(1/4126) Endocrine biomarkers of early fetal loss in cynomolgus macaques (Macaca fascicularis) following exposure to dioxin.

This study examines the endocrine alterations associated with early fetal loss (EFL) induced by an environmental toxin, TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/developmental model for humans. Females were administered single doses of 1, 2, and 4 microgram/kg TCDD (n = 4 per dose group) on gestational day (GD) 12. Urinary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorionic gonadotropin, relaxin) were measured to assess ovarian and placental endocrine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alterations associated with TCDD treatment were significant decreases in serum estradiol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less pronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonadotropin concentrations were not reduced by TCDD exposure at any level, indicating that TCDD targets specific components of the chorionic gonadotropin synthesis machinery within the trophoblast to alter the functional capacity of the hormone. These data demonstrate the value of endocrine biomarkers in identifying a toxic exposure to primate pregnancy many days before direct signs of reproductive toxicity were apparent. The increased EFL that occurred after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised embryonic circulation, and subsequent EFL.  (+info)

(2/4126) Neuronal activity in somatosensory cortex of monkeys using a precision grip. I. Receptive fields and discharge patterns.

Three adolescent Macaca fascicularis monkeys weighing between 3.5 and 4 kg were trained to use a precision grip to grasp a metal tab mounted on a low friction vertical track and to lift and hold it in a 12- to 25-mm position window for 1 s. The surface texture of the metal tab in contact with the fingers and the weight of the object could be varied. The activity of 386 single cells with cutaneous receptive fields contacting the metal tab were recorded in Brodmann's areas 3b, 1, 2, 5, and 7 of the somatosensory cortex. In this first of a series of papers, we describe three types of discharge pattern, the receptive-field properties, and the anatomic distribution of the neurons. The majority of the receptive fields were cutaneous and covered less than one digit, and a chi2 test did not reveal any significant differences in the Brodmann's areas representing the thumb and index finger. Two broad categories of discharge pattern cells were identified. The first category, dynamic cells, showed a brief increase in activity beginning near grip onset, which quickly subsided despite continued pressure applied to the receptive field. Some of the dynamic neurons responded to both skin indentation and release. The second category, static cells, had higher activity during the stationary holding phase of the task. These static neurons demonstrated varying degrees of sensitivity to rates of pressure change on the skin. The percentage of dynamic versus static cells was about equal for areas 3b, 2, 5, and 7. Only area 1 had a higher proportion of dynamic cells (76%). A third category was identified that contained cells with significant pregrip activity and included cortical cells with both dynamic or static discharge patterns. Cells in this category showed activity increases before movement in the absence of receptive-field stimulation, suggesting that, in addition to peripheral cutaneous input, these cells also receive strong excitation from movement-related regions of the brain.  (+info)

(3/4126) Neuronal activity in somatosensory cortex of monkeys using a precision grip. II. Responses To object texture and weights.

Three monkeys were trained to lift and hold a test object within a 12- to 25-mm position window for 1 s. The activity of single neurons was recorded during performance of the task in which both the weight and surface texture of the object were systematically varied. Whenever possible, each cell was tested with three weights (15, 65, and 115 g) and three textures (smooth metal, fine 200 grit sandpaper, and rough 60 grit sandpaper). Of 386 cells recorded in 3 monkeys, 45 cells had cutaneous receptive fields on the index or thumb or part of the thenar eminence and were held long enough to be tested in all 9 combinations of texture and weight. Recordings were made for the entire anterior-posterior extent of the thumb and index finger areas in somatosensory cortex including area 7b. However, the statistical analysis required a selection of only those cells for which nine complete recording conditions were available limiting the sample to cells in areas 2, 5, and 7b. Significant differences in the grip force accompanied 98% of the changes in texture and 78% of the changes in weight. Increasing the object weight also increased the force tangential to the skin surface as measured by the load or lifting force. The peak discharge during lifting was judged to be the most sensitive index of cell activity and was analyzed with a two-way analysis of variance (ANOVA). In addition, peak cell discharge was normalized to allow comparisons among different combinations of texture and weight as well as comparisons among different neurons. Overall, the peak firing frequency of 87% of the cells was significantly modulated by changes in object texture, but changes in object weight affected the peak activity of only 58% of the cells. Almost all (17/18, 94%) of the static cells were influenced by the object texture, and 81% of the dynamic cells that were active only briefly at grip and lift onset were modulated by texture. For some cells, surface texture had a significant effect on neuronal discharge that was independent of the object weight. In contrast, weight-related responses were never simple main effects of the weight alone and appeared instead as significant interactions between texture and weight. Four neurons either increased or decreased activity in a graded fashion with surface structure (roughness) regardless of the object weight (P < 0.05). Ten other neurons showed increases or decreases in response to one or two textures, which might represent either a graded response or a tuning preference for a specific texture. The firing frequency of the majority (31/45) of neurons reflected an interaction of both texture and weight. The cells with texture-related but weight-independent activities were thought to encode surface characteristics that are largely independent of the grip and lifting forces used to manipulate the object. Such constancies could be used to construct internal representations or mental models for planning and controlling object manipulation.  (+info)

(4/4126) Neuronal activity in somatosensory cortex of monkeys using a precision grip. III. Responses to altered friction perturbations.

The purpose of this investigation was to examine the activity changes in single units of the somatosensory cortex in response to lubricating and adhesive coatings applied to a hand-held object. Three monkeys were trained to grasp an object between the thumb and index fingers and to lift and hold it stationary within a narrow position window for 1 s before release. Grip forces normal to the skin surface, load forces tangential to the skin surface, and the displacement of the object were measured on each trial. Adhesive (rosin) and lubricant (petroleum jelly) coatings were applied to the smooth metal surface of the object to alter the friction against the skin. In addition, neuronal activity evoked by force pulse-perturbations generating shear forces and slip on the skin were compared with the patterns of activity elicited by grasping and lifting the coated surfaces. Following changes in surface coatings, both monkeys modulated the rate at which grip forces normal to the skin surface and load forces tangential to the skin surface were applied during the lifting phase of the task. As a result, the ratio of the rates of change of the two forces was proportionately scaled to the surface coating properties with the more slippery surfaces, having higher ratios. This precise control of normal and tangential forces enabled the monkeys to generate adequate grip forces and prevent slip of the object. From a total of 386 single neurons recorded in the hand area of the somatosensory cortex, 92 were tested with at least 1 coating. Cell discharge changed significantly with changes in surface coating in 62 (67%) of these cells. Of these coating-related cells, 51 were tested with both an adhesive and lubricating coating, and 45 showed significant differences in activity between the untreated metal surface and either the lubricant or the adhesive coating. These cells were divided into three main groups on the basis of their response patterns. In the first group (group A), the peak discharge increased significantly when the grasped surface was covered with lubricant. These cells appeared to be selectively sensitive to slip of the object on the skin. The second group (group B) was less activated by the adhesive surface compared with either the untreated metal or the lubricated surface, and they responded mainly to variations in the force normal to the skin surface. These cells provide useful feedback for the control of grip force. The third group (group C) responded to both slips and to changes in forces tangential to the skin. Most of these cells responded with a biphasic pattern reflecting the bidirectional changes in load force as the object was first accelerated and then decelerated. One hundred sixty-eight of the 386 isolated neurons were tested with brief perturbations during the task. Of these, 147 (88%) responded to the perturbation with a significant change in activity. In most of the cells, the response to the perturbation was shorter than 100 ms with a mean latency of 44.1 +/- 16.3 (SD) ms. For each of the cell groups, the activity patterns triggered by the perturbations were consistent with the activity patterns generated during the grasping and lifting of the coated object.  (+info)

(5/4126) Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey.

We investigated whether uninjured cutaneous C-fiber nociceptors in primates develop abnormal responses after partial denervation of the skin. Partial denervation was induced by tightly ligating spinal nerve L6 that innervates the dorsum of the foot. Using an in vitro skin-nerve preparation, we recorded from uninjured single afferent nerve fibers in the superficial peroneal nerve. Recordings were made from 32 C-fiber nociceptors 2-3 wk after ligation and from 29 C-fiber nociceptors in control animals. Phenylephrine, a selective alpha1-adrenergic agonist, and UK14304 (UK), a selective alpha2-adrenergic agonist, were applied to the receptive field for 5 min in increasing concentrations from 0.1 to 100 microM. Nociceptors from in vitro control experiments were not significantly different from nociceptors recorded by us previously in in vivo experiments. In comparison to in vitro control animals, the afferents found in lesioned animals had 1) a significantly higher incidence of spontaneous activity, 2) a significantly higher incidence of response to phenylephrine, and 3) a higher incidence of response to UK. In lesioned animals, the peak response to phenylephrine was significantly greater than to UK, and the mechanical threshold of phenylephrine-sensitive afferents was significantly lower than for phenylephrine-insensitive afferents. Staining with protein gene product 9.5 revealed an approximately 55% reduction in the number of unmyelinated terminals in the epidermis of the lesioned limb compared with the contralateral limb. Thus uninjured cutaneous C-fiber nociceptors that innervate skin partially denervated by ligation of a spinal nerve acquire two abnormal properties: spontaneous activity and alpha-adrenergic sensitivity. These abnormalities in nociceptor function may contribute to neuropathic pain.  (+info)

(6/4126) The fine structural organization of the cuneate nucleus in the monkey (Macaca fascicularis).

The fine structure of the cuneate nucleus of the monkey (Macaca fascicularis) has been studied. The neurons were classified into three groups according to their nuclear morphology, the arrangement of the rough endoplasmic reticulum (RER) and the appearance of the Golgi complexes. Group I neurons had a regular nucleus and contained abundant cytoplasm in which were found well-developed RER and Golgi complexes. Group II neurons had a slightly irregular nucleus and a variable arrangement of the RER and Golgi complexes. Group III neurons were characterized by a deeply indented nucleus, and scanty cytoplasm in which the cytoplasmic organelles were poorly developed. Group II neurons were the most commonly encountered while Group I neurons were the rarest. Axon terminals contained either round of flattened vesicles. Axon terminals and dendrites commonly formed synaptic complexes. In one type the axon terminal, containing round vesicles, formed the central element, which is presynaptic to the dendrites surrounding it; in addition it is postsynaptic to axon terminals containing flattened vesicles. In another type a large dendrite formed the central element which is postsynaptic to axon terminals containing round or flattened vesicles.  (+info)

(7/4126) Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats.

A marked difference in hepatic activity of aldehyde oxidase between rats and monkeys was found to be responsible for the previously reported marked species difference in the metabolism of Zaleplon in vivo. In the postmitochondrial fractions, S-9s, from liver homogenates of these animals, Zaleplon was transformed in the presence of NADPH into the side chain oxidation product, N-desethyl-Zaleplon, and the aromatic ring oxidation product, 5-oxo-Zaleplon. In the rat S-9, N-desethyl-Zaleplon and 5-oxo-Zaleplon were a major and a very minor metabolites, respectively. However, in the monkey S-9, Zaleplon was transformed into 5-oxo-Zaleplon at a much higher rate than that for N-desethyl-Zaleplon formation. N-Desethyl-Zaleplon was formed in the monkey S-9 at a rate almost equal to that in the rat S-9. N-Desethyl-5-oxo-Zaleplon was formed at a minor rate only in the monkey S-9 through N-desethyl-Zaleplon as an obligatory intermediate. The hepatic activity for the formation of 5-oxo-Zaleplon in the monkey and rat was localized in cytosol and did not require NADPH. Sensitivity to various inhibitors and requirement of water as oxygen source, using H218O, strongly suggested that the hepatic cytosolic formation of 5-oxo-Zaleplon was mediated by aldehyde oxidase. N-Desethyl-Zaleplon was formed in the presence of NADPH by microsomes from the liver of rats and monkeys, and its formation was strongly suggested using various cytochrome P-450 inhibitors to be mediated by a number of cytochrome P-450 isoforms, such as 3A, 2C, and 2D subfamilies.  (+info)

(8/4126) Visual motion analysis for pursuit eye movements in area MT of macaque monkeys.

We asked whether the dynamics of target motion are represented in visual area MT and how information about image velocity and acceleration might be extracted from the population responses in area MT for use in motor control. The time course of MT neuron responses was recorded in anesthetized macaque monkeys during target motions that covered the range of dynamics normally seen during smooth pursuit eye movements. When the target motion provided steps of target speed, MT neurons showed a continuum from purely tonic responses to those with large transient pulses of firing at the onset of motion. Cells with large transient responses for steps of target speed also had larger responses for smooth accelerations than for decelerations through the same range of target speeds. Condition-test experiments with pairs of 64 msec pulses of target speed revealed response attenuation at short interpulse intervals in cells with large transient responses. For sinusoidal modulation of target speed, MT neuron responses were strongly modulated for frequencies up to, but not higher than, 8 Hz. The phase of the responses was consistent with a 90 msec time delay between target velocity and firing rate. We created a model that reproduced the dynamic responses of MT cells using divisive gain control, used the model to visualize the population response in MT to individual stimuli, and devised weighted-averaging computations to reconstruct target speed and acceleration from the population response. Target speed could be reconstructed if each neuron's output was weighted according to its preferred speed. Target acceleration could be reconstructed if each neuron's output was weighted according to the product of preferred speed and a measure of the size of its transient response.  (+info)