Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

Abstract

A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a [125] I-IgG secondary antibody. The optical density corresponding to the level of CRHimmunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine-and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

“…Even so, it was necessary to pool from 8 to 10 micropunches to have enough CRF to measure accurately with freshly prepared radioactive tracer in a displacement radioimmunoassay using a sensitive and specific antisera to CRF. A preliminary immunohistochemical evaluation of CRF in the pontine region of suicides with depressive symptoms has documented an average 27% increase in CRF immunoreactivity in the depressed group of 12 matched pairs of control and depressed subjects (Austin and Murphy, 2000), and this agrees well with our finding of an average 20% increase in CRF protein in our depressed subjects.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…26,27 Further, it could be shown that the CRH levels in pontine brain areas of suicide victims with major depression in their medical history were up to 45% higher than in controls. 28 In living depressed patients there is significant in increased CRH concentrations in cerebrospinal fluid; this represents another line of evidence for the connection of HPA dysregulation and major depression. 29,30 The resolution of all previously dysregulated HPA axis parameters including hypercortisolemia, blunted ACTH response to CRH, hypersecretion of CRH, and adrenal hypertrophy following successful antidepressive treatment provides independent support for the involvement of the HPA axis in depression.…”

Role of corticotropin releasing factor in anxiety disorders: A translational research perspective

“…Studies show that CRF expression in the hypothalamus, raphe nucleus, locus coeruleus and frontal cortex is increased in depressed suicide victims (Austin et al, 2003;Merali et al, 2004;Raadsheer et al, 1994Raadsheer et al, ,1995. CRF receptor binding sites and expression are also reported to be lower in the cortex of depressed suicide victims, suggesting a down-regulation of receptor signaling in response to excessive CRF release Merali et al, 2004;Nemeroff et al, 1988), although these findings have not always been replicated (Hucks et al, 1997;Leake et al, 1990).…”

“…One of the most serious complications of major depression is suicide, though there is growing evidence that depression itself may be a risk factor for multiple adverse health sequelae including cardiovascular disease and stroke (Ebmeier et al, 2006). Altered HPA axis function (e.g., hypercortisolemia, most often evidenced as abnormal 24-hour circadian secretion, in concert with resistance to suppression by exogenous glucocorticoids such as dexamethasone) has been frequently (albeit inconsistently) observed in studies of patients with major depression (Barden, 2004), but findings in anxiety disorders are even less consistent (see below).Studies show that CRF expression in the hypothalamus, raphe nucleus, locus coeruleus and frontal cortex is increased in depressed suicide victims (Austin et al, 2003;Merali et al, 2004;Raadsheer et al, 1994Raadsheer et al, ,1995. CRF receptor binding sites and expression are also reported to be lower in the cortex of depressed suicide victims, suggesting a down-regulation of receptor signaling in response to excessive CRF release Merali et al, 2004;Nemeroff et al, 1988), although these findings have not always been replicated (Hucks et al, 1997;Leake et al, 1990).…”