Hippocampal damage associated with prolonged and fatal stress primates

Regional Primate Research Center, University of Wisconsin, Madison 53715-1299.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/1989; 9(5):1705-11.
Source: PubMed


Sustained exposure to glucocorticoids (GCs), adrenal hormones secreted during stress, can cause neural degeneration in the rat. This is particularly so in the hippocampus, a principal neural target site for GCs, in which GCs can exacerbate the rate of neuron death during normal aging, as well as the severity of neuronal damage after various neurological insults. Thus, stress can be a potent modulator of hippocampal degeneration in the rat. The present report suggests a similar association in the primate. Eight vervet monkeys, housed in a primate center in Kenya, that had died spontaneously from 1984 to 1986, were found at necropsy to have multiple gastric ulcers; a retrospective, neuropathological study was then done of this opportunistic population. Compared with controls euthanized for other research purposes, ulcerated monkeys had marked hippocampal degeneration that was apparent both quantitatively and qualitatively, and both ultrastructurally and on the light-microscopic level. Minimal damage occurred outside the hippocampus. Damage was unlikely to have been due to an agonal or post-mortem artifact. Instead, ulcerated monkeys appear to have been subject to sustained social stress, perhaps in the form of social subordinance in captive breeding groups: most came from social groups, had significantly high incidences of bite wounds at necropsy, and had hyperplastic adrenal cortices, indicative of sustained GC release. Moreover, the specific hippocampal cell fields damaged in ulcerated animals matched those damaged by GCs in the rodent hippocampus. Thus, this represents the first evidence suggesting that sustained stress, via GC hypersecretion, might be neurodegenerative in the primate.

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    • "Depleted area of MF terminals, dendritic atrophy, nuclear pyknosis in the CA3, soma shrinkage and cell loss in the CA1, CA3 subfields. Reduced hippocampal proliferation and survival Enhanced LTP threshold and potentiated LTD in the CA1 Impaired memory in the NOR task and the Y maze test Uno et al., 1989; Magarinos et al., 1996; McKittrick et al., 2000; Czeh et al., 2001; Rygula et al., 2005; Lagace et al., 2010; Wang et al., 2011a; Wagner et al., 2013 Uncontrollable stress (inescapable shock) Reduced hippocampal proliferation Impaired LTP, enhanced LTD in the CA1 Impaired object recognition memory in long acquisition to retrieval delay test Shors et al., 1989; de Quervain et al., 1998; Dagyte et al., 2009 Mixed stress "
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    ABSTRACT: Exposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.
    Reviews in the neurosciences 04/2015; DOI:10.1515/revneuro-2014-0083 · 3.33 Impact Factor
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    • "While mechanisms such as neuronal death (Reagan and McEwen, 1997; Uno et al, 1989) or a reduction in hippocampal neurogenesis (Saaltink and Vreugdenhil, 2014) might explain a reduction in hippocampal volume during extended exposure to exogenous corticosteroids, the observed rapid and reversible changes in hippocampal volume in the current report suggest other mechanism may be involved. Corticosteroids are sometimes administered for cerebral edema, and decreases in brain water with corticosteroids have been reported with magnetic resonance spectroscopy (Chumas et al, 1997). "
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    ABSTRACT: In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing’s syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=−0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.307 · 7.05 Impact Factor
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    • "In the marmoset monkey, auditory contact through phee calls has been shown to cause a reduction in cortisol levels [Rukstalis and French, 2005]. Unmodulated arousal is known to be damaging and even fatal to primates [Uno et al., 1989]. Thus, modulating arousal levels and cooperative behaviors are intertwined: both producing and hearing vocalizations reduces arousal levels ( fig. 3 ) [Rukstalis and French, 2005]. "
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    ABSTRACT: One pragmatic underlying successful vocal communication is the ability to take turns. Taking turns - a form of cooperation - facilitates the transmission of signals by reducing the amount of their overlap. This allows vocalizations to be better heard. Until recently, non-human primates were not thought of as particularly cooperative, especially in the vocal domain. We recently demonstrated that common marmosets (Callithrix jacchus), a small New World primate species, take turns when they exchange vocalizations with both related and unrelated conspecifics. As the common marmoset is distantly related to humans (and there is no documented evidence that Old World primates exhibit vocal turn taking), we argue that this ability arose as an instance of convergent evolution, and is part of a suite of prosocial behavioral tendencies. Such behaviors seem to be, at least in part, the outcome of the cooperative breeding strategy adopted by both humans and marmosets. Importantly, this suite of shared behaviors occurs without correspondence in encephalization. Marmoset vocal turn taking demonstrates that a large brain size and complex cognitive machinery is not needed for vocal cooperation to occur. Consistent with this idea, the temporal structure of marmoset vocal exchanges can be described in terms of coupled oscillator dynamics, similar to quantitative descriptions of human conversations. We propose a simple neural circuit mechanism that may account for these dynamics and, at its core, involves vocalization-induced reductions of arousal. Such a mechanism may underlie the evolution of vocal turn taking in both marmoset monkeys and humans. © 2014 S. Karger AG, Basel.
    Brain Behavior and Evolution 09/2014; 84(2):93-102. DOI:10.1159/000365346 · 2.01 Impact Factor
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