Ai-Min Bao

The stress system in the human brain in depression and neurodegeneration

Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimers disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.

Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders.

During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individuals perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that ones postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.

Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone.

Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. We here describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin‐releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus–pituitary–adrenal axis in the PVN, which may have implications for stress conditions such as depression. J. Comp. Neurol. 499:897–910, 2006.

Sex Differences in the Brain, Behavior, and Neuropsychiatric Disorders:

Sex differences in the brain are reflected in behavior and in the risk for neuropsychiatric disorders. The fetal brain develops in the male direction due to a direct effect of testosterone on the developing neurons, or in the female direction due to the absence of such a testosterone surge. Because sexual differentiation of the genitals takes place earlier in intrauterine life than sexual differentiation of the brain, these two processes can be influenced independently of each other. Gender identity (the conviction of belonging to the male or female gender), sexual orientation (heterosexuality, homosexuality, or bisexuality), pedophilia, sex differences in cognition, and the risks for neuropsychiatric disorders are programmed into our brains during early development. There is no proof that postnatal social environment has any crucial effect on gender identity or sexual orientation. Structural and functional sex differences in brain areas, together with changes in sex hormone levels and their receptors in development and adulthood, are closely related to sex differences in behavior and neuropsychiatric disorders. Knowing that such a relationship exists may help bring about sex-specific therapeutic strategies.

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.

Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression

To investigate whether depression is accompanied by changes in diurnal rhythms of free estradiol and cortisol in different phases of the menstrual cycle, we measured these two hormone levels in saliva samples collected every 2 h for 24 h from 15 healthy normally cycling women and 12 age-matched normally cycling women suffering from major depression taking antidepressants. The assessments were repeated four times over one menstrual cycle: during menstruation and in the late follicular/peri-ovulating, early to mid-luteal and late luteal phases, respectively. Quantification with a nonlinear periodic regression model revealed distinct diurnal rhythms in free estradiol and free cortisol in all subjects. For the diurnal cortisol rhythm, significant differences were found in the peak-width and ultradian amplitude among different menstrual phases, both in controls and depressed patients, while no significant differences were found between the two groups. The diurnal estradiol rhythm, on the other hand, was quite consistent among different menstrual phases within both groups, while the depressed patients had overall larger amplitudes than controls, which is negatively correlated with disease duration. Significant positive correlations between the two hormone rhythms were found for 24-h mean level (mesor), peak, and trough in late luteal phase, and for ultradian harmonics in early to mid-luteal phase in controls, but only for ultradian harmonics in late follicular/peri-ovulating phase and for acrophase in the menstruation phase in depressed patients. A sub-analysis was also performed in patients who received Fluoxetine (n = 7). The findings implicate a close correlation between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, both of which may be involved in depression.

Corticotropin-Releasing Hormone, Glutamate, and γ-Aminobutyric Acid in Depression:

Stress response and depression have a significant impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. The monoamine hypothesis, which postulates dysfunctional noradrenergic and serotonergic systems as the underlying primary cause of depression, has been valuable for the development of conventional antidepressants, which can reverse these dysfunctional states to some degree. However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo—pituitary—adrenal (HPA) system might be the final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by γ-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.

The Involvement of Retinoic Acid Receptor-α in Corticotropin-Releasing Hormone Gene Expression and Affective Disorders

BACKGROUND Corticotropin-releasing hormone (CRH) is considered the central driving force in the stress response and plays a key role in the pathogenesis of depression. Retinoic acid (RA) has been suggested by clinical studies to be associated with affective disorders. METHODS First, hypothalamic tissues of 12 patients with affective disorders and 12 matched control subjects were studied by double-label immunofluorescence to analyze the expression of CRH and retinoic acid receptor-alpha (RAR-alpha). Second, critical genes involved in the RA signaling pathways were analyzed in a rat model of depression. Finally, the regulatory effect of RAR-alpha on CRH gene expression was studied in vitro. RESULTS We found that the expression of RAR-alpha was colocalized with CRH neurons in human hypothalamic paraventricular nucleus (PVN). The density of RAR-alpha-immunoreactive neurons and CRH-RAR-alpha double-staining neurons was significantly increased in the PVN of patients with affective disorders. The ratio of the CRH-RAR-alpha double-staining neurons to the CRH-immunoreactive neurons in affective disorder patients was also increased. Recruitment of RAR-alpha by the CRH promoter was observed in the rat hypothalamus. A dysregulated RA metabolism and signaling was also found in the hypothalamus of a rat model for depression. Finally, in vitro studies demonstrated that RAR-alpha mediated an upregulation of CRH gene expression. CONCLUSIONS These results suggest that RAR-alpha might contribute to regulating the activity of CRH neurons in vivo, and the vulnerable character of the critical proteins in RA signaling pathways might provide novel targets for therapeutic strategies for depression.

Gender difference in age-related number of corticotropin-releasing hormone-expressing neurons in the human hypothalamic paraventricular nucleus and the role of sex hormones

Previous studies have shown that the total number of corticotropin-releasing hormone (CRH)-stained neurons in the human hypothalamic paraventricular nucleus (PVN) increases with age. To determine whether this age-related change depends on gender and whether circulating sex hormones play a role, we analyzed the total number of CRH-immunoreactive neurons by means of immunocytochemistry and image analysis in the postmortem hypothalamic PVN of 22 control subjects (11 males and 11 females) between the ages of 22 and 89 years, and of 10 subjects with abnormal sex hormone status. Our data show that men have a significantly larger number of CRH neurons than women (p = 0.004) and that the total number of CRH neurons increases significantly with age, but only in male controls (p = 0.032), not in female controls (p = 0.733). Female controls do not show a significant change in the total number of CRH neurons either before or after the age (50 years) of menopause (p = 0.792). Male subjects with low testosterone levels due to castration showed significantly fewer CRH neurons than well-matched intact males (p = 0.008), while castrated male-to-female (M-F) transsexuals with estrogen replacement showed normal numbers of CRH neurons. One male case, who had high estrogen levels due to an estrogen-producing tumor, showed a large number of CRH neurons. Thus, although circulating androgens and estrogens both seem to play a stimulatory role with respect to CRH neurons, the age-dependent increase in the number of CRH neurons in the PVN of men, which has been interpreted to reflect activation of the CRH neurons with age, seems to result from factors other than age-related changes of circulating sex hormone levels.

The human histaminergic system in neuropsychiatric disorders

Histaminergic neurons are exclusively located in the hypothalamic tuberomamillary nucleus, from where they project to many brain areas. The histaminergic system is involved in basic physiological functions, such as the sleep-wake cycle, energy and endocrine homeostasis, sensory and motor functions, cognition, and attention, which are all severely affected in neuropsychiatric disorders. Here, we present recent postmortem findings on the alterations in this system in neuropsychiatric disorders, including Parkinsons disease (PD), Alzheimers disease (AD), Huntingtons disease (HD), depression, and narcolepsy. In addition, we highlight the need to validate animal models for these diseases and also for Tourettes syndrome (TS) in relation to alterations in the histaminergic system. Moreover, we discuss the potential for, and concerns over, the use of novel histamine 3 receptor (H3R) antagonists/inverse agonists as treatment for such disorders.