Hippocampal GR expression is increased in elderly depressed females
Highlights
► Increased HPA-axis activity in depression may depend on hippocampal GR levels. ► GR-immunoreactivity correlated positively with age in postmortem brain of depressives. ► Hippocampal GR-immunoreactivity was increased in females, not males, with depression. ► The sex difference in GR may relate to the increased incidence of depression in women.
Introduction
Glucocorticoid hormones (GCs) are important mediators of the stress response in mammals including humans. Exposure to stress activates corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus, which stimulates ACTH secretion from the pituitary and eventually induces GC release from the adrenal gland. GCs are highly lipophilic transcription factors that exert numerous, often long lasting, effects on the brain and body, e.g., on metabolism, inflammation and cognition (de Kloet et al., 2005).
The activity of the hypothalamic–pituitary–adrenal (HPA)-axis is regulated through GC mediated feedback inhibition via glucocorticoid (GR) and tonic inhibition through mineralocorticoid receptors (MR), that are present in distinct brain regions. Both MR and GR belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors (Oakley and Cidlowski, 2010). After ligand binding, the hormone–receptor complex translocates from the cytoplasm to the nucleus where it influences gene transcription. In humans, there is a considerably diversity of GR transcripts and isoforms (Sinclair et al., 2011) but the predominant GR isoform is GR-alpha (Oakley and Cidlowski, 2010).
In both rodents and humans, GR is abundantly expressed in the hippocampal formation (Morimoto et al., 1996) (Wang et al., in press). The hippocampus participates not only in spatial navigation, cognition and mood (de Kloet et al., 2005), but, based on various pharmacological studies, has also been implicated in the modulation of hypothalamo–pituitary–adrenal (HPA)-axis activity, by GCs acting on hippocampal GRs; GR activation has been proposed to cause inhibition of the HPA-axis by some (Furay et al., 2008, Jacobson and Sapolsky, 1991, Juruena et al., 2006, Mizoguchi et al., 2003, Sapolsky et al., 1984), but others actually provided evidence for an activating role of hippocampal GRs with regard to the HPA-axis (van Haarst et al., 1997). Consequently, aberrant GR expression or function has been suggested to be involved in HPA control and implicated in stress resistance, anxiety and depression (Alt et al., 2010, de Kloet et al., 2005, Ridder et al., 2005).
Hyperactivity of the HPA-axis commonly occurs in depressed patients. This is based a.o. on the fact that a substantial proportion of depressed individuals show an exaggerated response to combined dexamethasone/CRH administration (Holsboer and Ising, 2010, Refojo and Holsboer, 2009), but also on human postmortem studies showing enhanced CRH expression in the hypothalamus (Raadsheer et al., 1995, Swaab et al., 2005). Given the generally accepted involvement of the hippocampus in the regulation of HPA-axis activity, there is surprisingly little known about GR protein in the human brain in general, and in the brain of depressed patients in particular. We recently demonstrated abundant GR protein expression in the hippocampus of healthy control subjects (Wang et al., in press). Here, we investigated whether GR protein expression is altered in the hippocampus of confirmed depressed (n = 9) and control (n = 9) subjects, that were carefully pair-wise matched for age, sex, CSF-pH and postmortem delay (PMD).
Section snippets
Human brain tissue
Postmortem human brain tissue was obtained from the Netherlands Brain Bank (NBB). Written permission was obtained from all patients or their next of kin for all brain autopsies and for the use of the tissues and clinical data for research purposes. The depressed patients (n = 9) were carefully pair-wise matched for sex age, PMD a CSF-pH with 9 control subjects as much as possible (female, n = 10; male, n = 8). All depressed patients had suffered from prolonged (from 3 to 63 years duration)
GR-immunohistochemistry in the hippocampus of human depressed patients
No significant differences were present in the age, pH or PMD of the depressive patients compared to the control subjects (n = 9 for each group; age, p = 0.757; PMD, p = 0.658; pH, p = 0.507). As before, prominent nuclear GR-immunoreactivity was observed in the pyramidal and granule neurons of the CA1–3 and DG subregions (Fig. 1). In the hippocampus of depressed patients, the distribution and intensity of GR-ir generally was found to be similar to that of control subjects and no obvious
Discussion
We studied hippocampal GR protein expression in a group of established depressed patients and well-matched controls. In contrast to rhesus monkey, where a relative absence of GR was found (Sanchez et al., 2000), prominent nuclear GR-ir was present in neurons of all main hippocampal subfields of the human hippocampus. In depression, GR-ir was increased significantly with age in the DG in both sexes, while depressed females expressed significantly higher GR-ir than depressed men, particularly in
Acknowledgements
We thank Mr. M. Kooreman from the Netherlands Brain Bank for his help with organizing and collecting human brain material and for histological assistance, Dr. J. Bauer (University Wien, Austria) for immuhistochemical advice and J. Van Heerikhuize for assistance with immunohistochemical quantification. We thank Ms. S. Cornelisse for her help with statistical analysis. QW, DFS and PJL are supported by the Royal Dutch Academy of Sciences (KNAW China Exchange programs # 09CDP011 to DFS and #
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2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :A recent retrospective analysis has shown that oral glucocorticoids were associated with a robust increased risk of suicide in a dose-dependent manner (Laugesen et al., 2021). Although previous findings did not reveal obvious alterations in the cellular integrity or total transcripts of the human HC in relation to depression or glucocorticoid treatment, we later observed an increased expression of the GR in hippocampal CA1 of MDD patients, which interestingly, appeared higher in females than in males (Klok et al., 2011; Müller et al., 2001; Wang et al., 2012). In addition, glucocorticoid stress hormones that act on the GR have been proven to interact with the BDNF Val66Met polymorphism to determine hippocampus-gated fear and spatial memory (Notaras et al., 2016).