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Biomedical subjects

A M Magariños

Publications and source records attributed to A M Magariños.

At least 19 recordsLinked to original sources
PubMed2001

Peritoneal implantation of macroencapsulated porcine pancreatic islets in diabetic rats ameliorates severe hyperglycemia and prevents retraction and simplification of hippocampal dendrites.

The hippocampus of rats with uncontrolled insulin-dependent diabetes undergoes retraction and simplification of apical dendrites of the CA3 pyramidal neurons and synaptic rearrangements within mossy fiber terminals that could alter hippocampal connectivity and function. The intraperitoneal implantation of hydrophilic agarose macrobeads containing porcine islets for 17 days in rats with streptozotocin-induced diabetes results in normalization of body weight gain, significant control of hyperglycemia and prevention of hippocampal dendritic remodeling, and therefore, provides an effective therapeutic option.

Animals↗
PubMed2000

Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress.

We report that 9 d of uncontrolled experimental diabetes induced by streptozotocin (STZ) in rats is an endogenous chronic stressor that produces retraction and simplification of apical dendrites of hippocampal CA3 pyramidal neurons, an effect also observed in nondiabetic rats after 21 d of repeated restraint stress or chronic corticosterone (Cort) treatment. Diabetes also induces morphological changes in the presynaptic mossy fiber terminals (MFT) that form excitatory synaptic contacts with the proximal CA3 apical dendrites. One effect, synaptic vesicle depletion, occurs in diabetes as well as after repeated stress and Cort treatment. However, diabetes produced other MFT structural changes that differ qualitatively and quantitatively from other treatments. Furthermore, whereas 7 d of repeated stress was insufficient to produce dendritic or synaptic remodeling in nondiabetic rats, it potentiated both dendritic atrophy and MFT synaptic vesicle depletion in STZ rats. These changes occurred in concert with adrenal hypertrophy and elevated basal Cort release as well as hypersensitivity and defective shutoff of Cort secretion after stress. Thus, as an endogenous stressor, STZ diabetes not only accelerates the effects of exogenous stress to alter hippocampal morphology; it also produces structural changes that overlap only partially with those produced by stress and Cort in the nondiabetic state.

Animals↗
PubMed2000

Oxidative stress and HNE conjugation of GLUT3 are increased in the hippocampus of diabetic rats subjected to stress.

Recent studies demonstrate that cellular, molecular and morphological changes induced by stress in rats are accelerated when there is a pre-existing strain upon their already compromised adaptive responses to internal or external stimuli, such as may occur with uncontrolled diabetes mellitus. The deleterious actions of diabetes and stress may increase oxidative stress in the brain, leading to increases in neuronal vulnerability. In an attempt to determine if stress, diabetes or stress+diabetes increases oxidative stress in the hippocampus, radioimmunocytochemistry was performed using polyclonal antisera that recognize proteins conjugated by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). Radioimmunocytochemistry revealed that HNE protein conjugation is increased in all subregions of the hippocampus of streptozotocin (STZ) diabetic rats, rats subjected to restraint stress and STZ diabetic rats subjected to stress. Such increases were not significant in the cortex. Because increases in oxidative stress may contribute to stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization, we examined the stress/diabetes mediated HNE protein conjugation of the neuron specific glucose transporter, GLUT3. GLUT3 immunoprecipitated from hippocampal membranes of diabetic rats subjected to stress exhibited significant increases in HNE immunolabeling compared to control rats, suggesting that HNE protein conjugation of GLUT3 contributes to decreases in neuronal glucose utilization observed during diabetes and exposure to stress. Collectively, these results demonstrate that the hippocampus is vulnerable to increases in oxidative stress produced by diabetes and stress. In addition, increases in HNE protein conjugation of GLUT3 provide a potential mechanism for stress- and diabetes-mediated decreases in hippocampal neuronal glucose utilization.

Aldehydes↗
PubMed2000

Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites.

Male rats housed in mixed-sex groups in a visible burrow system (VBS) form a dominance hierarchy in which subordinate animals show stress-related changes in behavior, endocrine function and neurochemistry. Dominants also appear to be moderately stressed compared to controls, although these animals do not develop the more pronounced behavioral and physiological deficits seen in the subordinates. In the present study, we examined the effects of chronic psychosocial stress on the morphology of Golgi-impregnated CA3 pyramidal neurons. In addition, since serotonin has been implicated in the mechanisms mediating the dendritic remodeling seen with other chronic stress regimens, we used quantitative autoradiography to measure binding to the serotonin transporter (5HTT) in hippocampus and dorsal and median raphe. Chronic social stress led to a decrease in the number of branch points and total dendritic length in the apical dendritic trees of CA3 pyramidal neurons in dominant animals compared to unstressed controls; subordinates also had a decreased number of dendritic branch points. [(3)H]paroxetine binding to the 5HTT was decreased in Ammon's horn in both dominants and subordinates compared to controls, while 5HTT binding remained unchanged in dentate gyrus and raphe. The similarity of the changes in 5HTT binding and dendritic arborization between both groups of VBS animals, despite apparent differences in stressor severity, suggests that these changes may be part of the normal adaptive response to chronic social stress. The mechanisms underlying dendritic remodeling in CA3 pyramidal neurons are likely to involve stress-induced changes in glucocorticoids and in 5HT and other transmitters.

Animals↗
PubMed1999

Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress.

Both repeated stress and corticosterone administration induce remodeling of apical dendrites of hippocampal CA3 pyramidal neurons. Circulating glucocorticoids are involved in the mechanism that produces atrophy, along with excitatory amino acids and serotonin (5-hydroxytryptamine, 5-HT). We used 5-HT-related antidepressants and a benzodiazepine in order to explore indirectly the role of serotonin and GABA(A)-benzodiazepine receptors in the stress-induced structural changes visualized by the Golgi impregnation of the rat hippocampus. The 5-HT reuptake enhancer (+/-)-tianeptine prevented the dendritic atrophy caused by repeated restraint stress in a non-stereoselective fashion and two 5-HT reuptake antagonists, fluoxetine and fluvoxamine, failed to block dendritic atrophy. Tianeptine also functions as a therapeutic tool since it reversed the already established hippocampal atrophy caused by treatment with corticosterone for 3 weeks. Finally, the benzodiazepine agonist adinazolam was effective in preventing the stress-induced dendritic atrophy. These findings suggest that the synaptic availability of 5-HT is involved in the mechanism leading to stress-induced dendritic remodeling and supports the idea that the hippocampal inhibitory GABAergic tone may play a regulatory role.

Animals↗
PubMed1999

Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.

This study investigated whether 21 days of restraint stress (6 hr/day) and the subsequent hippocampal dendritic atrophy would affect fear conditioning, a memory task with hippocampal-dependent and hippocampal-independent components. Restraint-stressed rats were injected daily (21 days) with tianeptine (10 mg/kg; to prevent hippocampal atrophy) or vehicle then tested on fear conditioning (Days 23-25, with 2 tone-shock pairings) and open field (Day 25). Restraint stress enhanced freezing to context (hippocampal-dependent behavior) and tone (hippocampal-independent) and decreased open-field exploration, irrespective of whether tianeptine was given. Results confirmed that stress produced CA3 dendritic atrophy and tianeptine prevented it. Moreover, CA3 dendritic atrophy was not permanent but reversed to control levels by 10 days after the cessation of restraint stress. These data argue that different neural substrates underlie spatial recognition memory and fear conditioning.

Animals↗
PubMed1999

Neurological changes induced by stress in streptozotocin diabetic rats.

Previous studies from our laboratory demonstrated that chronic stress produces molecular, morphological, and ultrastructural changes in the rat hippocampus that are accompanied by cognitive deficits. Glucocorticoid impairment of glucose utilization is proposed as a causative factor involved in stress-induced changes. Current studies have examined the neurological changes induced by stress in rats with a preexisting strain upon their homeostatic load--namely, in streptozotocin (stz)-diabetic rats. Administration of stz (70 mg/kg, i.v.) produced diabetic symptoms such as weight loss, polyuria, polydipsia, hyperglycemia, and neuroendocrine dysfunction. Morphological analysis of hippocampal neurons revealed that diabetes alone produced dendritic atrophy of CA3 pyramidal neurons, an effect potentiated by 7 days of restraint stress. Analysis of genes critical to neuronal homeostasis revealed that glucose transporter 3 (GLUT3) mRNA and protein levels were specifically increased in the hippocampus of diabetic rats, while stress had no effect upon GLUT3 expression. Insulin-like growth factor (IGF) receptor expression was also increased in the hippocampus of diabetic rats subjected to stress. In spite of the activation of these adaptive mechanisms, diabetic rats subjected to stress also had signs of neuronal damage and oxidative damage. Collectively, these results suggest that the hippocampus of diabetic rats is extremely susceptible to additional stressful events, which in turn can lead to irreversible hippocampal damage.

Animals↗
PubMed1999

Regulation of GLUT-3 glucose transporter in the hippocampus of diabetic rats subjected to stress.

Previous studies from our laboratory have demonstrated that chronic stress produces molecular, morphological, and ultrastructural changes in the rat hippocampus that are accompanied by cognitive deficits. Glucocorticoid attenuation of glucose utilization is proposed to be one of the causative factors involved in stress-induced changes in the hippocampus, producing an energy-compromised environment that may make hippocampal neuronal populations more vulnerable to neurotoxic insults. Similarly, diabetes potentiates neuronal damage in acute neurotoxic events, such as ischemia and stroke. Accordingly, the current study examined the regulation of the neuron-specific glucose transporter, GLUT-3, in the hippocampus of streptozotocin-induced diabetic rats subjected to restraint stress. Diabetes leads to significant increases in GLUT-3 mRNA and protein expression in the hippocampus, increases that are not affected by stress. Collectively, these results suggest that streptozotocin-induced increases in GLUT-3 mRNA and protein expression in the hippocampus may represent a compensatory mechanism to increase glucose utilization during diabetes and also suggest that modulation of GLUT-3 expression is not responsible for glucocorticoid impairment of glucose utilization.

Animals↗
PubMed1998

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox.

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 micrograms/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.

Administration, Oral↗
PubMed1997

Chronic stress alters synaptic terminal structure in hippocampus.

Repeated psychosocial or restraint stress causes atrophy of apical dendrites in CA3 pyramidal neurons of the hippocampus, accompanied by specific cognitive deficits in spatial learning and memory. Excitatory amino acids mediate this atrophy together with adrenal steroids and the neurotransmitter serotonin. Because the mossy fibers from dentate granule neurons provide a major excitatory input to the CA3 proximal apical dendrites, we measured ultrastructural parameters associated with the mossy fiber-CA3 synapses in control and 21-day restraint-stressed rats in an effort to find additional morphological consequences of stress that could help elucidate the underlying anatomical as well as cellular and molecular mechanisms. Although mossy fiber terminals of control rats were packed with small, clear synaptic vesicles, terminals from stressed animals showed a marked rearrangement of vesicles, with more densely packed clusters localized in the vicinity of active zones. Moreover, compared with controls, restraint stress increased the area of the mossy fiber terminal occupied by mitochondrial profiles and consequently, a larger, localized energy-generating capacity. A single stress session did not produce these changes either immediately after or the next day following the restraint session. These findings provide a morphological marker of the effects of chronic stress on the hippocampus that points to possible underlying neuroanatomical as well as cellular and molecular mechanisms for the ability of repeated stress to cause structural changes within the hippocampus.

Animals↗
PubMed1996

Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews.

We have shown previously that repeated laboratory restraint stress or daily corticosterone administration affects the structure of CA3 hippocampal neurons in rats. In the present study, we investigated the effect of repeated daily psychosocial stress on the structure of hippocampal CA3 pyramidal neurons in male tree shrews (Tupaia belangeri). Male tree shrews develop social hierarchies in which subordinates show characteristic changes in physiological and behavioral parameters when confronted with a dominant. In the present experiments, subordinate animals lost body weight soon after starting the daily social conflict, and urinary excretion of cortisol was elevated throughout the experiment as compared with the control period. Golgi-impregnated brain tissue from subordinates exposed to 28 d (1 hr/d) of social confrontations was compared with that from control nonstressed animals. The apical dendrites of the CA3 pyramidal cells from subordinates had a decreased number of branch points and total dendritic length as compared with controls. No differences were observed in apical dendritic spine density or in the basal dendritic tree morphology. The stress-induced CA3 apical dendritic atrophy in subordinates was prevented by administering daily oral doses of the antiepileptic drug phenytoin (Dilantin, Sigma, St. Louis, MO) (200 mg/kg), which interferes with excitatory amino acid (EAA) action. These results suggest that the naturalistic stressor psychosocial stress induces specific structural changes in hippocampal neurons of subordinate male tree shrews. These changes, like those in the rat after glucocorticoid treatment or restraint stress, probably are mediated by activation of the hypothalamo-pituitary-adrenal-axis acting in concert with endogenous EAAs from mossy fiber input.

Animals↗
PubMed1996

Restraint stress reversibly enhances spatial memory performance.

The effects of restraint stress on performance of a spatial memory task, the eight arm radial maze, was examined in rats. When stress was given for 6 h/day for 7 days and performance evaluated days 10-13 post stress, no effect on performance was noted; however, daily restraint stress for 13 days caused a small, but significant, enhancement of performance days 10-13 post stress. Stressed rats performed better than controls: their number of correct choices in the first 8 visits was higher than the controls, and stressed rats took fewer total choices to finish the maze than controls. Stress-dependent, enhanced performance does not appear permanent since further maze testing on days 14 and 15 post stress showed no differences between the groups. Performance of the stressed rats significantly correlated with their stress-induced, serum corticosterone levels measured after 6 h of restraint on the last day of restraint, day 13 (r = -0.63, P < 0.05); rats with higher levels of CORT took fewer choices to finish the task. Examination of hippocampal CA3c pyramidal neurons with Golgi techniques showed no effect of stress on the basal or apical dendritic arbors. Since our previous study showed that 21 days of restraint stress is associated with impaired spatial memory performance (10), these results suggest that the duration of stress may differentially affect learning/memory with shorter periods of stress serving an adaptive function while longer durations causing maladaptive changes.

Animals↗
PubMed1995

Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation.

Studies were performed in vivo on the dentate gyrus to investigate the possible involvement of Type I and Type II adrenal steroid receptors in the mediation of reported adrenal steroid effects on long-term potentiation, through the use of specific Type I and Type II receptor agonists and antagonists. In adrenalectomized rats, administration of aldosterone, a specific Type I agonist, produced a marked enhancement in long-term potentiation, in comparison to either the adrenalectomized or sham adrenalectomized controls. Administration of RU 28318, a Type I antagonist, which by itself had minimal effects, blocked the aldosterone enhancement. In contrast, administration of the specific Type II agonist, RU 28362, produced a marked decrement in the induction of long-term potentiation. The RU 28362 effect was blocked by a prior injection of the Type II antagonist, RU 38486. Neither adrenalectomy nor administration of any of the steroid agonists or antagonists had noticeable effects on neuronal excitability (as determined by the field potentials), nor on post-tetanic potentiation. These findings are consistent with other studies that have shown a biphasic effect of increasing levels of corticosterone on long-term or prime burst potentiation. Taken together, these studies suggest that Type I receptors, with a high affinity for corticosterone, and Type II receptors, having a lower affinity for corticosterone, form a two-level recognition system to modulate induced synaptic plasticity in opposite directions in the dentate gyrus and possibly also in Ammon's horn.

Adrenal Cortex Hormones↗
PubMed1995

Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors.

Repeated restraint stress induces an atrophy of apical dendrites of CA3c pyramidal neurons in the hippocampus, but the relationship between stress and adrenocortical activation has not been thoroughly investigated. In order to better understand the relationship between neural and non-neural indices of the severity of stress, we investigated the temporal relationship between CA3c dendritic atrophy and indices of adrenal steroid stress responsiveness. For this purpose, we used two different stress regimens: repeated restraint stress (6 h/day) and a chronic multiple stress paradigm (shaking, restraint and swimming, each day), differing in the degree of adrenal activation produced over 14 and 21 days. Atrophy of dendrites of CA3c neurons was found after 21 days of stress, but not after 14 days, and was of a similar magnitude for both stressors. However, non-neural measures differed between the two stress paradigms: (i) chronic restraint stress caused a significant habituation by day 21 in the corticosterone response to acute restraint, whereas chronic multiple stress exposure was not accompanied by habituation of the corticosterone response to restraint; (ii) chronic restraint stress caused neither adrenal hypertrophy nor thymus atrophy, but did reduce the rate of body weight gain throughout the 21 days, whereas chronic multiple stress caused a transient adrenal hypertrophy (on day 14), delayed suppression of thymus weight (on day 21) and transient reduction of body weight gain (on days 7 and 14, but not on day 21). Thus the non-neural indices of response to stress--although complex in their time course--suggest that the multiple stress regimen is a somewhat more potent chronic stressor for corticosterone and adrenal responses. Yet both stress regimens produced the same degree of apical dendritic atrophy in CA3c pyramidal neurons. These results are consistent with a model in which adrenocortical secretion plays a permissive role in enabling another agent, namely, excitatory amino acids, to produce the final effect.

Animals↗
PubMed1995

Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors.

Repeated restraint stress of rats for 21 days causes atrophy of apical dendrites of hippocampal CA3c pyramidal neurons. This effect is mimicked by daily corticosterone treatment for 21 days and is prevented y the anti-epileptic drug, phenytoin, known to interfere with excitatory amino acid release and action. The present study was designed to investigate the involvement of endogenous corticosterone secretion and excitatory amino acid receptors in the stress-induced hippocampal dendritic atrophy. Treatment of chronically stressed rats with the steroid synthesis blocker cyanoketone prevented stress-induced dendritic atrophy. Cyanoketone-treated animals showed an impaired corticosterone secretion in response to the stressor, while basal levels were maintained. Besides the involvement of endogenous corticosterone secretion, N-methyl-D-aspartate receptors also play a role, since the competitive receptor antagonist, CGP 43487, blocked stress-induced dendritic atrophy. In contrast, NBQX, a competitive inhibitor of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, was ineffective at a dose that blocks ischemic damage. These results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-D-aspartate receptors play a major role in driving the atrophy.

2-Amino-5-phosphonovalerate↗
PubMed1995

Hippocampal homosynaptic long-term depression/depotentiation induced by adrenal steroids.

The effects of adrenal steroids on synaptic plasticity were investigated in the dentate gyrus of the hippocampus. Experiments were performed in either adrenalectomized or intact (non-adrenalectomized), anesthetized rats. High-frequency stimulation was applied to the medial perforant pathway at three different frequencies; 100, 200 or 400 Hz, either post- or pre- and post-administration of the specific Type-II adrenal steroid receptor agonist RU 28362. High-frequency stimulation prior to RU 28362 administration produced a frequency-dependent long-term potentiation of the population spike, with 100 Hz showing no long-term potentiation and 400 Hz the highest degree of potentiation. In contrast, following administration of RU 28362, high-frequency stimulation produced a long-term depression (in comparison to baseline). In the experiments in which high-frequency stimulation was applied both pre- and post-RU 28362 administration, the size of the population spike was initially potentiated and then depotentiated after the RU 28362 injection. This effect was also frequency dependent, although opposite to the long-term potentiation effect. That is, 400 Hz was the least effective frequency for inducing long-term depression/depotentiation, while 100 Hz was the most effective. Long-term depression/depotentiation was immediate following high-frequency stimulation and lasted for the extent of the recording session, in some cases longer than 1 h. Similar to the finding reported in the accompanying paper, induction of long-term potentiation was substantially suppressed by RU 28362. However, in a number of experiments long-term potentiation could still be induced after RU 28362 administration, even after long-term depression/depotentiation had been established. In these cases, stimulation at the higher frequencies was necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

Type I adrenal steroid receptors prolong hippocampal long-term potentiation.

The effects of Type I adrenal steroid receptors in prolonging synaptic plasticity in the dentate gyrus of freely behaving rats was investigated. Rats were implanted with chronic, bilateral stimulating and recording electrodes in the perforant pathway and dentate gyrus, respectively, and adrenalectomized (ADX). After a 2-3 day recovery period, baseline recordings of field potentials were made followed by administration of aldosterone or vehicle. One hour later, high frequency stimulation (HFS; chosen to produce comparable long-term potentiation (LTP) in the aldosterone-treated and control groups) was applied unilaterally and recording was continued for 1 h and again performed at 3, 24 and 48 h. LTP in ADX controls decayed significantly within 3 h, and returned to baseline levels at 24 h. In contrast, the aldosterone-treated animals showed enhanced LTP at 3, 24 and 48 h. These findings demonstrate that aldosterone both enhances and prolongs hippocampal plasticity.

Adrenal Glands↗