Search

Background Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. Methods PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Results PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. Conclusion The results support the possibility that PACAP plays a role in mood disorder pathophysiology.

According to the neuro-hormonal theory, sexual orientation in humans develops in the womb under the influence of sex hormones. In this article, we review the evidence from basic research on the possible role of neurotransmitters on influencing sexual orientation. We show that pharmacological or genetically induced changes in neurotransmitter systems during development might, by hormone-mediated structural and functional brain changes, result in alterations in sexual preference in animal models. We propose that in humans this mechanism may contribute to the relationship between non-heterosexual orientation and increased prevalence of neuropsychiatric disorders. Data to support this idea are reviewed. We suggest that altered neurotransmitter levels during development will increase the chance for both non-heterosexual differentiation of the brain and neuropsychiatric disorders. This possibility may have clinical implications, because medication given to a pregnant woman may, in this way, alter brain development of the fetus in a permanent way.

Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

AIMS Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, β-amyloid (Aβ) and hyperphosphorylated Tau (p-Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals. METHODS We first analysed the entire post-mortem brain collection of all non-demented 'controls' and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aβ, Aβ42 and p-Tau in the entorhinal cortex of well-matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals. RESULTS Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p-Tau, but not Aβ or Aβ42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p-Tau but not Aβ or Aβ42. CONCLUSIONS Enhanced p-Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.

In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible LED devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that SCN activity was suppressed by light. The suppressions were observed not only in response to narrowband blue light (λmax: 470nm) but remarkably, also in response to green (λmax: 515nm) and orange (λmax: 590nm), but not to violet light (λmax: 405nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive.

Early-life stress (ELS) leads to stress-related psychopathology in adulthood. Although dysfunction of corticotropin-releasing hormone (CRH) signaling in the bed nucleus of the stria terminalis (BNST) mediates chronic stress-induced maladaptive affective behaviors that are historically associated with mood disorders such as anxiety and depression, it remains unknown whether ELS affects CRH function in the adult BNST. Here we applied a well-established ELS paradigm (24 h maternal separation (MS) at postnatal day 3) and assessed the effects on CRH signaling and electrophysiology in the oval nucleus of BNST (ovBNST) of adult male mouse offspring. ELS increased maladaptive affective behaviors, and amplified mEPSCs and decreased M-currents (a voltage-gated K+ current critical for stabilizing membrane potential) in ovBNST CRH neurons, suggesting enhanced cellular excitability. Furthermore, ELS increased the numbers of CRH+ and PACAP+ (the pituitary adenylate cyclase-activating polypeptide, an upstream CRH regulator) cells and decreased STEP+ (striatal-enriched protein tyrosine phosphatase, a CRH inhibitor) cells in BNST. Interestingly, ELS also increased BNST brain-derived neurotrophic factor (BDNF) expression, indicating enhanced neuronal plasticity. These electrophysiological and behavioral effects of ELS were reversed by chronic application of the CRHR1-selective antagonist R121919 into ovBNST, but not when BDNF was co-administered. In addition, the neurophysiological effects of BDNF on M-currents and mEPSCs in BNST CRH neurons mimic effects and were abolished by PKC antagonism. Together, our findings indicate that ELS results in a long-lasting activation of CRH signaling in the mouse ovBNST. These data highlight a regulatory role of CRHR1 in the BNST and for BDNF signaling in mediating ELS-induced long-term behavioral changes.

BACKGROUND: Suicide, psychotic features and gender influence the epidemiology and clinical prognosis of bipolar disorder (BD). Differences in glial function between the genders might contribute to these clinical variables. Here we studied expression of glial genes in human post-mortem prefrontal cortex of BD and control subjects in relation to suicide, psychotic features and sex.METHODS: Real time PCR was used to detect transcriptional alterations of 16 glia-related genes in two brain areas, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), from 30 patients with BD subdivided by suicide and psychotic features, and from 34 well-matched control cases.RESULTS: We found no evidence of immune activation in BD. Instead, we found three microglial genes to be downregulated in the DLPFC of non-suicidal individuals with BD, i.e. CD68, triggering receptor expressed on myeloid cells 2 (TREM2) and purinergic receptor 12 (P2RY12). A remarkable sex difference was observed in the DLPFC of patients with BD: 14 glia-related genes were expressed at significantly higher levels in males, including all three glial cell types. A subset analysis showed that the sex differences were closely associated with the presence of psychotic features.CONCLUSIONS: No evidence of immune activation was found in these two brain regions in BD. The sex-specific differences in glial gene expression in BD, found particularly in patients with psychotic features, may be associated with the potential co-existence of mania and psychotic features and could potentially contribute to the gender-biased characteristics in BD.

The article focuses on age-related morphofunctional changes in the human brain and the issue of compensatory-adaptive mechanisms developed in normal aging. According to the scientific literature, the volume of white matter is reduced to a greater extent with aging, the fact associating with myelin fibers degeneration, the appearance of Virchow–Robin spaces and a decrease in the effectiveness of the blood-brain barrier. Atrophic processes in gray matter are currently associated not only with the death of neurons, but with degenerative changes in synapses, a decrease in their number, and reduction of dendritic branches and spines. A decrease in the size of pericarions resulting in a decrease in the number of large neurocytes and an increase in the proportion of small neurons is noted in certain brain structures. However, age-related neuronal hypertrophy is observed in the nuclei of the hypothalamus, Meinert’s basal nucleus. This is mostly manifested in the female group, and is undoubtedly associated with a decrease in estrogen levels and the period of menopause. An increase in the metabolic activity of neurons manifested by related changes in the size of the pericarions and nuclei of neurons and their Golgi complex can be attributed to compensatory-adaptive mechanisms that can delay or prevent the development of neurodegenerative disorders, such as Alzheimer's disease. Neurons with a higher metabolic activity have better ability to self-repair. Due to this, neuron reactivation techniques are being developed with aging based on the selection of the correct stimulus. The growth of the glial cell population is also considered to be compensatory, since these cells are crucial for neuron adaptation and able to affect the level of neuronal RNA synthesis. Furthermore, the article highlights literature data on possible triggers of the compensatory capabilities of the brain with aging and under pathological processes.

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K+current that stabilizes membrane potential) inex vivoslices. CVMS also increased c-fos+cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH+and pituitary adenylate cyclase-activating polypeptide+(PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase+(a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors.SIGNIFICANCE STATEMENTChronic stress and acute activation of oval bed nucleus of the stria terminalis (ovBNST) induces maladaptive behaviors in rodents. However, the precise molecular and electrophysiological mechanisms underlying these effects remain unclear. Here, we demonstrate that chronic variable mild stress activates corticotropin-releasing hormone (CRH)-associated stress signaling and CRH neurons in ovBNST by potentiating mEPSC amplitude and decreasing M-current in male mice. These electrophysiological alterations and maladaptive behaviors were mediated by BNST protein kinase A-dependent CRHR1 signaling. Our results thus highlight the importance of BNST CRH dysfunction in chronic stress-induced disorders.

Background: Patients with schizophrenia (SCZ) run a lifelong risk of suicide. Alterations in glia activities in the prefrontal cortex (PFC) have been reported in relation to suicide in patients with SCZ. While immune processes in the CNS have been related to the susceptibility and course of SCZ, there are hardly any direct comparisons between individuals with SCZ, both those who died of natural causes and those that committed suicide, and healthy controls.Materials and methods: We compared mRNA expression using real time qPCR of 16 glia-related genes in the dorsal lateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) between 35 patients with SCZ (7 suicide completers and 28 patients who died of natural causes) and 34 well-matched controls without psychiatric or neurological diseases.Results: We found an increased expression of the astrocytic gene aldehyde dehydrogenase-1 family member L1 (ALDH1L1) mRNA, a marker involved in dopaminergic activity, in SCZ versus controls. Excluding individuals with SCZ that committed suicide resulted in an elevated expression in the DLPFC of both ALDH1L1 and glutamine synthetase (GS) genes in patients with SCZ, compared to suicide completers and non-psychiatric controls. Regarding microglia genes: in the ACC, homeostatic markers such as chemokine (C-X3-C motif) ligand 1 (CX3CR1) mRNA expression was increased in SCZ without suicide as compared to suicide completers, while no change was found when compared to controls. Another, purinergic receptor 12 (P2RY12) mRNA was exclusively elevated in the ACC of suicide completers, compared to either other group. Triggering receptor expressed on myeloid cells 2 (TREM2) expression, which maintains microglial metabolism, was reduced in non-suicide patients with SCZ, compared to suicide victims and control subjects.Conclusions: Differential changes are found in astrocyte and microglia genes in the PFC subregions in relation to SCZ and suicide, indicating possible disturbances of glia homeostasis in these conditions.

Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post-mortem brains, we observed 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN) and significantly less CRH-positive fibers in the median eminence, while CRH-neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: i.e. vasopressin, oxytocin, tyrosine hydroxylase and thyrotropin releasing hormone-expressing neurons. Other hypothalamic cell groups, i.e. the suprachiasmatic, ventrolateral preoptic, infundibular and supraoptic nuclei and nucleus basalis of Meynert were unaffected. The surprising selective decrease in CRH-neurons provide novel targets for diagnostics and therapeutic interventions. This article is protected by copyright. All rights reserved.

The subthalamic nucleus (STN) is successfully used as a surgical target for deep brain stimulation in the treatment of movement disorders. Interestingly, the internal structure of the STN is still incompletely understood. The objective of the present study was to investigate three-dimensional (3D) immunoreactivity patterns for 12 individual protein markers for GABA-ergic, serotonergic, dopaminergic as well as glutamatergic signaling. We analyzed the immunoreactivity using optical densities and created a 3D reconstruction of seven postmortem human STNs. Quantitative modeling of the reconstructed 3D immunoreactivity patterns revealed that the applied protein markers show a gradient distribution in the STN. These gradients were predominantly organized along the ventromedial to dorsolateral axis of the STN. The results are of particular interest in view of the theoretical underpinning for surgical targeting, which is based on a tripartite distribution of cognitive, limbic and motor function in the STN. Electronic supplementary material The online version of this article (10.1007/s00429-019-01960-3) contains supplementary material, which is available to authorized users.

BACKGROUND: To establish whether major depressive disorder (MDD), suicidal behaviors and psychotic features contribute to glial alterations in the human prefrontal cortex.MATERIALS AND METHODS: We compared mRNA expression using real-time qPCR of 17 glia related genes in the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) between 24 patients with MDD and 12 well-matched controls without psychiatric or neurological diseases. The MDD group was subdivided into i) MDD who died of suicide (MDD-S) or natural causes (MDD-NS) and ii) MDD with or without psychotic features (MDD-P and MDD-NP). The results were followed up with confounder factor analysis.RESULTS: Astrocyte gene aldehyde dehydrogenase-1 L1 (ALDH1L1) showed an increased expression in the DLPFC of MDD-NS and the ACC of MDD-NP. S100 calcium-binding protein B (S100B) was upregulated in the DLPFC of MDD compared to the controls. Microglial markers CD11B and purinergic receptor 12 (P2RY12) both showed decreased expression in the ACC of MDD-NS. CD68 was increased in the DLPFC of MDD in both, MDD-S and MDD-P, compared to the controls. In addition, there was increased translocator protein (TSPO) expression in the DLPFC of MDD, especially MDD-NS. In the ACC, this gene had a lower expression in MDD-P than in MDD-NP. Myelin basic protein (MBP) mRNA in the DLPFC increased in MDD, in relation to psychotic features, but not to suicide.LIMITATIONS: Sample volumes are relatively small.CONCLUSIONS: Different glial functions in MDD were related to specific brain area, suicide or psychotic features.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, P

Manuel de Falla was a Spanish musician of the XIXth and XXth centuries who had international recognition likely due to his musical fusion talent. His knowledge about Spanish musical traditions gave to his early compositions a new and fresh intellectual interpretation for the typical Spanish folk music. However, in the middle of his musical career, he suffered a strange disease of his eyes named recurrent acute iridocyclitis. This eye flushing is caused by an inflammation of 2 structures of the anterior pole of the ocular globe, the iris, and the ciliary body. It is usually a symptom of another disease and it causes many psychological impairments and disabilities (severe eye pain in bright light, blurry vision, headache, stress for organization (orderliness), and depression in some cases). This soreness of his eyes had an effect over Falla’s compositions and marked an inflection point in his line of musical creations. Eyes in music have been so relevant in another composers and musicians throughout history.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10−8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10−8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10−8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10−9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10−9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic-pituitary-adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

A major challenge in the field of the biogenic amine histamine is the search for new-generation histamine receptor specific drugs. Daniel Bovet and Sir James Black received their Nobel Prizes for Medicine for their work on histamine-1 receptor (H

Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological 'fingerprints' of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.

Gender identity (an individual's perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during early development. During the intrauterine period in the second half of pregnancy, a testosterone surge masculinizes the fetal male brain. If such a testosterone surge does not occur, this will result 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 and can result in gender dysphoria. Nature produces a great variability for all aspects of sexual differentiation of the brain. Mechanisms involved in sexual differentiation of the brain include hormones, genetics, epigenetics, endocrine disruptors, immune response, and self-organization. Furthermore, structural and functional differences in the hypothalamus relating to gender dysphoria and sexual orientation are described in this review. All the genetic, postmortem, and in vivo scanning observations support the neurobiological theory about the origin of gender dysphoria, i.e., it is the sizes of brain structures, the neuron numbers, the molecular composition, functions, and connectivity of brain structures that determine our gender identity or sexual orientation. There is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity or sexual orientation.

The central brain region of interest for neuroendocrinology is the hypothalamus, a name coined by Wilhelm His in 1893. Neuroendocrinology is the discipline that studies hormone production by neurons, the sensitivity of neurons for hormones, as well as the dynamic, bidirectional interactions between neurons and endocrine glands. These interactions do not only occur through hormones, but are also partly accomplished by the autonomic nervous system that is regulated by the hypothalamus and that innervates the endocrine glands. A special characteristic of the hypothalamus is that it contains neuroendocrine neurons projecting either to the neurohypophysis or to the portal vessels of the anterior lobe of the pituitary in the median eminence, where they release their neuropeptides or other neuroactive compounds into the bloodstream, which subsequently act as neurohormones. In the 1970s it was found that vasopressin and oxytocin not only are released as hormones in the circulation but that their neurons project to other neurons within and outside the hypothalamus and function as neurotransmitters or neuromodulators that regulate central functions, including the autonomic innervation of all our body organs. Recently magnocellular oxytocin neurons were shown to send not only an axon to the neurohypophysis, but also axon collaterals of the same neuroendocrine neuron to a multitude of brain areas. In this way, the hypothalamus acts as a central integrator for endocrine, autonomic, and higher brain functions. The history of neuroendocrinology is described in this chapter from the descriptions in De humani corporis fabrica by Vesalius (1537) to the present, with a timeline of the scientists and their findings.

The quality of postmortem hypothalamus research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathological investigation of the entire brain of both the cases and the controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of the clinical neurological diagnoses, despite being made in first rate clinics, have to be revised or require extra diagnoses after a complete and thorough neuropathologic review by the NBB. The neuropathology examination may reveal for instance that the elderly "controls" already have preclinical neurodegenerative alterations. In postmortem studies, the patient and control groups must be matched for as many as possible of the known confounding factors. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present (i) before, (ii) during, and (iii) after death. They are, respectively: (i) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, clock- and seasonal time of death, and lateralization; (ii) agonal state, stress of dying; and (iii) postmortem delay, freezing procedures, fixation, and storage time. Agonal state is generally estimated by measuring the pH of the brain. However, there are disorders in which pH is lower as a part of the disease process. Because of the large number of potentially confounding factors that differ according to, for instance, brain area and disease, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, the influence of the confounders may be determined by statistical methods, such as analysis of variance or the regression models.

Since the discovery of ketamine anti-depressant effects in last decade, it has effectively revitalized interest in investigating excitatory synapses hypothesis in the pathogenesis of depression. In the present study, we aimed to reveal the excitatory synaptic regulation of corticotropin-releasing hormone (CRH) neuron in the hypothalamus, which is the driving force in hypothalamic-pituitary-adrenal (HPA) axis regulation. This study constitutes the first observation of an increased density of PSD-93-CRH co-localized neurons in the hypothalamic paraventricular nucleus (PVN) of patients with major depression. PSD-93 overexpression in CRH neurons in the PVN induced depression-like behaviors in mice, accompanied by increased serum corticosterone level. PSD-93 knockdown relieved the depression-like phenotypes in a lipopolysaccharide (LPS)-induced depression model. Electrophysiological data showed that PSD-93 overexpression increased CRH neurons synaptic activity, while PSD-93 knockdown decreased CRH neurons synaptic activity. Furthermore, we found that LPS induced increased the release of glutamate from microglia to CRH neurons resulted in depression-like behaviors using fiber photometry recordings. Together, these results show that PSD-93 is involved in the pathogenesis of depression via increasing the synaptic activity of CRH neurons in the PVN, leading to the hyperactivity of the HPA axis that underlies depression-like behaviors.