Neurogenesis and Helplessness Are Mediated by Controllability in Males But Not in Females

Shors, Tracey J.; Mathew, Jason; Sisti, Helene M.; Edgecomb, Carol; Beckoff, Steven; Dalla, Christina

doi:10.1016/j.biopsych.2006.10.033

Cited by 127 publications

(97 citation statements)

References 47 publications

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“…In this study, we demonstrate that acute, and chronic, stress suppress hippocampal cell proliferation, consistent with previous reports (12,32,33) and that the antiproliferative effect of stress is blocked by inhibition of IL-1RI. In vitro studies show that suppression of cell proliferation is mediated by direct actions of IL-1␤ on IL-1RI receptors localized on adult hippocampal progenitor cells via a reduction in cell cycling and not increased cell death.…”

Section: Discussionsupporting

confidence: 93%

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

Koo

Duman

2008

Proc. Natl. Acad. Sci. U.S.A.

775

564

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Stress decreases neurogenesis in the adult hippocampus, and blockade of this effect is required for the actions of antidepressants in behavioral models of depression. However, the mechanisms underlying these effects of stress have not been identified. Here, we demonstrate an essential role for the proinflammatory cytokine IL-1␤. Administration of IL-1␤ or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1␤ receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-B signaling pathway. These findings demonstrate that IL-1␤ is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.cytokine ͉ depression ͉ neurogenesis T he profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function (1, 2). In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders (3, 4). Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders (5-7). Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients (8-10). In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress (11,12), and reduces or even reverses hippocampal atrophy (9, 11). Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety (13, 14) with some exceptions (15,16).Despite this progress, the mechanisms underlying the antineurogenic and behavioral actions of stress remain ill defined. One possibility is that excessive proinflammatory cytokines, particularly IL-1␤, contribute to the actions of stress. Animal studies demonstrate that exposure to stress increases IL-1␤ in several brain areas, including the hippocampus (17-20), and central administration of IL-1␤ produces several stress-like effects, including activation of the hypothalamic-pituitary-adrenal (HPA) axis (17, 21), inhibition of hippocampal long-term potentiation (22), down-regulation of hippocampal brain-derived neurotrophic factor (23), and impaired hippocampal-dependent contextual fear conditioning (24). In contrast, blockade of the receptor, IL-1RI that mediates the actions of IL-1␤ (25) inhibits these stress-like effects (23, 24) and blocks the antiproliferative effects of INF-␣ in the hippocampus (26).Based on this evidence, the current study was undertaken to test the hypothesis that the antineurogenic and depressiv...

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Section: Discussionsupporting

confidence: 93%

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

Koo

Duman

2008

Proc. Natl. Acad. Sci. U.S.A.

775

564

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“…Rats exposed to 30 trials of mild footshock for 7 d showed a decrease in the latency to escape the shock (controllable). In contrast, the yoked littermates who were unable to control the stressor (uncontrollable) did not attempt to escape after the first day of training and performed poorly on a subsequent test (FR2) demonstrating their inability to learn to escape the shock (Shors et al, 2007). These observations suggest that the animals subjected to uncontrollable stress exhibit a form of learned helplessness that is an accepted model of depression.…”

Section: Vgf Is Downregulated In Animal Models Of Depression and Prodmentioning

confidence: 95%

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

Krol²,

et al. 2007

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Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and BDNF produces antidepressant-like effects in behavioral models of depression. In our previous work, we identified genes induced by BDNF and defined their specific roles in hippocampal neuronal development and plasticity. To identify genes downstream of BDNF that may play roles in psychiatric disorders, we examined a subset of BDNF-induced genes also regulated by 5-HT (serotonin), which includes the neuropeptide VGF (nonacronymic). To explore the function of VGF in depression, we first investigated the expression of the neuropeptide in animal models of depression. VGF was downregulated in the hippocampus after both the learned helplessness and forced swim test (FST) paradigms. Conversely, VGF infusion in the hippocampus of mice subjected to FST reduced the time spent immobile for up to 6 d, thus demonstrating a novel role for VGF as an antidepressant-like agent. Recent evidence indicates that chronic treatment of rodents with antidepressants increases neurogenesis in the adult dentate gyrus and that neurogenesis is required for the behavioral effects of antidepressants. Our studies using

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“…Estimates of total numbers of BrdU-labeled cells were made using a modified unbiased stereology protocol (8,11,55,56). This was accomplished by counting the number of BrdU-labeled cells in the SGZ, GCL, and hilus on every twelfth unilateral section throughout the DG (21.88 to 24.52 mm anteroposterior) (57).…”

Section: Methodsmentioning

confidence: 99%

Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi

Dalla

Papachristos

Whetstone

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

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Learning increases the survival of new cells that are generated in the hippocampal formation before the training experience, especially if the animal learns to associate stimuli across time [Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999) Nat Neurosci 2:260 -265]. All relevant studies have been conducted on male rats, despite evidence for sex differences in this type of learning. In the present study, we asked whether sex differences in learning influence the survival of neurons generated in the adult hippocampus. Male and female adult rats were injected with one dose of bromodeoxyuridine (BrdU; 200 mg/kg), to label one population of dividing cells. One week later, half of the animals were trained with a temporal learning task of trace eyeblink conditioning, while the other half were not trained. Animals were killed 1 day after training (12 days after the BrdU injection). Hippocampal tissue was stained for BrdU and a marker of immature neurons, doublecortin. Both sexes learned to emit the conditioned eyeblink response during the trace interval. As a consequence, more new neurons remained in their hippocampi than in sex-matched controls. In individual animals, the number of surviving cells correlated positively with asymptotic performance; those that expressed more learned responses retained more new neurons. However, animals that learned very well retained even more new cells if they required many trials to do so. Because females emitted more learned responses than males did, they retained nearly twice as many new cells per unit volume of tissue. This effect was most evident in the ventral region of the hippocampal formation. Thus, sex differences in learning alter the anatomical structure of the hippocampus. As a result, male and female brains continue to differentiate in adulthood.eyeblink conditioning ͉ learning ͉ neurogenesis ͉ sex differences ͉ stem cell

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Neurogenesis and Helplessness Are Mediated by Controllability in Males But Not in Females

Cited by 127 publications

References 47 publications

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

The Neuropeptide VGF Produces Antidepressant-Like Behavioral Effects and Enhances Proliferation in the Hippocampus

Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi

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