Stress, Depression and Hippocampal Apoptosis

Centre for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) (Impact Factor: 2.63). 10/2006; 5(5):531-46. DOI: 10.2174/187152706778559273
Source: PubMed

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.

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Available from: Paul J Lucassen, Sep 28, 2015
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    • "In depression, the main structural modification described consists in the reduction of the gray matter within the prefrontal cortex, the hippocampus and the striatum ([64], reviewed in [65]). Several evidences point out that this structural atrophy may be due to impaired neurogenesis within the hippocampus and an excess of neural loss by apoptotic processes, which have been frequently matched to the effects of antidepressants and depressive-like behavior in animal models ([66]–[68], reviewed in [69]). However, other papers do not describe such alterations [70], [71]. "
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    ABSTRACT: We have previously identified 15 genes that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha and ribavirin in the peripheral blood of hepatitis C virus infected patients. An enhanced expression of these genes was also found in the blood of psychiatric patients suffering severe depressive episode. Herein, we demonstrate that the same depression-related interferon-inducible genes (DRIIs) are also upregulated in post-mortem brains of suicidal individuals. Using cultured mouse hippocampal and prefrontal neurons we show that costimulation with murine IFN (mIFN) and the TLR3 agonist poly(I:C) promotes the expression of the described DRIIs, at the same time inducing pro-inflammatory cytokine expression through Stat1 and Stat3 activation, promoting neuronal apoptosis. Consequently, the upregulation of selective DRIIs, production of inflammatory cytokines and inhibition of neuronal plasticity may be involved in the pathogenesis of IFN-associated depression.
    PLoS ONE 12/2013; 8(12):e83149. DOI:10.1371/journal.pone.0083149 · 3.23 Impact Factor
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    • "Indeed, hippocampus-dependent memory impairment was correlated with hippocampal volume reduction [58]. Chronic psychosocial stress can lead to a reduction in hippocampal volume and downregulation of glucocorticoid and mineralocorticoid receptors, which may in turn inhibit synaptoplastic mechanisms associated with cognitive function in patients with depression [25]–[27],[59]. In the coronal hippocampal slice, tetanic simulation of the SC projection to CA1 pyramidal cells can induce LTP [9]. Tree shrews also showed robust LTP in this glutamatergic pathway, while social defeat stress led to LTP failure, providing a possible explanation for the cognitive deficits associated with social defeat [60],[61]. "
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    ABSTRACT: Chronic stress is the major cause of clinical depression. The behavioral signs of depression, including anhedonia, learning and memory deficits, and sleep disruption, result from the damaging effects of stress hormones on specific neural pathways. The Chinese tree shrew (Tupaia belangeri chinensis) is an aggressive non-human primate with a hierarchical social structure that has become a well-established model of the behavioral, endocrine, and neurobiological changes associated with stress-induced depression. The tricyclic antidepressant clomipramine treats many of the core symptoms of depression in humans. To further test the validity of the tree shrew model of depression, we examined the effects of clomipramine on depression-like behaviors and physiological stress responses induced by social defeat in subordinate tree shrews. Social defeat led to weight loss, anhedonia (as measured by sucrose preference), unstable fluctuations in locomotor activity, sustained urinary cortisol elevation, irregular cortisol rhythms, and deficient hippocampal long-term potentiation (LTP). Clomipramine ameliorated anhedonia and irregular locomotor activity, and partially rescued the irregular cortisol rhythm. In contrast, weight loss increased, cortisol levels were even higher, and in vitro LTP was still impaired in the clomipramine treatment group. These results demonstrate the unique advantage of the tree shrew social defeat model of depression.
    PLoS ONE 12/2013; 8(12):e80980. DOI:10.1371/journal.pone.0080980 · 3.23 Impact Factor
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    • "the hippocampus with both acute and chronic stress (Lucassen et al., 2006). However, these effects vary by stressor intensity, duration, and frequency; for example, some have reported that repeated intermittent restraint stress increases neurotrophin-3 mRNA expression and granule cell survival in the hippocampus (Smith et al., 1995; Snyder et al., 2009). "
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    ABSTRACT: Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.
    Journal of Psychiatric Research 03/2013; 47(6). DOI:10.1016/j.jpsychires.2013.02.008 · 3.96 Impact Factor
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