Band 7, Heft 2 - Issue 2: Special issue Hormones and the Brain - Part A – August

No abstract available

Adrenal glucocorticoid hormones modulate neuronal activity to support an adaptive response to stress. They modulate brain circuitry mediating physiological responses, emotion and cognitive processing. Chronically elevated glucocorticoid exposure is however linked to the development of mental disease. Glucocorticoid effects depend on mineralo- and glucocorticoid receptors, which are powerful transcription factors, but also can act via a diversity of non-genomic mechanisms. Here, I review generic factors that determine neuronal glucocorticoid sensitivity, in relation to brain function. First, pre-receptor mechanisms determine ligand availability. Second, there may be considerable variation in the receptor splice- and translation variants. Third, other transcription factors and many transcriptional coregulators interact with steroid receptors, determining nature and magnitude of steroid responses, in part through epigenetic regulation of DNA accessibility. Which factors underlie adaptive and pathogenic effects of stress hormones is largely unknown. Genome-wide identification of the receptor-DNA interactions in specific behavioural and physiological contexts provides a way of assessing the complete genomic range of glucocorticoid modes of action. Novel ligands that induce selective activation of particular receptor signalling modes will aid our understanding of receptor signalling and may allow selective targeting of glucocorticoid effects in emotional or cognitive domains, in research and, hopefully, in clinical settings.

The major endocrine response to stress occurs via activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading ultimately to increases in circulating glucocorticoids, which are essential for the metabolic adaptation to stress. The major players in the HPA axis are the hypothalamic neuropeptide, corticotropin releasing hormone (CRH), the pituitary hormone adrenocorticotropic hormone, and the negative feedback effects of adrenal glucocorticoids. In addition, a number of other neuropeptides, including vasopressin (VP), angiotensin II, oxytocin, pituitary adenylate cyclase activating peptide, orexin and cholecystokinin, and nesfatin can affect HPA axis activity by influencing the expression and secretion of CRH, and also by modulating pituitary corticotroph function or adrenal steroidogenesis. Of these peptides, VP co-secreted with CRH from axonal terminals in the external zone of the median eminence plays a prominent role by potentiating the stimulatory effect of CRH and by increasing the number of pituitary corticotrophs during chronic challenge. Although the precise role and significance of many of these neuropeptides in regulating HPA axis activity requires further investigation, it is likely that they are part of a multifactorial system mediating the fine tuning of HPA axis activity during adaptation to a variety of physiological and stressful conditions.

Aging of the brain causes important reductions in quality of life and has wide socio-economic consequences. An increase in oxidative stress, and the associated inflammation and apoptosis, could be responsible for the pathogenesis of aging associated brain lesions. Melatonin has neuroprotective effects, by limiting the negative effects of oxygen and nitrogen free radicals. Growth hormone (GH) might exert additional neuro-protective and or neurogenic effects on the brain. The molecular mechanisms of the protective effects of GH and melatonin on the aging brain have been investigated in young and old Wistar rats. A reduction in the total number of neurons in the hilus of the dentate gyrus was evident at 24 months of age and was associated with a significant increase in inflammation markers as well as in pro-apoptotic parameters, confirming the role of apoptosis in its reduction. Melatonin treatment was able to enhance neurogenesis in old rats without modification of the total number of neurons, whereas GH treatment increased the total number of neurons without enhancing neurogenesis. Both GH and melatonin were able to reduce inflammation and apoptosis in the hippocampus. In conclusion, neuroprotective effects demonstrated by GH and melatonin in the hippocampus were exerted by decreasing inflammation and apoptosis.

Leptin, which comes from the Greek root leptos meaning thin, has been the focus of intense investigation since its discovery in 1994. This hormone belongs to the cytokine family and is produced by adipocytes and circulates in proportion to fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. However, it participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of its various receptor isoforms. Leptin is involved in brain development, most notably in development of hypothalamic centers that control metabolism, but also in other brain areas. It acts as a nutritional cue to indicate adequacy of energy stores for pubertal development and reproductive capacity. The effects of this hormone on behavior and cognition are less well studied, but it clearly is involved in specific aspects of these physiological phenomena. As obesity is a major health problem in many areas of the world, the search for pharmacological treatments to decrease appetite and increase energy expenditure is intense. Understanding the mechanisms of actions of all physiological effects of this hormone is of great interest in the pursuit of such treatment.

Estradiol is synthesized from cholesterol in hippocampal neurons of adult rats by cytochrome P450 and hydroxysteroid dehydrogenase enzymes. These enzymes are expressed in the glutamatergic neurons of the hippocampus. Surprisingly, the concentration of estradiol and androgen in the hippocampus is significantly higher than that in circulation. Locally synthesized estradiol rapidly and potently modulates synaptic plasticity within the hippocampus. E2 rapidly potentiates long-term depression and induces spinogenesis through synaptic estrogen receptors and kinases. The rapid effects of estradiol are followed by slow genomic effects mediated by both estrogen receptors located at the synapse and nucleus, modulating long-term potentiation and promoting the formation of new functional synaptic contacts. Age-related changes in hippocampally derived estradiol synthesis and distribution of estrogen receptors may alter synaptic plasticity, and could potentially contribute to age-related cognitive decline. Understanding factors which regulate hippocampal estradiol synthesis could lead to the identification of alternatives to conventional hormone therapy to protect against age-related cognitive decline.