Roberta E. Brinton

Glucocorticoids Regulate the Synthesis of Glial Fibrillary Acidic Protein in Intact and Adrenalectomized Rats but Do Not Affect Its Expression Following Brain Injury

Short (5 days)‐to long‐term (4 months) corticosterone (CORT) administration by injection, pellet implantation, or in the drinking water decreased glial fibrillary acidic protein (GFAP) by 20–40% in hippocampus and cortex of intact rats. In contrast to CORT, adrenalectomy (ADX) caused elevations (50–125%) in hippocampus and cortex GFAP within 12 days of surgery that persisted for at least 4 months. CORT replacement of ADX rats decreased GFAP amount in hippocampus and cortex. The effects of long‐term CORT and ADX on GFAP in hippocampus and cortex were also seen in striatum, midbrain, and cerebellum, findings suggestive of brain‐wide adrenal steroid regulation of this astrocyte protein. The changes in GFAP amount due to CORT and ADX were paralleled by changes in GFAP mRNA, indicating a possible transcriptional or at least genomic effect of adrenal steroids. Glucocorticoid regulation of GFAP was relatively specific; it could not be generalized to other astrocyte proteins or other major structural proteins of neurons. The negative regulation of GFAP and GFAP mRNA by adrenal steroids suggested that increases in GFAP that result from brain injury may be attenuated by glucocorticoids. However, chronic CORT treatment of intact rats did not reverse or reduce the large increases in GFAP caused by trauma‐or toxicant‐induced brain damage. Thus, glucocorticoids and injury appear to regulate the expression of GFAP through different mechanisms. In contrast to the lack of effects of CORT on brain damage‐induced increases in GFAP, CORT treatment begun in 2‐week ADX rats, after an increase in GFAP had time to occur, did reverse the ADX‐induced increase in GFAP. These results suggest that the increase in GFAP resulting from ADX is not mediated through an injury‐linked mechanism.

Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain

The role of glucocorticoids in the in vivo regulation of glial fibrillary acidic protein (GFAP) was examined. Corticosterone administration to adult rats resulted in decreased levels of GFAP throughout the brain whereas adrenalectomy caused levels of GFAP to increase. Corticosterone administration to adrenalectomized rats lowered GFAP levels to values below those of sham controls. Thus, the expression of GFAP throughout the brain appears to be physiologically regulated by adrenal glucocorticoids.

Chapter 2 Neuroendocrine aspects of adaptation

Publisher Summary This chapter discusses the interplay among glucocorticoids and the important neuromodulatory peptide, vasopressin, and the involvement of these neuroactive substances in the process of adaptation. Neural plasticity is characterized by adaptation of neurochemical, neuroanatomical, and behavior systems. Adaptations to environmental stimuli are alterations in the responses of individual and complex ensembles of neurons, which lead to long lasting changes in their functional capabilities. The endocrine system plays an important role in this type of adaptation by acting as a signaling network that triggers both chemical and morphological changes in select populations of neurons and glial cells. The hippocampus responds to glucocorticoids both during the diurnal cycle and in response to stress. Among other effects, results of glucocorticoid actions during the diurnal cycle modify synaptic efficacy within a hippocampal system that is involved in learning and memory and is also influenced by the neuropeptide, vasopressin. A common site of vasopressin and glucocorticoid action is the noradrenaline-stimulation of cyclic AMP formation.

Glucocorticoid Receptors and Behavior: Implications for the Stress Response

Stress-induced release of glucocorticoids is one of two modes of operation of the pituitary-adrenal axis, the other being the diurnal variation of glucocorticoid levels. Both operating modes are, of course, driven by CNS release of the releasing factor, CRH, in combination with other modulators such as vasopressin and oxytocin (Vale, this volume; Plotsky, this volume; (1)). However, stress-induced release is due to environmental and experiential factors such as heat, cold, anxiety, trauma and exertion, and it results in high levels of glucocorticoids in the blood. On the other hand, diurnal variation in pituitary-adrenal function is based upon an endogenous oscillator (2), although both the light-dark cycle and the anticipation of food entrain the rhythm (3, 4).

Impact of Environmental Stress on the Expression of Insulin-Dependent Diabetes Mellitus

To investigate the influence of environmental factors on inherited tendencies, the impact of chronic environmental stress on the expression of a genetically determined autoimmune disease was explored in the bio-breeding (BB) rat, which is an animal model for human autoimmune insulin-dependent diabetes mellitus. Animals assigned at random to the experimental group received a triad of stressors designed to model chronic moderate stress over a 14-week period. Animals from 25 to 130 days of age were weighed and tested for glycosuria twice weekly. Weekly blood sampling was performed on all animals. Diabetes was diagnosed on the basis of weight loss, 2+ glycosuria, and blood glucose levels of 250+ mg/dl. We found that in the BB rat chronic stress significantly increased the incidence of the phenotypic expression of the gene for Type I diabetes. Eighty percent of the male stress and 70% of the female stress animals developed diabetes, compared with 50% in both control groups. Stressed males developed manifest diabetes at the same time as their matched controls, whereas stressed females had significantly delayed onset in relation to controls.

The Hippocampus: A Site for Modulatory Interactions Between Steroid Hormones, Neurotransmitters and Neuropeptides

The brain is a dynamic and changing organ in which synapses, dendrites and the neurochemicals of synaptic neurotransmission are continually being renewed and remodeled during the entire lifespan of an individual. Gene activity, controlled by environmental signals and mediated by circulating hormones, is fundamental to this plasticity (1). Our understanding of these relationships has arisen in part from studies that have identified and characterized the receptor sites for adrenal, gonadal and thyroid hormones in the brain (2). Together with ongoing advances in many aspects of neuroscience, and in our understanding of how steroid and thyroid hormone receptors regulate gene expression (3,4), this information has stimulated a new field of investigation into how the brain changes in response to circulating hormones.

Neuromodulation: Associative and nonlinear adaptation

Neuromodulation, the interaction between at least two chemical messengers in the nervous system, serves as a mechanism by which biochemical association can occur. A simple, yet compelling, hypothesis is that the criteria for expression of associative learning and memory are subserved by biochemical events which are also associative in nature. A neuromodulatory interaction that has been linked to memory function and which has been the subject of biochemical inquiry is the interaction between the catecholamine, norepinephrine (NE) and the neuropeptide, vasopressin (AVP). Studies described in this report show that vasopressin acts to potentiate norepinephrine (NE)-induced cyclic adenosine monophosphate (cAMP) accumulation in the hippocampus by a calcium-dependent mechanism. Results of these studies are considered in the context of the nonlinear properties of synergism and conditionality and in the context of the associative learning requirements of spatial and temporal coupling. Secondly, the calcium dependency of AVP-induced neuromodulation is considered in relation to the calcium dependency for induction of associative long-term potentiation. Lastly, the potential for changes in neuronal morphology in response to neuromodulatory events is considered. By using vasopressin potentiation of noradrenalin-induced cAMP formation as a model system, I have applied the theoretical framework of associative learning and memory to test the hypothesis that neuromodulation can serve as a biochemical analog of associative cognitive events.

Diurnal Differences and Adrenal Involvement in Calmodulin Stimulation of Hippocampal Adenylate Cyclase Activity

Calciam/calmodulin‐dependent processes are altered by manipulations of the hypothalamic‐pituitary‐adrenal axis, and are associated with changes in synaptic efficacy in the hippocampus, such as long‐term potentiation. Recent evidence indicates that there are diurnal variations in the threshold for long‐term potentiation, as well as diverse effects of the adrenals and of adrenal steroids on electrical activity related to long‐term potentiation. In order to probe possible mechanisms underlying these observations, we investigated the effects of the diurnal cycle, as well as adrenalectomy (ADX) and adrenal demedullation on adenylate cyclase activity. In hippocampal, but not cortical, membranes the adenylate cyclase response to calmodulin was higher during the beginning of the dark phase of the cycle, when endogenous corticosterone levels are high. Basal and forskolin‐stimulated adenylate cyclase activity did not exhibit diurnal variation in either brain region. ADX (6 and 14 days) depressed the adenylate cyclase response to calmodulin in hippocampal membranes, and abolished the diurnal difference. ADX had smaller effects on this response in cortical membranes. ADX also attenuated basal and forskolin‐stimulated adenylate cyclase activity, but these changes were less striking than effects on calmodulin‐stimulated activity. Demedullation (14 days), generating corticosterone levels in the low physiological range, mirrored the effects of ADX on hippocampal adenylate cyclase activity. Corticosterone (20 to 25 μg/ml in the drinking water) did not consistently prevent ADX effects on adenylate cyclase activity. These results demonstrate that adrenal effects on adenylate case activity are regionally specific within the brain, and they suggest that other adrenal secretions besides glucocorticoids may be involved in the feedback of the diurnal rhythm on the hippocampus. Taken together with our recent finding that chronic stress or corticosterone injection selectively attenuated the adenylate cyclase response to calmodulin in cortical, but not hippocampal membranes our findings provide further support for a role of the pituitary‐adrenal axis in modulating neural calmodulin‐dependent adenylate cyclase activity.