TUB gene expression in hypothalamus and adipose tissue and its association with obesity in humans.

BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity.

Walking the line: a randomised trial on the effects of a short term walking programme on cognition in dementia.

BACKGROUND: Walking has proven to be beneficial for cognition in healthy sedentary older people. The aim of this study was to examine the effects of a walking intervention on cognition in older people with dementia. METHODS: 97 older nursing home residents with moderate dementia (mean age 85.4 years; 79 female participants; mean Mini-Mental State Examination 17.7) were randomly allocated to the experimental or control condition. Participants assigned to the experimental condition walked for 30 min, 5 days a week, for 6 weeks. To control for personal communication, another group received social visits in the same frequency. Neuropsychological tests were assessed at baseline, directly after the 6 week intervention and again 6 weeks later. Apolipoprotein E (ApoE) genotype was determined. RESULTS: Differences in cognition between both groups at the three assessments were calculated using a linear mixed model. Outcome measures included performance on tests that formed three domains: a memory domain, an executive function domain and a total cognition domain. Results indicate that there were no significant time x group interaction effects or any time x group x ApoE4 interaction effects. CONCLUSION: Possible explanations for the lack of a beneficial effect of the walking programme on cognition could be the level of physical activation of the intervention or the high frequency of comorbid cardiovascular disease in the present population of older people with dementia.

Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances.

Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-beta and tumor necrosis factor-alpha, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-alpha, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.

A sexually dimorphic nucleus in the human brain.

A sexually dimorphic cell group is described in the preoptic area of the human hypothalamus. Morphometric analysis revealed that the volume of this nucleus is 2.5 +/- 0.6 times (mean +/- standard error of the mean) as large in men as in women, and contains 2.2 +/- 0.5 times as many cells. Between the ages of 10 and 93 years, the nucleus decreases greatly in volume and in cell number. Although no function has yet been established for this nucleus, it is located within an area that is essential for gonadotropin release and sexual behavior in other mammals.

Hippocampal estrogen receptor-alpha splice variant TADDI in the human brain in aging and Alzheimer's disease.

BACKGROUND/AIMS: Estrogen receptor-alpha (ER alpha) splice variants are important for understanding estrogen effects on the brain and estrogen therapy pitfalls. We addressed the question whether a novel ER alpha splice variant TADDI is expressed at the protein level in the human brain and whether it changes in relation to aging and Alzheimer's disease (AD). METHODS: Immunoreactivity (-ir) for TADDI was assessed on postmortem human brain material from a total of 116 cases. RESULTS: The highest levels of this splice form were found in the hypothalamic supraoptic nucleus (SON), pontine nuclei, medulla oblongata, gray matter of the spinal cord, the hippocampus, glomeruli of the cerebellum, the nucleus basalis of Meynert (NBM), and the tuberomamillary nucleus (TMN). TADDI-ir was mainly confined to the cytoplasm but was also determined in the nuclei of hippocampal neurons from young patients. In the hippocampus, the NBM, and the TMN, TADDI-ir was higher in postmenopausal women than in women

The stress system in depression and neurodegeneration: focus on the human hypothalamus.

The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen-responsive element in the CRH gene promoter region initiates a suppressing effect on CRH expression. The decreased activity of the SCN is the basis for the disturbances of circadian and circannual fluctuations in mood, sleep and hormonal rhythms found in depression. Neuronal loss was also reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. Because of the inhibitory control of the hippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over time. This 'glucocorticoid cascade hypothesis' of stress and hippocampal damage was proposed to be causally involved in age-related accumulation of hippocampal damage in disorders like Alzheimer's disease and depression. However, in postmortem studies we could not find the presumed hippocampal damage of steroid overexposure in either depressed patients or in patients treated with synthetic steroids.

Mature astrocytes in the adult human neocortex express the early neuronal marker doublecortin.

Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and is considered to be a reliable marker of neurogenesis. DCX has been used to study the relation between neurogenesis in adult human brain and neurological and neurodegenerative disease processes in the search for putative therapeutic strategies. Using autopsy and surgically resected tissue from a total of 60 patients, we present evidence that DCX is present in several cellular compartments of differentiated astrocytes in the adult human neocortex. One of these compartments consisted of peripheral processes forming punctate envelopes around mature neuronal cell bodies. Markers of glial activation, such as GFAP and HLA, were not associated with DCX immunoreactivity, however, the presence of cytoarchitectural alterations tended to correlate with reduced DCX staining of astrocytic somata. Interestingly, local Alzheimer pathology that showed no relation with cytoarchitectural abnormalities appeared to correlate negatively with the expression of DCX in the astrocytic somata. In combination with the literature our data support the view that DCX in the adult human neocortex may have a function in glia-to-neuron communication. Furthermore, our results indicate that in the adult human neocortex DCX is neither a reliable nor a selective marker of neurogenesis.

Prefrontal alterations in GABAergic and glutamatergic gene expression in relation to depression and suicide.

People that committed suicide were reported to have enhanced levels of gene transcripts for synaptic proteins in their prefrontal cortex (PFC). Given the close association of suicide with major depressive disorder (MDD), we here assessed whether these changes are related to suicide or rather to depression per se. We used quantitative PCR to determine mRNA levels of 32 genes encoding for proteins directly involved in glutamatergic or GABAergic synaptic transmission in postmortem samples of the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). Seventy-two brain samples from 3 groups of subjects were derived from the Stanley Medical Research Institute (SMRI): i) patients with MDD who committed suicide (MDD-S), ii) MDD patients who died of non-suicidal causes (MDD-NS) and iii) age-matched, non-psychiatric control subjects. In the ACC, a significantly enhanced expression of genes related to glutamatergic or GABAergic synaptic transmission was found only in MDD-S patients, whereas in MDD-NS patients, decreased levels for these transcripts were found. Moreover, in the DLPFC, expression of these genes was decreased in MDD-S, relative to MDD-NS patients, whereas both groups showed increased expression compared to control subjects. In conclusion, our findings indicate that MDD is associated with increases in GABA and glutamate related genes in the DLPFC (irrespective of suicide), while in the ACC, the increase in GABA and glutamate related genes may relate to suicide, rather than to MDD per se.

Hypothalamic dysfunction and neuroendocrine and metabolic alterations in Huntington's disease: clinical consequences and therapeutic implications.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by cognitive, psychiatric, behavioural and motor disturbances. Although the course of HD is also frequently complicated by unintended weight loss, sleep disturbances and autonomic nervous system dysfunction, the aetiology of these signs and symptoms remains largely unknown. In recent years, many novel findings from both animal and human studies have emerged that indicate considerable hypothalamic, endocrine and metabolic alterations in HD. However, a comprehensive overview of these findings is lacking and their precise clinical significance is far from clear. Therefore, in this review we attempt to put these recent developments in the field into perspective by integrating them with previous findings in a comprehensible manner, and by discussing their clinical relevance, with a special focus on body weight, sleep and autonomic functions in HD, which will also allow for the identification of future lines of research in this area.

Alterations in the human brain in menopause.

In a series of studies we showed that menopause in women causes alterations not only in the neuronal expression of estrogen receptors (ER) alpha and beta, but also in local estrogen production in several brain areas and in the rate of neuronal metabolism. Although such changes are clearly brain region-specific, there seems to be no evidence at present for a decrease in neuronal metabolic rate. On the contrary, an increase in the neuronal metabolic activity and in the level of ERalpha in postmenopausal women was noted. In the supraoptic nucleus (SON) that is a major source of plasma arginine-vasopressin (AVP) we found that neuronal metabolic activity as judged from the Golgi apparatus and cell size was markedly enhanced in women after menopause accompanied by an increase in ERalpha and a decrease in ERbeta. Similar changes were noted in the medial mamillary nucleus and in the hippocampus that are involved in the regulation of learning and memory. Recently we aimed at determining whether in addition to the canonical ERalpha and ERbeta, estrogen receptor splice variants lacking entire exons may also be involved in the menopause-associated changes in the human brain. We detected del. 2 (missing exon 2), del. 4 (lacking exon 4), del. 7 (exon 7 absent) and MB1 (deletion of 168 nucleotides in the exon 1) in the frozen hippocampal tissue of 6 women (46, 52, 59, 64, 77 and 83 years of age). No age-related changes were observed for the mentioned splice forms in women of this group.

Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation.

Recently, sex differences in the structures of the human hypothalamus and adjacent brain structures have been observed that seem to be related to gender, to gender problems such as transsexuality, and to sexual orientation, that is, heterosexuality and homosexuality. Although these observations have yet to be confirmed, and their exact functional implications are far from clear, they open up a whole new field of physiological structural-functional relationships in human brain research that has so far focused mainly on such relationships in pathology.

Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide.

There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.

Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus.

The way glucocorticoids affect TRH mRNA expression in the paraventricular nucleus of the hypothalamus is still unclear. In view of its relevance for Cushing's syndrome and depression, we measured TRH mRNA expression in human hypothalami obtained at autopsy by means of quantitative TRH mRNA in situ hybridization. In corticosteroid-treated subjects (n = 10), TRH mRNA hybridization signal was decreased as compared with matched control subjects (n = 10) (Mann-Whitney U test, P = 0.02). By inference, hypercortisolism as present in patients with Cushing's syndrome or major depression may contribute to lower serum TSH or symptoms of depression by lowering hypothalamic TRH expression.

Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression.

BACKGROUND: Cerebrospinal fluid levels of arginine vasopressin (AVP) and oxytocin (OXT) have been found to change in mood disorders. In the present study, the numbers of AVP-immunoreactive (IR) and OXT-IR neurons were determined in the paraventricular nucleus (PVN) of the human hypothalamus. METHODS: Postmortem brain tissue was fixed in formalin, embedded in paraffin, and stained for AVP and OXT using immunocytochemical techniques. The number of IR neurons in the PVN was estimated by morphometry in eight depressed patients ranging in age from 21 to 85 years and eight age-matched controls ranging in age from 23 to 88 years. RESULTS: The numbers of AVP-IR and OXT-IR neurons in the PVN of patients with mood disorder were increased by 56% and 23%, respectively. No differences were found in AVP-IR or OXT-IR cell numbers between three patients with major depression and three patients with bipolar depression. The numbers of AVP-IR and OXT-IR neurons in two patients with depression not otherwise specified were within the same range as in the six other patients with a mood disorder. CONCLUSIONS: The AVP and OXT neurons were activated in the PVN in patients with major depression or bipolar disorder. This activation may be associated with activation of the hypothalamic-pituitary-adrenal axis in these patients, since both AVP and OXT are known to potentiate the effects of corticotropin-releasing hormone. Because of their central effects, activation of AVP and OXT neurons may also be related to symptoms of major depression or bipolar disorder.

Lack of association between depression and loss of neurons in the locus coeruleus in Alzheimer disease.

BACKGROUND: Depression, one of the most frequent psychiatric disturbances in Alzheimer disease (AD), is proposed to have its neurobiological basis in neuron loss in the noradrenergic locus coeruleus, although this is not the case in idiopathic depression. METHODS: We performed image analyzer-assisted morphometry of the locus coeruleus in 6 depressed, 6 transiently depressed, and 6 nondepressed patients with AD and in 8 control subjects, emphasizing longitudinal psychiatric evaluations and matching for the clinical and neuropathological severity of dementia. RESULTS: The mean (+/-SD) number of pigmented neurons in the locus coeruleus in controls (11 607+/-946) was higher than in patients with AD, regardless of being depressed (5165+/-928; P=.001), transiently depressed (5647+/-1163; P=.003), or nondepressed (3717+/-661; P=.001). No significant difference was found in the number of pigmented neurons between patients with AD who were depressed, transiently depressed, and nondepressed. Patients who had depression at the onset of AD had a higher pigmented neuron number than other patients with AD. CONCLUSIONS: We confirmed the loss of pigmented neurons in the locus coeruleus of patients with AD; however, no supplementary loss of pigmented neurons in the locus coeruleus was found in patients with depression and AD. This finding resembles the situation in idiopathic depression, but is in contrast with earlier studies on depression in AD.

Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression.

BACKGROUND: Circadian rhythm disturbances are frequently found in depressed subjects. Although it has been presumed that these disturbances may reflect a disorder of the circadian pacemaker, this has never been established. The suprachiasmatic nucleus (SCN) is the pacemaker of the circadian timing system in mammals, and arginine vasopressin (AVP) is one of its major neuropeptides. As peptide content is often taken as a measure for activity, we hypothesized that a decreased number of AVP-immunoreactive (AVP-IR) neurons and amount of AVP-messenger RNA (mRNA) would be present in the SCN of depressed subjects. METHODS: Brains of 11 subjects suffering from major depression (8 cases) and bipolar disorder (3 cases), and of 11 controls, matched for sex, age, and clock time at death, were collected. The number of AVP-IR neurons in the SCN was determined by means of a digitizer (CalComp Inc, Reading, England). The amount of AVP-mRNA expression in the SCN was quantified with the Interaktive Bild Analyse System image analysis system (Kontron, Munich, Germany). RESULTS: In depressed subjects, the number of AVP-IR neurons in the SCN was more than one and a half times higher than in controls, while the total masked area of silver grains, as an estimate of the amount of AVP-mRNA, was about one half that of controls. CONCLUSIONS: Contrary to our hypothesis, an increase in the number of AVP-IR neurons in the SCN in depression was found, together with an expected decrease in AVP-mRNA. These findings suggest that, in depressed patients, both the synthesis and release of AVP in the SCN is reduced, resulting in an impaired functional ability. A disbalance between AVP production and transport needs further investigation in future studies.

[Chronic pain in dementia and in disorders with a high risk for congnitive impairment]. / Chronische pijn bij dementie en bij aandoeningen met een verhoogd risico op cognitieve achteruitgang.

Ageing increases the risk for the etiology of chronic pain and dementia. hence, the increase in the number of elderly people implies that the number of elderly with dementia suffering from chronic pain will increase as well. A key question relates to if and how patients with dementia perceive pain. the inadequateness of pain assessment, particularly in a more advanced stage, is also reflected in a decreased use of analgesics by elderly people with dementia. Insight into possible changes in pain experience as have been observed in the few available clinical studies, could be enhanced by knowledge about the neuropathology which may differ per subtype of dementia. It is striking that pain has not been examined in degenerative diseases of the central nervous system with a high risk for cognitive impairment such as Parkinson's disease and multiple sclerosis. In these disorders, pain is a prominent clinical symptom and to date it is not known whether the experience of pain will change in a stage in which patients become cognitively impaired. Finally, a number of instruments which are most appropriate to assess pain in communicative and non-communicative patients are discussed.

Chronische pijn bij dementie en bij aandoeningen met een verhoogd risico op cognitieve achteruitgang.

Chronic pain in dementia and in disorders with a high risk for cognitive impairment. Ageing increases the risk for the etiology of chronic pain ánd dementia. Hence, the increase in the number of elderly people implies that the number of elderly with dementia suffering from chronic pain will increase as well. A key question relates to if and how patients with dementia perceive pain. The inadequateness of pain assessment, particularly in a more advanced stage, is also reflected in a decreased use of analgesics by elderly people with dementia. Insight into possible changes in pain experience as have been observed in the few available clinical studies, could be enhanced by knowledge about the neuropathology which may differ per subtype of dementia. It is striking that pain has not been examined in degenerative diseases of the central nervous system with a high risk for cognitive impairment such as Parkinson's disease and multiple sclerosis. In these disorders, pain is a prominent clinical symptom and to date it is not known whether the experience of pain will change in a stage in which patients become cognitively impaired. Finally, a number of instruments which are most appropriate to assess pain in communicative and non-communicative patients are discussed.

Diurnal and seasonal rhythms of neuronal activity in the suprachiasmatic nucleus of humans.

The mammalian suprachiasmatic nucleus (SCN) is considered to be a critical component of a neural system implicated in the temporal organization of a wide variety of biological processes. Since the environmental light-dark cycle is the main zeitgeber for many of these rhythms, photic information may have a synchronizing effect on the endogenous clock in the SCN by inducing periodic changes in the activity of certain groups of neurons. The present study was conducted to investigate whether the daily light-dark cycle as well as seasonal variations in photoperiod would affect the vasopressin cell population of the human SCN. To that end, the brains of 30 young human subjects (ranging in age from 6 to 47 years) were investigated. We found that the subdivision of the human SCN that contains vasopressin-producing neurons fluctuated significantly over the 24-hr period. The volume of the vasopressin cell population was, on average, 1.4 times as large during the daytime (1000-1800 hr) as during the nighttime (2200-0600 hr), and contained 1.8 times as many vasopressin-immunoreactive neurons. Peak values in both vasopressin volume and vasopressin cell number were observed in the early morning (0600-1000 hr). In general, the SCN contained fewer vasopressin-immunoreactive neurons during the night than during any other period of the natural light-dark cycle. In addition to the diurnal cycle of the SCN, a marked seasonal rhythm was observed. The volume of the vasopressin cell population was, on average, 2.4 times as large in the autumn as in the summer, and contained 3 times as many vasopressin-immunoreactive neurons. In general, the annual cycle of the human SCN showed a nonsinusoidal pattern with a maximum in early autumn, a lower plateau in winter, and a deep trough in late spring and early summer. In contrast with the periodic fluctuations in the number of vasopressin-immunoreactive neurons in the SCN, no significant diurnal or seasonal variations could be detected in the numerical cell density or cell nuclear diameter of vasopressin neurons. In conclusion, the findings indicate that the synthesizing activity of the vasopressin neurons of the human SCN exhibits a diurnal as well as a seasonal rhythm, and that the temporal organization of these processes becomes disturbed later in life.

Long-term fitness training improves the circadian rest-activity rhythm in healthy elderly males.

In old age, the circadian timing system loses optimal functioning. This process is even accelerated in Alzheimer's disease. Because pharmacological treatment of day-night rhythm disturbances usually is not very effective and may have considerable side effects, nonpharmacological treatments deserve attention. Bright light therapy has been shown to be effective. It is known from animal studies that increased activity, or an associated process, also strongly affects the circadian timing system, and the present study addresses the question of whether an increased level of physical activity may improve circadian rhythms in elderly. In the study, 10 healthy elderly males were admitted to a fitness training program for 3 months. The circadian rest-activity rhythm was assessed by means of actigraphy before and after the training period and again 1 year after discontinuation. As a control for possible seasonal effects, repeated actigraphic recordings were performed during the same times of the year as were the pre and post measurements in a control group of 8 healthy elderly males. Fitness training induced a significant reduction in the fragmentation of the rest-activity rhythm. Moreover, the fragmentation of the rhythm was negatively correlated with the level of fitness achieved after the training. No seasonal effect was found. Previous findings in human and animal studies are reviewed, and several possible mechanisms involved in the effect of fitness training on circadian rhythms are discussed. The results suggest that fitness training may be helpful in elderly people suffering from sleep problems related to circadian rhythm disturbances.