Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

Abstract

The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two ‘non-major depressed’ subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression.

Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress

“…It has been revealed that CRH mRNA level is increased in PVN after chronic mild stress [13] . Our finding is consistent with the previous reports that demonstrate hyperactivation of CRH neurons in PVN both in stressed rats [13] and in the brain of depressive patients [3,4] . Besides, we have found in the same model that CRH mRNA expression is increased after CUMS [27] .…”

“…Patients with depression exhibit elevated CRH mRNA and peptide levels [3,4] , suggesting that the hyperactivity of CRH-containing neurons is associated with, or contributes to the pathophysiology of depression. This idea is reinforced by the following observations: (1) CRH level is increased in cerebral spinal fluid of depressed patients [5] ; (2) Antidepressant drugs can decrease HPA-axis activity [6] ; (3) CRH injection into the brain of laboratory animals induces signs and symptoms of major depression, and the same syndromes are observed in transgenic mice in which CRH is over-produced [7] ; (4) The finding that single-nucleotide polymorphisms (SNPs) in CRH receptor1 gene (CRHR1) are associated with increased susceptibility to major depression [8] is an argument for the direct involvement of CRH in the symptomatology of depression. The behavioral response to stress is associated with CRH changes in the central nervous system (CNS) [9] .…”

Discovering Endophenotypes for Major Depression

“…The evidence for the specificity, and clinical and biological plausibility of endophenotypes related to dysfunctions of the hypothalamic and extrahypothalamic CRH system for MDD is abundant: Levels of CRH in the CSF are elevated in some depressed subjects (Nemeroff et al, 1984), while the pituitary response to CRH appears appropriate given the high cortisol levels (Gold et al, 1986); the number of CRHsecreting neurons in limbic brain regions is increased (Raadsheer et al, 1994); the number of CRH binding sites in the frontal cortex is reduced, possibly as a compensatory response to increased CRH concentrations (Nemeroff et al, 1988); CRH produces a number of physiological and behavioral alterations that resemble the symptoms of major depression including decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations (Nemeroff, 1996); and anxiety and depression scores have been reduced following CRH-1 receptor blockade (Zobel et al, 2000).…”

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

“…Clinical studies have also addressed the hypothesis that AVP is associated with depressive state. Raadsheer et al (1994) showed that the PVN of depressed patients contains 4 times the number of CRH expressing cells and 3 times the number of CRH neurons that coexpressed AVP as compared to normal controls. Similarly, the number of AVP-ir neurons is increased in the PVN of depressed patients (Purba et al, 1996).…”