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Biomedical subjects

R M Sapolsky

Publications and source records attributed to R M Sapolsky.

At least 19 recordsLinked to original sources
PubMed1995

Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypoglycemia. Microinfusion of GT vectors into the rat hippocampus also reduces kainic acid-induced seizure damage in the CA3 cell field. Furthermore, delivery of the vector even after onset of the seizure is protective, suggesting that HSV-mediated gene transfer for neuroprotection need not be carried out in anticipation of neurologic crises. Using the bicistronic vector v alpha 22 beta gal alpha 4GT, which coexpresses both GT and the Escherichia coli lacZ marker gene, we further demonstrate an inverse correlation between the extent of vector expression in the dentate and the amount of CA3 damage resulting from the simultaneous delivery of kainic acid.

Animals↗
PubMed1995

Adrenocorticotropin secretagog release: stimulation by frustration and paradoxically by reward presentation.

Colchicine blockade of axonal transport from the paraventricular nucleus to the median eminence was used to indirectly infer adrenocorticotropin (ACTH) secretagog release in response to a reward presentation and the psychological stressor of frustration. After training rats to drink at the same time of day for 30 min for 2-3 weeks, basal arginine vasopressin (AVP), but not corticotropin-releasing factor (CRF) or oxytocin (OT), concentrations were elevated. The frustration of presenting empty water bottles resulted in increased corticosterone concentrations. Concordantly, CRF, AVP, and OT contents in the median eminence decreased compared to controls. All three secretagogs are thus apparently involved in the corticosterone response to frustration. As expected, water presentation decreased both ACTH and corticosterone. Paradoxically, however, CRF, AVP, and OT contents also decreased compared to controls. The discrepancy of ACTH and corticosterone concentrations declining despite release of secretagogs cannot be explained by decreased adrenal or pituitary sensitivities since both exogenous ACTH and CRF elevated corticosterone and ACTH, respectively, in rewarded rats. Secretagog release, therefore, may not always be associated with stimulation of ACTH release.

Adrenocorticotropic Hormone↗
PubMed1995

Herpes simplex virus vector system: analysis of its in vivo and in vitro cytopathic effects.

With its natural propensity to infect and establish life-long latency in neurons, herpes simplex virus type 1 (HSV-1) has been successfully employed by various laboratories as vectors for gene transfer into neurons. However, analysis of its cytopathic effects in vivo and in vitro has been limited. In this study, we examined the cytopathic effects of 2 HSV-1 alpha 4 mutants (ts756 and d120) on adult rat hippocampus and striatum and of d120 on hippocampal neurons in culture. We assessed damage by stringent counting of surviving neurons after infection and demonstrated that while neither ts756 nor d120 infection resulted in any gross anatomical or behavioral changes of the animals, ts756, but not d120, produced a significant amount of damage in the CA4 cell field and dentate gyrus of the hippocampus. Thus, since crude examination is insufficient to detect subtle but significant degrees of neuron loss, the cytopathic effects of HSV or any vector system must be carefully analyzed. Furthermore, we also observed that uninfected cell lysates damaged neurons, both in vivo and in vitro. This cytotoxicity occurred within the first 24 h post-inoculation and probably arose through the activation of glutamate receptors. For the preparation of HSV vectors, purification of the virus from soluble cellular components by a simple pelleting step can significantly decrease such acute toxicity.

Cell Count↗
PubMed1995

Patterns of adrenocorticotropin secretagog release in response to social interactions and various degrees of novelty.

Colchicine blockade of axonal transport from the paraventricular nucleus to the median eminence was used to indirectly infer ACTH secretagog release in response to the psychological stressors of social interactions and various degrees of novelty. Placing a rat in a new cage with either the smell or presence of a novel conspecific decreased arginine vasopressin and oxytocin (OT) contents, but not corticotropin-releasing factor content. Secretagog contents were unchanged in rats in their home cages faced with a novel conspecific. Secretagog release during social stress is thus primarily a function of being in a novel setting. For different degrees of novelty, rats were placed in either a novel cage, a novel bucket, or a novel bucket smelling of another rat. Whereas secretagog contents were unchanged with a novel cage, OT content alone decreased in response to both the bucket and the unclean bucket. Despite a graded corticosterone response, there was no distinction in the OT response, suggesting that the colchicine technique cannot accurately reflect gradations of stressors.

Adaptation, Psychological↗
PubMed1995

Stress and cognitive function.

Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.

Animals↗
PubMed1995

Defective herpes simplex virus vectors expressing the rat brain glucose transporter protect cultured neurons from necrotic insults.

Because neurons are postmitotic, they are irreplaceable once they succumb to necrotic insults such as hypoglycemia, ischemia, and seizure. A paucity of energy can exacerbate the toxicities of these insults; thus, a plausible route to protect neurons from necrotic injury would be to enhance their glucose uptake capability. We have demonstrated previously that defective herpes simplex virus (HSV) vectors overexpressing the rat brain glucose transporter (GT) gene (gt) can enhance glucose uptake in adult rat hippocampus and in hippocampal cultures. Furthermore, we have observed that such vectors can maintain neuronal metabolism during hypoglycemia and reduce kainic acid-induced seizure damage. In this study, we have developed bicistronic vectors that coexpressed gt and Escherichia coli lacZ as a reporter gene, which allows us to identify directly neurons that are infected with the vectors. Overexpression of GT from these vectors protected cultured hippocampal, spinal cord, and septal neurons against various necrotic insults, including hypoglycemia, glutamate, and 3-nitropropionic acid. Our observations demonstrate the feasibility of using HSV vectors to protect neurons from necrotic insults. Although this study has concentrated on the delivery of gt, other genes with therapeutic or protective capability might also be used.

Animals↗
PubMed1994

Glucocorticoids increase extracellular [3H]D-aspartate overflow in hippocampal cultures during cyanide-induced ischemia.

Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, exacerbate neuronal death in the hippocampus during ischemia. Since ischemia brain damage is ascribed to an elevated level of extracellular excitatory amino acids (EAAs), this study was undertaken to investigate the effect of GCs on EAA homeostasis in hippocampal cell cultures during the insult of cyanide exposure. Using D-[2,3-3H]aspartic acid ([3H]D-Asp) as a tracer, we found that corticosterone (CORT, the physiological GC in rats) increased the accumulation of extracellular [3H]D-Asp by 25% in hippocampal cultures during cyanide-induced ischemia. CORT had no effect on the release of [3H]D-Asp. Instead, analysis of [3H]D-Asp uptake kinetics indicates that CORT decreased the maximum uptake rate and the Michaelis constant by 44% and 50%, respectively, in cells treated with cyanide. It is concluded that, during cyanide-induced ischemia, CORT might enhance extracellular overflow of [3H]D-Asp by decreasing its uptake, thereby endangering neurons.

Animals↗
PubMed1994

Glucocorticoids accelerate ATP loss following metabolic insults in cultured hippocampal neurons.

Glucocorticoids (GCs), adrenal steroids released during stress, can damage the hippocampus outright and increase hippocampal vulnerability to metabolic insults. Changes in ATP levels were measured in response to aglycemia and to cyanide in cultured hippocampal neurons that had been exposed to high- and low-GC conditions. GCs did not depress baseline ATP levels but did accelerate the rate of the decline in ATP concentrations observed during the metabolic insults. These results support the hypothesis that GCs increase neuronal vulnerability by disrupting cellular metabolism and agree with similar findings in hippocampal astrocytes.

Adenosine Triphosphate↗
PubMed1994

Characterization of mineralocorticoid and glucocorticoid receptors in primate brain.

Characteristics of neural corticosteroid receptors were studied in 51 adrenally-intact macaque monkeys using a modification of a corticosteroid receptor assay developed in this laboratory for rodent studies. Using cortisol as a ligand, two receptor subtypes could be distinguished and with similar Kd's to those observed in rodents, as measured with corticosterone. The time course showed maximum binding for mineralocorticoid receptors at 24 h and for glucocorticoid at 4 h. There were regional differences in the number of available binding sites for each receptor type, as well as an inverse correlation between the concentration of cortisol in the blood at the time of death and the number of available binding sites. In general this paper emphasizes the similarities between such receptors in primate and those in other species, similarities that could be detected despite the technical constraints of studying tissue taken from non-adrenalectomized animals.

Animals↗
PubMed1994

Physiological elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus.

Glucocorticoids (GCs) are secreted during stress and can damage the hippocampus over the course of aging and impair the capacity of hippocampal neurons to survive excitotoxic insults. Using microdialysis, we have previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid-induced seizures. In that study, adrenalectomized rats maintained on minimal GC concentrations were compared with those exposed to GCs elevated to near-pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate and aspartate profiles; this was done by implanting adrenalectomized rats with GC-secreting pellets, which produce stable and controllable circulating GC concentrations. We observe that incremental increases in GC concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glutamate response to kainic acid. Elevating GC concentrations from the circadian trough to peak doubled cumulative glutamate accumulation, whereas a rise into the stress range caused a fourfold increase in accumulation. Similar, although smaller, effects also occurred with aspartate accumulation (as well as with taurine but not glutamine accumulation). These data show that the highly elevated GC concentrations that accompany neurological insults such as seizure or hypoxia-ischemia will greatly exacerbate the glutamate accumulation at that time. Furthermore, stress levels of GCs augmented glutamate accumulation even in the absence of an excitotoxic insult, perhaps explaining how sustained stress itself damages the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1994

Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability.

We have studied some of the neuroendocrine and social correlates of dexamethasone resistance in a nonhuman primate population. Subjects were 51 male Macaca fascicularis monkeys with known behavioral histories and who had been given dexamethasone (DEX) suppression tests a week prior to killing. We compared the subset of monkeys who were most DEX responsive (post-DEX cortisol values of 3.1 +/- 0.5 micrograms/dl) versus a DEX-resistant subset (cortisol values of 9.2 +/- 2.0 micrograms/dl); we found two features that distinguished these groups: (a) DEX-resistant monkeys had significantly fewer available glucocorticoid receptor (GR) binding sites in the hippocampus; they did not differ in numbers of mineralocorticoid receptor (MR) sites in the hippocampus, nor in numbers for either receptor in the cortex or hypothalamus as a whole. (b) Animals had resided for a number of years in social groups that were either stable or were repeatedly destabilized by changing of group membership; the latter has been shown to constitute a sustained stressor. DEX-resistant animals were more than twice as likely to have come from an unstable group as were DEX-responsive monkeys. Rodent studies have shown that sustained stress can cause a selective downregulatory decrease in the numbers of hippocampal corticosteroid receptors, and that such a loss is associated with DEX resistance. The present data suggest similar associations in the primate, and may be of relevance to the DEX resistance observed in a subset of human depressives.

Animals↗
PubMed1993

Potential behavioral modification of glucocorticoid damage to the hippocampus.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, can damage the hippocampus, a principal neural target site for GCs. The extent of cumulative exposure to GCs influences the rate of neuron loss in the aging hippocampus, such that stress can accelerate senescent hippocampal degeneration. Moreover, under circumstances where GC exposure is insufficient to damage neurons, the hormones impair the capacity of neurons to survive neurological insults such as hypoxia-ischemia, seizure, or hypoglycemia. Considerable progress has been made in understanding how GCs endanger hippocampal neurons. The effect is a direct one, in that the endangerment is mediated by GC receptors and occurs in cultured hippocampal neurons. The endangerment is energetic in nature--the insults worsened by GCs represent energetic crises, and the GC endangerment is prevented by supplementation of neurons with energy substrates. As the likely mechanism by which GCs induce an energetic vulnerability, the steroids inhibit glucose transport in hippocampal neurons and glia. As a result of this effect of GCs upon energetics is that neurons are less capable of the costly task of containing the damaging fluxes of glutamate and calcium triggered by the neurological insults. Thus, following such insults, GCs disrupt glutamate removal and elevate synaptic glutamate concentrations, enhance the magnitude and duration of the subsequent mobilization of free cytosolic calcium, and exacerbate the magnitude of calcium-dependent degenerative events. Thus, stress has the capacity to damage the hippocampus and exacerbate the toxicity of some common neurological disorders; nevertheless, some behavioral interventions are known to cause sustained diminution of GC concentrations, and thus have the potential to protect the hippocampus from these deleterious effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Patterns of adrenocorticotropin secretagog release with hypoglycemia, novelty, and restraint after colchicine blockade of axonal transport.

Colchicine blockade of axonal transport from the paraventricular nucleus to the median eminence was used to indirectly infer hypothalamic ACTH secretagog release in awake rats. Median eminence contents of CRF, arginine vasopressin (AVP) and oxytocin (OT) were determined by RIA after insulin-induced hypoglycemia, restraint, and novelty. Insulin decreased circulating glucose concentrations and increased ACTH and corticosterone values. Median eminence CRF and AVP content declined but OT content did not. Both novelty and restraint stressors increased circulating ACTH and corticosterone concentrations. Secretagog measurements indicated decreases in OT content without concomitant decreases in either CRF or AVP with both stressors. These results indicate that: 1) colchicine blockade of axonal transport is useful in studying patterns of secretagog release in animals undergoing psychological stressors; 2) in contrast to physical stressors, OT appears to be a major component of the hypothalamic-pituitary-adrenal response to psychological stress; 3) the patterns of secretagog release differ with regards to physical and psychological stressors.

Adrenocorticotropic Hormone↗
PubMed1992

Possible mechanism by which stress accelerates growth of virally derived tumors.

Stress accelerates the growth of certain types of tumors. Here we report a possible metabolic mechanism underlying this phenomenon. Some early features of transformation include increased number of glucose transporters and greatly enhanced rates of glucose uptake; this adaptation accommodates the vast energy demands needed for neoplastic growth. In contrast, glucocorticoids, a class of steroid hormones secreted during stress, inhibit glucose transport in various tissues; this is one route by which circulating glucose concentrations are raised during stress. We reasoned that should transformed cells become resistant to this inhibitory action of glucocorticoids, such cells would gain preferential access to these elevated concentrations of glucose. In agreement with this, we observed that Fujinami sarcoma virus-transformed fibroblasts became resistant to this glucocorticoid action both in vitro and in the rat. As a result, under conditions where glucocorticoids exerted catabolic effects upon nontransformed fibroblasts (inhibition of metabolism and ATP concentrations), the opposite occurred in the virally transformed cells. We observe that this glucocorticoid resistance upon transformation cannot be explained by depletion of glucocorticoid receptors; previous studies have suggested that transformation causes an alteration in trafficking of such receptors. Because of this resistance of transformed fibroblasts to the inhibitory effects of glucocorticoids upon glucose transport, glucose stores throughout the body are, in effect, preferentially shunted to such tumors during stress.

Adenosine Triphosphate↗
PubMed1992

Corticosterone accelerates hypoxia- and cyanide-induced ATP loss in cultured hippocampal astrocytes.

Glucocorticoids potentiate injury to the rodent hippocampus following a variety of metabolic insults, including hypoxia/ischemia, both in vitro and in vivo. We have examined whether corticosterone (CORT), the principal glucocorticoid in the rat, could exacerbate hypoxic energy failure in cultured hippocampal astrocytes. Exposure to 6 h of atmospheric hypoxia (100% N2) or to 30 min of cyanide did not cause any detectable cell injury, although moderate astrocyte damage did occur alter 6 h of hypoxia in the absence of glucose. Both cyanide and hypoxia significantly reduced astrocyte ATP content, a decline that was further reduced when glucose was omitted. A 30 min exposure to 100 microM glutamate elevated ATP content under normoxic conditions but enhanced the cyanide-induced loss of ATP. A 24 h pre-treatment with CORT did not influence normoxic ATP levels but potentiated the loss of ATP following both cyanide and hypoxia. CORT also exacerbated the loss of ATP seen after combined exposure to cyanide and glutamate, as well as that following cyanide + 0 mM glucose. These results indicate that both CORT and glutamate can potentiate hypoxia-induced energy failure in hippocampal astrocytes, albeit by different mechanisms.

Adenosine Triphosphate↗
PubMed1992

Stress, glucocorticoids, and aging.

Attention has long been focused on the relationship between stress and aging, both under the guise of stress as an accelerator of normal aging and of aging as a time of impaired ability to cope with stress. This review examines the considerable amount of evidence in support of these views. We address these ideas with respect to glucocorticoids, the adrenal steroid hormones secreted during stress. In particular, we concentrate on three model systems: 1) programmed senescence in marsupial mice and semelparous fish as mediated by glucocorticoid excess; 2) glucocorticoid hypersecretion in rats and its role in damaging the aging brain; and 3) potential human and primate adrenocortical dysfunction during aging. We discuss physical and cognitive consequences of adrenocortical dysfunction in these systems, and how they may relate to human aging.

Adrenal Cortex↗
PubMed1992

Behavioral, endocrine, and immunological correlates of immigration by an aggressive male into a natural primate group.

A very aggressive young adult male entered one of three long-term study groups of yellow baboons. Papio cynocephalus, approximately 3 weeks after an immobilization project began. The immigrant male's rate of agonistic encounters was appreciably higher than average, and these interactions disproportionately involved adult females as targets. Basal cortisol concentrations were higher and total lymphocyte counts lower for individuals immobilized during the immigration situation than for other individuals; these effects were greater for females than for males. Among animals whose endocrine data were obtained during the immigration period, some were specific targets of the immigrant male's aggression and others were not. Lymphocyte counts were significantly lower for those individuals who were victims of the male's aggression than for noninvolved individuals; a nonsignificant tendency toward higher basal cortisol concentrations for victims was observed as well. The immigrant male himself had a high basal cortisol concentration, a low lymphocyte count, and a testosterone concentration that was triple the average for adult males and almost double the second highest value in the population.

Aggression↗