Jian-nian Zhou

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-β and tumor necrosis factor-α, (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-α, 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 direct androgenic involvement in the expression of human corticotropin-releasing hormone

We investigated the possibility of a direct action of androgens on the expression of the human corticotropin-releasing hormone (CRH), which plays a central role in the hypothalamic–pituitary–adrenal (HPA)-axis. Colocalization of CRH and nuclear/cytoplasmic androgen receptor (AR) was found in neurons of the paraventricular nucleus (PVN) in the human hypothalamus. A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE. Expression of AR in combination with testosterone repressed CRH promoter activity through the ARE. We conclude that androgens may directly affect CRH neurons in the human PVN via AR binding to the CRH-ARE, which may have consequences for sex-specific pathogenesis of mood disorders.

Suprachiasmatic nucleus of the human brain: An immunocytochemical and morphometric analysis

The present paper describes the immunocytochemical and morphometric characteristics of two major cell groups of the suprachiasmatic nucleus (SCN) in the human hypothalamus: the vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neuronal subdivisions. The dimensions (volume and length) and the number of neurons expressing each peptide in the two subdivisions were obtained, as well as the mean diameter of the cell nuclei. All morphometric parameters were studied in relation to sex and age.

Interaction of prefrontal cortical and hypothalamic systems in the pathogenesis of depression

Publisher Summary Hypothalamo-pituitary adrenal (HPA)-axis hyperactivity leads to increased production of corticotrophin-releasing hormone (CRH) and cortisol; the central effects of these hormones form the final common pathway in the pathogenesis of symptoms of depression. HPAaxis activity may not only be caused by glucocorticoid receptor resistance, developmental sequelae or stress in adulthood, but also by stroke, especially if the left prefrontal cortex is affected. Transcranial cortical stimulation seems to be an effective new treatment for depression. HPA hyperactivity leads, in addition, to a decreased frontal metabolism, probably due to the inhibiting effect of glucocorticoids on the brain metabolism. The hyperactivity of the HPA axis may also explain at least part of the changes in the HPT-axis and contribute to decreased bioavailability of T3 in the brain. Hypofrontality and hyperactivity of the HPA-axis reinforce each others actions in the development of the signs and symptoms of depression.

Biological rhythms in the human life cycle and their relationship to functional changes in the suprachiasmatic nucleus

Biological rhythms play a prominent role in the human life cycle. The endogenous rhythms are entrained by the environment and have an astronomical counterpart which is obvious for daily, monthly, and yearly rhythms, and may possibly also be present in weekly rhythms. Circadian rhythms are present in, e.g. testosterone levels, spontaneous birth, strokes, and death from cardiovascular causes. Circaseptan rhythms are present in, e.g. spontaneous birth, 17-ketosteroid levels, myocardial infarctions, and strokes. The relationship of these rhythms with the suprachiasmatic nucleus (SCN) has not yet been established. Circatrigintan rhythms, such as the menstrual cycle, have so far not been associated with the SCN. Circannual rhythms are present in, e.g. mood, suicides, reproduction, birth weight, sleep and season of birth of psychiatric patients. The human SCN shows strong circadian and circannual fluctuations in the number of neurons expressing vasopressin. The vasopressin and VIP cell population of the SCN develop late, i.e. for a major part postnatally. After the age of 50 the amplitudes of circadian and circannual fluctuations of the vasopressin cell numbers are reduced whereas the number of vasopressin expressing neurons decreases after the age of 80 and do so even more and earlier in Alzheimers disease. Sex differences are present in the shape of the vasopressin subnucleus of the SCN and in the vasoactive intestinal polypeptide (VIP) cell number. The sex differences in the SCN, the doubling of the number of vasopressin neurons in the SCN of homosexual men, and a variety of animal experimental observations indicate that the SCN is involved in sexual behavior and reproduction. The exact role of the SCN in these processes is subject to current research.

Development of vasoactive intestinal polypeptide neurons in the human suprachiasmatic nucleus in relation to birth and sex

The development of vasoactive intestinal polypeptide (VIP) neurons was determined in the human suprachiasmatic nucleus (SCN) of 43 subjects ranging from 27 weeks of gestation to 30 years of age using immunocytochemistry and morphometry. VIP neurons were first observed at 31 weeks of gestation in the ventrolateral part of the SCN. From 3 months postnatally onwards, VIP positive neurons were observed in some subjects in the centromedial part of the SCN. The centromedial type of VIP staining became a constant finding only at 19 years of age, at term the SCN was still very immature. Only in a few subjects some VIP neurons stained in the ventrolateral SCN and their number and nuclear diameter was small. Postnatally the number of VIP neurons increased gradually until around 3 years of age adult values were reached. After the age of 10 a clear sex difference in the number of VIP neurons was found: males having on average twice as many VIP neurons in the SCN as females. The adult VIP cell numbers in the SCN amounted only 35% of those found earlier for vasopressin. The present data do not support a particular role for VIP neurons in those rhythms that are already present in early development, e.g., of the temperature rhythm in prematures of around 30 weeks gestational age. Our observations in this and earlier papers as well as animal studies do suggest though a possible role for VIP neurons in the SCN in sexual dimorphic functions such as reproduction and sexual behavior.

No changes in the number of vasoactive intestinal polypeptide (VIP)-expressing neurons in the suprachiasmatic nucleus of homosexual men; comparison with vasopressin-expressing neurons

In an earlier study we found more than twice as many vasopressin (AVP) neurons in the suprachiasmatic nucleus (SCN) of homosexual men as compared to heterosexual men. The present measurements in the same individuals showed that there is no difference in the number of vasoactive intestinal polypeptide (VIP)-expressing neurons in the SCN. The reduced nuclear diameter of both VIP and AVP neurons in the SCN as found in homosexual men points to metabolic alterations in the SCN in relation to sexual orientation.