiology of hypogonadism in the majority of patients after treatment with hypothalamic or pituitary surgery or cranial irradiation. Therefore, exogenous pulsatile GnRH represents a physiological replacement therapy that completely restores normal gonadotropin dynamics, resulting in ovulation and fertility.
Adolescent↗
New approaches to the study of the neuroendocrine abnormalities of women with the polycystic ovarian syndrome.
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Female↗
An overview of the diagnostic considerations in polycystic ovarian syndrome.
The past ten years have been particularly exciting with regard to the elucidation of the pathophysiology of PCOS. It appears that PCOS is about to yield some of its mysteries and to have some of its discrete subsets defined, as Cushing syndrome did 50 years ago. However, future studies of PCOS will require a complex interplay of clinical investigation, molecular and genetic probes, increasingly refined anatomic observations, and fundamental neuroendocrine studies. Each observer has a bias, which must be acknowledged in his/her studies. However, a true synthesis of the abnormalities characteristic of PCOS must continually be sought, for only through a comprehensive view of this syndrome will we come to understand its true pathophysiology; and only then can rational therapies be designed.
Androgens↗
Postmenopausal hormone-replacement therapy.
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Cardiovascular Diseases↗
Expression of the mas proto-oncogene in the rat hippocampal formation is regulated by neuronal activity.
The mas proto-oncogene encodes a seven membrane-spanning G-protein-coupled receptor which is activated by angiotensins. In the postnatal and adult rat, mas mRNA is specifically expressed at high levels in hippocampal neurons. We report here using in situ hybridization and RNase protection that brief seizure episodes lead to a significant and transient increase in mas mRNA in the hippocampus. Increased levels of mas transcripts were detected 2, 4, and 6 h following seizure. By 24 h post seizure, baseline levels were detected. The presumed subsequent increase of the mas receptor protein may contribute to anatomical and physiological plasticity that is associated with intense activation of hippocampal pathways.
Animals↗
Multiple molecular weight forms of immunoreactive alpha-inhibin in human seminal plasma.
The purpose of these studies was to determine whether the total immunoreactive alpha-inhibin protein concentration in seminal plasma correlated with serum gonadotropin levels or semen characteristics and to identify the forms of alpha-inhibin present in seminal plasma. Thirty-eight serum samples from men being evaluated for infertility were selected for study based on their serum hormone profiles and semen parameters. Serum LH and testosterone levels were normal, but FSH levels ranged from normal to hypergonadotropic (> 20 IU/L). Most semen parameters were within normal ranges, but germ cell numbers ranged from normal to azoospermic. Thus, seminal plasma from these men provided a unique opportunity to examine the antigenic forms of alpha-inhibin in individuals in whom strong correlations between inhibin and FSH levels might be predicted because of the observed ranges of FSH levels and germ cell numbers. Seminal plasma alpha-inhibin was characterized by RIA or Western blotting, using an antiserum directed against the N-terminal of the alpha-subunit of mature [32,000 mol wt (M(r))] inhibin. The antiserum recognized the alpha-subunit of dimeric inhibin as well as free alpha-inhibin and alpha-inhibin precursor proteins. Total immunoreactive alpha-inhibin ranged from 8.21-43.99 nmol/L in seminal plasma. However, alpha-inhibin levels were not statistically correlated with serum FSH levels or any of the measured semen parameters (including germ cell number). In contrast, the immunoreactive alpha-inhibin concentration in seminal plasma was negatively correlated (P < 0.01) with the serum LH level. Western blot analyses revealed that multiple forms of immunoreactive alpha-inhibin are present in seminal plasma. The majority of immunoreactivity was associated with monomeric proteins (ranging from 58,000-95,000 M(r)) that were larger than the alpha-subunit (21,000 M(r)) predicted for mature dimeric human inhibin (32,000 M(r)). The relative amounts of individual forms of immunoreactive alpha-inhibin varied among the patients studied, but could not be correlated with other serum or seminal parameters measured. Our observations demonstrate that various monomeric alpha-inhibin proteins are present in human seminal plasma. It is unlikely that these proteins alone or combined with inhibin beta-subunit proteins have identical biological activities. Thus, until assays specific for each of the various forms of immunoreactive alpha-inhibin are developed, their role as well as that of inhibin in the endocrine or local modulation of testicular function cannot be deduced from RIA data alone.
Blotting, Western↗
Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea.
To compare the efficacy and safety of ovulation induction with exogenous gonadotropins vs. pulsatile GnRH in patients with hypogonadotropic amenorrhea, results from 30 patients in 111 cycles of gonadotropins and 41 patients in 118 cycles of pulsatile GnRH were analyzed retrospectively. Exogenous gonadotropins were administered using an individually adjusted protocol, using a starting dose of 150 IU. Pulsatile GnRH was delivered iv at a physiological frequency based upon our normative data. The doses administered ranged from 75-250 ng/kg. Preovulatory serum estradiol (E2) and luteal phase progesterone (P) levels were compared to those in normal cycling women (n = 87). The mean body mass index, age, and baseline gonadotropin levels were similar in the two groups. Overall ovulatory rates and conception rates per cycle and per patient were not significantly different between the two groups. However, the cumulative chance of conception after six cycles of treatment by life table analysis appeared to be higher with pulsatile GnRH treatment (96%) than with exogenous gonadotropins (72%). The risk of multiple gestation was also higher with exogenous gonadotropins (14.8% vs. 8.3%), although this was not statistically significant. All higher order multiple gestations (triplets or more) occurred in the gonadotropin-treated group. More than two dominant follicles were seen on ultrasound in 47.6% of gonadotropin-treated cycles compared to 18.9% of cycles with pulsatile GnRH treatment (P < 0.01). Three or more follicles were seen in 16.6% of the gonadotropin cycles compared to 5.4% with pulsatile GnRH (P < 0.05). No case of severe ovarian hyperstimulation was observed in either group, although the mean luteal phase ovarian size was significantly higher in the gonadotropin group (P < 0.05). Mean peak preovulatory E2 levels were significantly higher in the gonadotropin group (1684.5 +/- 124.4 vs. 1315.3 +/- 74.9 pmol/L; P < 0.05). The mean luteal phase P level 1 week after ovulation was significantly higher than normal in the gonadotropin group (84.9 +/- 10.8 vs. 61.1 +/- 3.2 nmol/L; P < 0.05), but was not significantly different from that in the pulsatile GnRH group (70.3 +/- 6.0 nmol/L). We conclude that pulsatile GnRH, when compared to exogenous gonadotropins, results in high rates of ovulation and conception, but a decreased risk of multiple folliculogenesis, higher order multiple gestations, and ovarian enlargement.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
The neurobiology of primate vision.
Studies of the visual system of the primate have taken two directions. One group of neurobiologists have studied the oculomotor system, while an entirely separate group have analysed sensory processing in the retinogeniculo-cortical circuits. However, the versatility and adaptability of the primate visual system is only possible because sensory and oculomotor processing are highly integrated. More than any other species, primates have exploited the advantages of extensive and coordinated binocular eye movements to improve their visuomotor performance. This chapter describes the basic apparatus of primate vision. The integrated nature of visuomotor function is illustrated by two examples: smooth pursuit eye movements and stereovision. Both of these tasks require huge amounts of sensory processing in many different visual centres and, simultaneously, very precise control of binocular eye position. These examples illustrate the difficulty and artificiality of assigning unique functions to any component part of the system. Each part of the visual system, from the retina through the brain to the oculomotoneurones that drive the eye muscles, is involved in many different functions. This integration within the system raises the problem of how we represent and recognize our visual world in the brain. The traditional view from sensory psychology is that single nerve cells in the visual cortex signal significant percepts. As this chapter shows, the activity of single cortical neurones is influenced by multiple factors, including the qualities of the visual stimulus, the position of the eyes, and the attention being paid to the stimulus. Thus, the activity of single neurones is an ambiguous indicator of both perceptual and motor events. Only the collective action of many nerve cells, it seems, represents unique percepts and actions. Given this indivisibility of function, patients with localized brain lesions will invariably present with multiple visuomotor deficits.
Animals↗