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Lawrence P Reagan

Publications and source records attributed to Lawrence P Reagan.

14 recordsLinked to original sources
PubMed2006

Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus.

BACKGROUND: In the rat hippocampus, the predominate glutamate transporters are GLT-1 and its recently identified isoform, GLT-1b. Chronic restraint stress increases GLT-1b expression throughout the hippocampus while more selectively increasing GLT-1 expression in the CA3 region. These studies suggest that GLT-1b expression is regulated by stress levels of glucocorticoids (GCs) and GLT-1 expression is regulated by stress-induced increases in extracellular glutamate levels in the CA3 region. METHODS: In order to differentiate between the actions of GCs and glutamate, we examined GLT-1 isoform expression in adrenalectomized (ADX) rats and rats exposed to stress levels of GCs. RESULTS: ADX rats revealed no significant differences in GLT-1b mRNA or protein levels compared to sham-operated controls or ADX rats given GC replacement. However, rats exposed to stress levels of GCs exhibited increases in GLT-1b protein expression in the CA3 region and the dentate gyrus. GLT-1 mRNA expression was increased by ADX, increases that were inhibited by GC replacement. Similarly, stress levels of GCs increased GLT-1 protein expression throughout the hippocampus. CONCLUSIONS: Taken together, these data indicate that GLT-1b protein expression is regulated by stress levels of GCs while the regulation of GLT-1 mRNA and protein expression provides another example of the biphasic actions of GCs in the central nervous system.

Adrenalectomy↗
PubMed2005

Neuronal insulin signal transduction mechanisms in diabetes phenotypes.

The hippocampus is an important integration center for learning and memory in the mammalian central nervous system (CNS) and is particularly sensitive and responsive to changes in insulin and glucose concentrations. Insulin administration improves cognitive performance in a variety of physiological and pathophysiological settings, including diabetes phenotypes. Our previous studies demonstrated that hyperglycemia produces behavioral, neuroanatomical and neurochemical changes in the adult rat hippocampus that are indicative of accelerated brain aging. In addition, the trafficking of insulin-sensitive glucose transporters (GLUTs) is impaired in experimental models of diabetes. Such results suggest that insulin receptor (IR) signaling may be disrupted in diabetes phenotypes, although the signaling mechanisms utilized by neurons are not clearly defined. To this end, we have employed in vivo and in vitro approaches to determine the insulin signaling pathways utilized by neurons. These methodologies provide insight into the signaling mechanisms utilized by neuronal IRs and ultimately will allow for determination of the IR signaling deficits that may contribute to accelerated brain aging in the hippocampus of diabetic subjects.

Animals↗
PubMed2005

Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity.

The genetically obese Zucker rat is a widely investigated model of pathological changes associated with type 2 diabetes. To assess cognitive function, obese and lean Zucker rats were tested on a variable-interval delayed alternation test of learning and memory. There were no group differences in learning the alternation rule or at short intervals, but obese rats were impaired at longer intervals where performance is hippocampus dependent. Plasma membrane association of the insulin sensitive glucose transporter, GLUT4, was reduced in the hippocampus of obese rats in the absence of changes in total GLUT4 and insulin receptor expression. These results parallel those of human studies in pointing to the susceptibility of the hippocampus and related structures to the adverse environment of diabetes mellitus.

Analysis of Variance↗
PubMed2004

Biphasic effects of stress upon GLUT8 glucose transporter expression and trafficking in the diabetic rat hippocampus.

Disease states such as diabetes mellitus are known to impair hippocampal glucoregulatory activities, which may contribute to cognitive deficits observed in diabetic subjects. Stress or exposure to stress levels of glucocorticoids (GCs) are also intimately involved in hippocampal glucoregulatory activities and the actions of GCs are often most evident in hyperglycemic states. Glucose transporter (GLUT) expression, activity and translocation represent components of the glucoregulatory activities of the hippocampus that may be disrupted by diabetes and stress. Accordingly, the current study examined the effects of stress, streptozotocin (STZ)-induced diabetes and the combined actions of stress and hyperglycemia upon GLUT8 mRNA expression, protein levels and intracellular trafficking in the rat hippocampus. Short-term stress in euglycemic rats had no effect upon GLUT8 mRNA, while restraint stress normalized diabetes mediated increases in GLUT8 mRNA expression in STZ treated rats. Radioimmunocytochemical analysis revealed that total GLUT8 protein levels were not altered by diabetes, short-term stress or the combined actions of hyperglycemia and stress. However, subcellular compartmentalization of GLUT8 was modulated by stress in that hippocampal GLUT8 protein levels were increased in high-density microsomal (HDM) fractions isolated from rats subjected to stress. In contrast, STZ-diabetes decreased GLUT8 protein levels in the HDM fraction, an effect that was potentiated by stress. Collectively, these results demonstrate that the actions of GCs may be dramatically different in euglycemic and hyperglycemic/insulinopenic states, suggesting that stress may increase hippocampal neuronal responsiveness under normal physiological conditions while increasing hippocampal neuronal vulnerability in pathophysiological settings such as in type 1 diabetes.

Animals↗
PubMed2004

Glucose transporter expression in the central nervous system: relationship to synaptic function.

The family of facilitative glucose transporter (GLUT) proteins is responsible for the entry of glucose into cells throughout the periphery and the brain. The expression, regulation and activity of GLUTs play an essential role in neuronal homeostasis, since glucose represents the primary energy source for the brain. Brain GLUTs exhibit both cell type and region specific localizations suggesting that the transport of glucose across the blood-brain barrier is tightly regulated and compartmentalized. As seen in the periphery, insulin-sensitive GLUTs are expressed in the brain and therefore may participate in the central actions of insulin. The aim of this review will be to discuss the localization of GLUTs expressed in the central nervous system (CNS), with a special emphasis upon the recently identified GLUT isoforms. In addition, we will discuss the regulation, activity and insulin-stimulated trafficking of GLUTs in the CNS, especially in relation to the centrally mediated actions of insulin and glucose.

Animals↗
PubMed2004

Stress-induced structural remodeling in hippocampus: prevention by lithium treatment.

Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder.

Animals↗
PubMed2004

Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine.

Excitatory amino acids play a key role in stress-induced remodeling of dendrites in the hippocampus as well as in suppression of neurogenesis in the dentate gyrus. The regulation of extracellular glutamate levels has been suggested as a potential mechanism through which repeated stress causes dendritic remodeling of CA3 pyramidal neurons. Accordingly, the current study examined the distribution and regulation of the glia glutamate transporter GLT-1 and the recently identified GLT isoform, GLT-1b, in the hippocampus of rats subjected to chronic restraint stress (CRS). We also examined the ability of the antidepressant tianeptine, which blocks CRS-induced dendritic remodeling, to modulate CRS-mediated changes in GLT-1 and GLT-1b expression. CRS increased GLT-1 mRNA expression in the dentate gyrus and CA3 region of Ammon's horn, increases that were inhibited by tianeptine. CRS more selectively increased GLT-1 protein levels in the subregion where dendritic remodeling is most prominent, namely the CA3 region, increases that were also inhibited by tianeptine administration. In contrast, GLT-1b mRNA expression was not modulated in the hippocampus in any of these groups, but CRS increased GLT-1b protein levels in all hippocampal subfields examined, increases that were unaffected by tianeptine treatment. These results point to the importance of understanding the mechanism for the differential and subregional regulation of GLT-1 isoforms in neuronal and glial compartments in the hippocampus as a basis for understanding the effects of chronic stress on structural plasticity as well as the neuroprotective properties of agents such as tianeptine.

Animals↗
PubMed2003

Decreases in neurokinin-3 tachykinin receptor-immunoreactive and -mRNA levels are associated with salt appetite in the deoxycorticosterone-treated rat.

Tachykinins are a family of neuropeptides that inhibit salt appetite. Although decreased tachykinin-mRNA levels are observed in natriorexic sodium-deplete rats, no decrease is seen in natriorexic sodium-replete rats that are administered the aldosterone-mimetic deoxycorticosterone acetate (DOCA). Since reduced synthesis of tachykinins could not account for increased appetite, we hypothesized that increased salt appetite was due to a downregulation of tachykinin receptors. Thus, we injected rats with DOCA once daily for 11 days and analyzed tachykinin receptor subtype, neurokinin 3 (NK3r)-immunoreactivity by Western blot analysis since intracerebroventricular injection of senktide (NK3r agonist) attenuates salt intake in DOCA-treated animals. We examined NK3r-immunoreactivity in several brain regions thought to be associated with the control of water and electrolyte balance including the bed nucleus of the stria terminalis, central nucleus of the amygdala, diagonal band of Broca, hippocampus, nucleus tractus solitarius, parabrachial nucleus, paraventricular nucleus of the hypothalamus, and supraoptic nucleus. Consistent with our hypothesis, we found decreased NK3r-immunoreactivity in all brain regions analyzed except for increases in the amygdala and no changes in the paraventricular nucleus of the hypothalamus. To examine whether DOCA's effects on NK3r synthesis are direct, we used differentiated N1E-115 neuroblastoma cells that express NK3r and treated them with a range of concentrations of DOCA and found a dose-dependent decrease in NK3r-mRNA abundance via Northern blotting. The present results suggest that the tachykinin receptors are downregulated after subchronic DOCA treatment and this finding is consistent with the hypothesis that suppressed inhibition of salt appetite as mediated through the tachykininergic system.

Animals↗
PubMed2003

Acute and chronic restraint stress alter the incidence of social conflict in male rats.

Stress and elevated stress hormone levels are known to alter cognition, learning, memory, and emotional responses. Three weeks of chronic stress or glucocorticoid exposure is reported to alter neuronal morphology in the hippocampus, the amygdala, and the prefrontal cortex, and to decrease neurogenesis in the dentate gyrus. Here we examine the effects of acute and chronic restraint stress exposure on the incidence of emotional responses throughout a 3-week period among adult rat conspecifics. Our data indicate that acute restraint stress (i.e., a single 6-h exposure) results in a significant reduction in aggressive conflicts among stressed males compared to experimental controls. In contrast, on Days 14 and 21, repeatedly restrained rats exhibited significantly more aggressive behaviors than controls. Blood samples taken 18 h after the last restraint session indicate that plasma concentrations of the stress hormone corticosterone (CORT) in stressed rats were equivalent to those of unstressed rats; however, the number of individually initiated aggressive acts observed positively correlated with plasma CORT measures taken at the end of the study. In contrast to studies of psychosocial stress or intruder paradigms, here we observe spontaneous emotional responses to an uncontrollable stressor in the homecage. This study provides a novel examination of the effects of chronic restraint stress on emotional responses in the home environment among cagemates. These results indicate that acute and chronic restraint stress alter the incidence of aggression, and emphasize the relevance of this model of chronic stress to studies of stress-responsive disorders characterized by aggressive behavior.

Acute Disease↗
PubMed2002

Peripheral glucose administration stimulates the translocation of GLUT8 glucose transporter to the endoplasmic reticulum in the rat hippocampus.

The expression and localization of glucose transporter isoforms play essential roles in the glucoregulatory activities of the hippocampus and ultimately contribute to cognitive status in physiological and pathophysiological settings. The recently identified glucose transporter GLUT8 is uniquely expressed in neuronal cell bodies in the rat hippocampus and therefore may contribute to hippocampal glucoregulatory activities. We show here that GLUT8 has a novel intracellular distribution in hippocampal neurons and is translocated to intracellular membranes following glucose challenge. Immunoblot analysis revealed that GLUT8 is expressed in high-density microsomes (HDM), suggesting that GLUT8 is associated with intracellular organelles under basal conditions. Immunogold electron microscopic analysis confirmed this observation, in that GLUT8 immunogold particles were associated with the rough endoplasmic reticulum (ER) and cytoplasm. Peripheral glucose administration produced a rapid twofold increase in GLUT8 levels in the HDM fraction while decreasing GLUT8 levels in low-density microsomes. Similarly, peripheral glucose administration significantly increased GLUT8 association with the rough ER in the hippocampus. Conversely, under hyperglycemic/insulinopenic conditions, namely, in streptozotocin (STZ) diabetes, hippocampal GLUT8 protein levels were decreased in the HDM fraction. These results demonstrate that GLUT8 undergoes rapid translocation to the rough ER in the rat hippocampus following peripheral glucose administration, trafficking that is impaired in STZ diabetes, suggesting that insulin serves as a stimulus for GLUT8 translocation in hippocampal neurons. Because glucose is liberated from oligosaccharides during N-linked glycosylation events in the rough ER, we propose that GLUT8 may serve to transport glucose out of the rough ER into the cytosol and in this manner contribute to glucose homeostasis in hippocampal neurons.

Animals↗
PubMed2002

Diabetes, but not stress, reduces neuronal nitric oxide synthase expression in rat hippocampus: implications for hippocampal synaptic plasticity.

Neuronal nitric oxide synthase (nNOS) plays an important role in synaptic plasticity and learning and memory. Since deficits in long-term potentiation (LTP) and learning are observed in diabetic rats and following stress, we examined the expression of nNOS mRNA and protein in the hippocampus of streptozotocin (STZ) diabetic rats and rats subjected to restraint stress. Stress did not modulate nNOS expression, while nNOS mRNA and protein levels were significantly decreased in the hippocampus of STZ diabetic rats. These results suggest that: (1) decreased expression of nNOS mRNA and protein may contribute to deficits in hippocampal dependent learning and LTP in diabetic rats; and (2) other mechanisms may be involved in stress mediated decreases in hippocampal synaptic plasticity.

Animals↗
PubMed2002

GLUT8 glucose transporter is localized to excitatory and inhibitory neurons in the rat hippocampus.

Fluorescence immunohistochemistry was performed to characterize the distribution and phenotype of GLUT8-positive neurons in rat brain and to compare the cellular distribution of GLUT8 with GLUT3 in the hippocampus. Based upon the absence of co-localization with the non-neuronal markers GFAP (astroglial) and OX42 (microglial), it appears that GLUT8 is expressed exclusively in neurons. At the cellular level, GLUT8 immunofluorescence was localized to neuronal cell bodies and the most proximal dendrites of inhibitory and excitatory neurons while GLUT3 immunofluorescence was localized to the neuropil in the hippocampus. These results demonstrate that GLUT8 is a neuron-specific glucose transporter expressed in the neuronal cell bodies of excitatory and inhibitory neurons in the rat hippocampus.

Animals↗
PubMed2002

Studies of hormone action in the hippocampal formation: possible relevance to depression and diabetes.

OBJECTIVES: The goal is to review the plasticity and vulnerability of the hippocampus, a brain structure involved in episodic, declarative, contextual and spatial learning and memory, as well as its being a component in the control of autonomic and vegetative functions such as ACTH secretion. It discusses its possible role in the regulation of glucose homeostasis, and the need of hippocampal neurons for glucose because of their high metabolic activity. The hippocampus is also vulnerable to damage by stroke and head trauma and susceptible to damage during aging and repeated stress, and is sensitive to the effects of diabetes. METHODS: A summary of recent work in the author's laboratory and related work in the field using citations of literature based, in part, on Medline searches. CONCLUSIONS: In addition to its vulnerability, the hippocampus is also a plastic and adaptable brain region that is capable of considerable structural reorganization, including remodeling of dendrites and neurogenesis of dentate gyrus granule neurons in response to repeated stress. Animal models of Type 1 diabetes show accelerated remodeling of dendrites, and Type 2 diabetes remains to be studied in this regard. This is relevant to major depressive illness, in which a progressive atrophy of the hippocampal formation is reported and is accompanied by impairment of cognitive function in those subjects with hippocampal shrinkage. Therefore, hippocampal atrophy in depression, as well as in diabetes, may reflect either damage or plasticity involving structural reorganization that is potentially treatable.

Aging↗