Glucocorticoids influence brain glycogen levels during sleep deprivation

We investigated whether glucocorticoids [i.e., corticosterone (Cort) in rats] released during sleep deprivation (SD) affect regional brain glycogen stores in 34-day-old Long-Evans rats. Adrenalectomized (with Cort replacement; Adx+) and intact animals were sleep deprived for 6 h beginning at lights on and then immediately killed by microwave irradiation. Brain and liver glycogen and glucose and plasma glucose levels were measured. After SD in intact animals, glycogen levels decreased in the cerebellum and hippocampus but not in the cortex or brain stem. By contrast, glycogen levels in the cortex of Adx+ rats increased by 43% (P < 0.001) after SD, while other regions were unaffected. Also in Adx+ animals, glucose levels were decreased by an average of 28% throughout the brain after SD. Intact sleep-deprived rats had elevations of circulating Cort, blood, and liver glucose that were absent in intact control and Adx+ animals. Different responses between brain structures after SD may be due to regional variability in metabolic rate or glycogen metabolism. Our findings suggest that the elevated glucocorticoid secretion during SD causes brain glycogenolysis in response to energy demands.     

Glucocorticoids and the hippocampus

When threatened, the rapid induction of fear and anxiety responses is adaptive. This article summarizes the current knowledge of the neurobiological development of behavioral inhibition, a prominent response occurring in fear and anxiety-provoking situations. In the rat, behavioral inhibition as exemplified by freezing first appears near the end of the second postnatal week. This emergence of freezing coincides with the developmental period marked by the rapid increase in plasma concentrations of glucocorticoids. Studies show that removal of glucocorticoids at this time severely impairs the age-dependent appearance of freezing. This behavioral impairment produced by adrenalectomy, however, is prevented by exogenous glucocorticoid administration. The effectiveness of glucocorticoids in facilitating the development of freezing appears to be caused by its actions in the hippocampus. In particular, glucocorticoids appear to play a vital role in the postnatal cellular development of the hippocampal dentate gyrus. Doses of glucocorticoids shown to reverse the behavioral inhibitory deficits occurring after adrenalectomy are ineffective when hippocampal dentate granule neurons are destroyed by neurotoxins. Notably, site-specific administration of glucocorticoids to the dorsal hippocampus is successful in promoting the occurrence of freezing in the adrenalectomized rat pup. It is hypothesized that glucocorticoids exert their behavioral inhibitory effects by influencing the development of the septohippocampal cholinergic system. Support for this hypothesis is derived from work demonstrating the importance of glucocorticoids on nerve growth factor systems that play a critical role in septohippocampal cholinergic survival.     

Hedgehog trafficking, cilia and brain functions

The primary cilium has recently emerged as an important center for transduction of the Sonic Hedgehog (Shh) signal. Genetic studies have shown that Shh signaling at the level of primary cilia is essential for patterning the ventral neural tube and regulating adult stem cells. Some defects observed in human diseases and resulting from mutations affecting the organization of the primary cilium have been attributed to defective Shh signaling. The recent development of Shh pathway inhibitors for treating tumors linked to perturbations of Shh signaling has fostered studies to understand their mechanism of action in Shh receptor complex trafficking at the primary cilium.     

Glucocorticoids and fetal lung development

Acceleration of fetal lung development by administration of glucocorticoid hormones has been demonstrated in a number of mammalian species. Dexamethasone 10⁻⁵ M significantly depressed protein content per explant in the presence and absence of insulin. Insulin did not alter the protein content but significantly increased radioactive choline incorporation. However, dexamethasone provided no added stimulation above that observed with insulin alone. The incorporation of radioactive choline and specific activities in isolated phosphatidylcholine were almost identical in control and dexamethasone (10⁻⁷ M) treated explants. The data presented demonstrate a modest but significant increase in choline incorporation using a concentration of dexamethasone of 10⁻⁹ M. At higher concentrations of dexamethasone, the incorporation was significantly depressed using an 8 day exposure time. Although choline incorporation increases as a function of gestational age with a burst in rate on the last day of fetal life, dexamethasone suppresses this activity at all developmental ages past 19.5 days. The only conclusion that appears valid at this time is the rat fetal lung system reported here differs in an unknown way when compared to the rabbit monolayer system, the human organ culture, and the in vivo situation.     

Metabolism and functions of phosphatidylserine in mammalian brain

Phosphatidylserine (PtdSer) is involved in cell signaling and apoptosis. The mechanisms regulating its synthesis and degradation are still not defined. Thus, its role in these processes cannot be clearly established at molecular level. In higher eukaryotes, PtdSer is synthesized from phosphatidylethanolamine or phosphatidylcholine through the exchange of the nitrogen base with free serine. PtdSer concentration in the nervous tissue membranes varies with age, brain areas, cells, and subcellular components. At least two serine base exchange enzymes isoforms are present in brain, and their biochemical properties and regulation are still largely unknown because their activities vary with cell type and/or subcellular fraction, developmental stage, and differentiation. These peculiarities may explain the apparent contrasting reports. PtdSer cellular levels also depend on its decarboxylation to phosphatidylethanolamine and conversion to lysoPtdSer by phospholipases. Several aspects of brain PtdSer metabolism and functions seem related to the high polyunsaturated fatty acids content, particularly docosahexaenoic acid (DHA).     

Structure and functions of the brain orexin-containing neurons

The results of investigations of the new discovered brain orexin neurons, their chemical structure, localization and functions are reviewed. The following data are described: the specifics of orexins mRNA, orexins A and B and their receptors; connections between orexin neurons and neurons from different structures of the brain and spinal cord and the participation of the orexin neuron system in the functional regulation.     

Glucocorticoids and acute phase proteins

Glucocorticoids as well as acute phase proteins participate in non-specific host defence as well as in restoring host integrity after injury. Plasma levels of both compounds augment during the inflammatory reaction. However, glucocorticoids also have physiological effects that share similar molecular mechanisms with the family of steroids. During the inflammatory reaction, and for participating in host defense, glucocorticoids, together with augmented cytokines, use new signalling pathways. In doing so, they participate in the positive or negative control of inflammatory mediator synthesis. For example, they induce the synthesis of acute phase proteins in synergy with interleukin 6, interleukin 1 and TNF alpha.     

Zinc homeostasis and functions of zinc in the brain

The brain barrier system, i.e., the blood-brain and blood-cerebrospinal fluid barriers, is important for zinc homeostasis in the brain. Zinc is supplied to the brain via both barriers. A large portion of zinc serves as zinc metalloproteins in neurons and glial cells. Approximately 10% of the total zinc in the brain, probably ionic zinc, exists in the synaptic vesicles, and may serve as an endogenous neuromodulator in synaptic neurotransmission. The turnover of zinc in the brain is much slower than in peripheral tissues such as the liver. However, dietary zinc deprivation affects zinc homeostasis in the brain. Vesicular zinc-enriched regions, e.g., the hippocampus, are responsive to dietary zinc deprivation, which causes brain dysfunctions such as learning impairment and olfactory dysfunction. Olfactory recognition is reversibly disturbed by the chelation of zinc released from amygdalar neuron terminals. On the other hand, the susceptibility to epileptic seizures, which may decrease vesicular zinc, is also enhanced by zinc deficiency. Therefore, zinc homeostasis in the brain is closely related to neuronal activity. Even in adult animals and probably adult humans, adequate zinc supply is important for brain functions and prevention of neurological diseases.     

Endocrine functions of brain in adult and developing mammals

The main prerequisite for organism’s viability is the maintenance of the internal environment despite changes in the external environment, which is provided by the neuroendocrine control system. The key unit in this system is hypothalamus exerting endocrine effects on certain peripheral organs and anterior pituitary. Physiologically active substances of neuronal origin enter blood vessels in the neurohemal parts of hypothalamus where no blood-brain barrier exists. In other parts of the adult brain, the arrival of physiologically active substances is blocked by the blood-brain barrier. According to the generally accepted concept, the neuroendocrine system formation in ontogeny starts with the maturation of peripheral endocrine glands, which initially function autonomously and then are controlled by the anterior pituitary. The brain is engaged in neuroendocrine control after its maturation completes, which results in a closed control system typical of adult mammals. Since neurons start to secrete physiologically active substances soon after their formation and long before interneuronal connections are formed, these cells are thought to have an effect on brain development as inducers. Considering that there is no blood-brain barrier during this period, we proposed the hypothesis that the developing brain functions as a multipotent endocrine organ. This means that tens of physiologically active substances arrive from the brain to the systemic circulation and have an endocrine effect on the whole body development. Dopamine, serotonin, and gonadotropin-releasing hormone were selected as marker physiologically active substances of cerebral origin to test this hypothesis. In adult animals, they act as neurotransmitters or neuromodulators transmitting information from neuron to neuron as well as neurohormones arriving from the hypothalamus with portal blood to the anterior pituitary. Perinatal rats—before the blood-brain barrier is formed—proved to have equally high concentration of dopamine, serotonin, and gonadotropin-releasing hormone in the systemic circulation as in the adult portal system. After the brain-blood barrier is formed, the blood concentration of dopamine and gonadotropin-releasing hormone drops to zero, which indirectly confirms their cerebral origin. Moreover, the decrease in the blood concentration of dopamine, serotonin, and gonadotropin-releasing hormone before the brain-blood barrier formation after the microsurgical disruption of neurons that synthesize them or inhibition of dopamine and serotonin synthesis in the brain directly confirm their cerebral origin. Before the blood-brain barrier formation, dopamine, serotonin, gonadotropin-releasing hormone, and likely many other physiologically active substances of cerebral origin can have endocrine effects on peripheral target organs—anterior pituitary, gonads, kidney, heart, blood vessels, and the proper brain. Although the period of brain functioning as an endocrine organ is not long, it is crucial for the body development since physiologically active substances exert irreversible effects on the targets as morphogenetic factors during this period. Thus, the developing brain from the neuron formation to the establishment of the blood-brain barrier functions as a multipotent endocrine organ participating in endocrine control of the whole body development.     

Imaging emotional brain functions: Conceptual and methodological issues

This article reviews the psychophysiological and brain imaging literature on emotional brain function from a methodological point of view. The difficulties in defining, operationalising and measuring emotional activation and, in particular, aversive learning will be considered. Emotion is a response of the organism during an episode of major significance and involves physiological activation, motivational, perceptual, evaluative and learning processes, motor expression, action tendencies and monitoring/subjective feelings. Despite the advances in assessing the physiological correlates of emotional perception and learning processes, a critical appraisal shows that functional neuroimaging approaches encounter methodological difficulties regarding measurement precision (e.g., response scaling and reproducibility) and validity (e.g., response specificity, generalisation to other paradigms, subjects or settings). Since emotional processes are not only the result of localised but also of widely distributed activation, a more representative model of assessment is needed that systematically relates the hierarchy of high- and low-level emotion constructs with the corresponding patterns of activity and functional connectivity of the brain.     

Glucocorticoids and endothelial cell barrier function

Glucocorticoids (GCs) are steroid hormones that have inflammatory and immunosuppressive effects on a wide variety of cells. They are used as therapy for inflammatory disease and as a common agent against edema. The blood brain barrier (BBB), comprising microvascular endothelial cells, serves as a permeability screen between the blood and the brain. As such, it maintains homeostasis of the central nervous system (CNS). In many CNS disorders, BBB integrity is compromised. GC treatment has been demonstrated to improve the tightness of the BBB. The responses and effects of GCs are mediated by the ubiquitous GC receptor (GR). Ligand-bound GR recognizes and binds to the GC response element located within the promoter region of target genes. Transactivation of certain target genes leads to improved barrier properties of endothelial cells. In this review, we deal with the role of GCs in endothelial cell barrier function. First, we describe the mechanisms of GC action at the molecular level. Next, we discuss the regulation of the BBB by GCs, with emphasis on genes targeted by GCs such as occludin, claudins and VE-cadherin. Finally, we present currently available GC therapeutic strategies and their limitations.     

Glucocorticoids in cancer therapy

Glucocorticoids are often included with other agents in cancer treatment although the mode of action is not clear. They are useful in the primary combination chemotherapy of both acute and chronic lymphocytic leukaemias, Hodgkins' and non-Hodgkin's lymphomas, multiple myeloma and breast cancer. Other uses for glucocorticoids in cancer patients include an anti-inflammatory action for the oedema of cranial and spinal metastases, a weak antihypercalcaemic effect and the ability to suppress tumour-related fever.     

Visualizing genetic influences on human brain functions

, in this issue of Cell, integrate genetics and functional brain imaging by showing that variation in the human brain-derived neurotrophic factor (BDNF) gene is associated with variation in episodic memory ability and in hippocampal neurochemistry and function.     

Complex brain and behavioral functions disrupted by mutations in Drosophila

Reproductive behavior in Drosophila involves a complex series of actions which is perturbed by many different kinds of mutations. Some of the most interesting courtship variants are those originally isolated with respect to disruptions of general learning and memory. Several types of genetically abnormal males have their “conditioned courtship” blocked or attenuated by the learning and memory mutations, some of which, in turn, are known to cause abnormal levels of specific monoamines or cyclic nucleotides. Recent studies of the defective courtship performed by the conditioning mutants involve “mosaic focusing” of the neural tissues affected by the behavioral/biochemical mutations. These experiments address the question of whether there are localized influences of the relevant genetic loci in their control of conditioned courtship, in spite of the fact that the protein products of the genes have a broad tissue distribution. Female responses to courting Drosophila males can also be dependent on the former's prior experiences. This pertains to enhancing aftereffects of prestimulation by the courtship song that is produced by a male; and the same learning and memory mutations, expressed in females, impinge on the normal aftereffects. One element of acoustical communication in courtship is a rhythmic oscillation in a particular component of the song. This short-term behavioral rhythm is altered in males expressing circadian rhythm mutations. To investigate the neural and cellular mechanisms by which these genes act, a mosaic analysis has been initiated on the ganglia affected by a clock mutation in its disruption of the courtship rhythm and of circadian cycles. A molecular isolation and identification of the normal form of this genecalled period—has also begun, in order to probe the locus's structure and function in detail. Such an investigation will include a comparison of the mosaic results with a direct determination of the various tissues in which the gene's product is expressed. In addition, interspecific transfers of the purified period gene will augment the current studies of species-specific features of the rhythmic courtship songs.     

Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.