Stress, Depression and Hippocampal Apoptosis

Abstract

In this review, we summarize and discuss recent studies on structural plasticity changes, particularly apoptosis, in the mammalian hippocampus in relation to stress and depression. Apoptosis continues to occur, yet with very low numbers, in the adult hippocampal dentate gyrus (DG) of various species. Stress and steroid exposure modulate the rate of apoptosis in the DG. Contrary to earlier studies, the impact of chronic stress on structural parameters of the hippocampus like cell number and volume, is rather modest, and requires prolonged and severe stress exposure before only small reductions (< 10 %) become detectable. This does not exclude other structural parameters, like synaptic terminal structure, or dendritic arborization from being significantly altered in critical hippocampal subregions like the DG and/or CA3. Neither does it imply that the functional implications of the changes after stress are also modest. Of interest, most of the structural plasticity changes appear transient and are generally reversible after appropiate recovery periods, or following cessation or blockade of the stress or corticosteroid exposure. The temporary slowing down of both apoptosis and adult proliferation, i.e. the DG turnover, after chronic stress will affect the overall composition, average age and identity of DG cells, and will have considerable consequences for the connectivity, input and properties of the hippocampal circuit and thus for memory function. Modulation of apoptosis and neurogenesis, by drugs interfering with stress components like MR and/or GR, and/or mediators of the cell death cascade, may therefore provide important drug targets for the modulation of mood and memory.

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…Particularly, within the hippocampus, there is a close association between apoptosis and neurogenesis and the precise balance drives the continuous turnover of cells in this region (Biebl et al, 2000;Heine et al, 2004). Besides slowing down neurogenesis, stress and steroid hormones temporally reduce the dentate cell turnover, by modulating the ongoing rate of apoptosis (Lucassen et al, 2006;Czeh and Lucassen, 2007). Although, the impact of chronic stress on total hippocampal cell number and volume is modest (o10%) and these changes are transient, the functional consequences on dentritic arborization and synaptic plasticity over time could contribute to the structural impairments observed in depressive disorders (Lucassen et al, 2006;Czeh and Lucassen, 2007).…”

“…On the other hand, antidepressants are hypothesized to mediate their long-term therapeutic effects by triggering cellular protective mechanisms to counteract the structural impairments Duman, 2004;Lucassen et al, 2006). In support of this hypothesis, chronic ADT increases the expression of brain-derived neurotrophic factor (BDNF; Nibuya et al, 1995) and neurogenesis in the adult hippocampus (Malberg et al, 2000) as well as enhances cell proliferation in the Fr cortex (Kodama et al, 2004).…”

“…In animal stress paradigms, stress, and stress hormones decrease neurogenesis in the hippocampus (Gould et al, 1998), modulate apoptosis in the cortex and hippocampus (Lucassen et al, 2001a(Lucassen et al, , 2006, reduce the number and length of apical dendrites of CA3 hippocampal neurons (Magarinos et al, 1996), and induce contrasting patterns of dendritic remodeling in amygdaloid and hippocampal neurons (Vyas et al, 2002;Dulawa and Hen, 2005).…”

“…Although excitotoxic cell death (necrosis) is one mechanism of cell death in the adult brain following exposure to stress (for review, see Sapolsky, 2000), research has shown that apoptosis also plays a role (D'Sa and Duman, 2004;Lucassen et al, 2006). There is some evidence that apoptosis occurs in depressed patients.…”

Middle-aged rat hippocampus and some early changes accompanying aging

“…Histopathological studies showed that neurodegenerative diseases affect hippocampal subfields differently, e.g. neuronal loss was found especially in the CA1 area in Alzheimer disease [11][12][13]. Recently attention has been given also to brain metabolites and changes of their content during aging.…”