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. 2010 Sep 29;30(39):13005-15.
doi: 10.1523/JNEUROSCI.1784-10.2010.

Hippocampal Dysfunction and Cognitive Impairments Provoked by Chronic Early-Life Stress Involve Excessive Activation of CRH Receptors

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Free PMC article

Hippocampal Dysfunction and Cognitive Impairments Provoked by Chronic Early-Life Stress Involve Excessive Activation of CRH Receptors

Autumn S Ivy et al. J Neurosci. .
Free PMC article

Abstract

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF(1)) located on pyramidal cell dendrites. Additionally, chronic CRF(1) occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF(1) receptors. Central or peripheral administration of a CRF(1) blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF(1) interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF(1) occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

Figures

Figure 1.
Figure 1.
The number of CRH-immunoreactive cells was augmented in middle-aged rats that had experienced CES, compared to age-matched CTL rats. Representative sections from control (A1, B1) and CES (A2, B2) demonstrate a larger number of basket cell-like neurons within the pyramidal cell layers of area CA1 (A1, A2) and CA3 (B1, B2) in 12-month-old early-stressed rats (arrows) (n = 3 rats per group). Insets show individual CRH-immunoreactive interneurons. C, Quantitative analyses demonstrate significantly larger numbers of CRH-immunoreactive neurons detectable by ICC in the CA1 and CA3 regions of hippocampi from the early-stressed rats. ICCs were performed concurrently on all sections, and analyzed without knowledge of treatment group. (*p < 0.05, vs controls). Error bars indicate SEM. Scale bar, 100 μm.
Figure 2.
Figure 2.
CRH application onto hippocampal organotypic slice cultures reduced dendritic complexity. Cultures were prepared from postnatal day 1 mice and grown in the presence of CRH (100 nm) for 2 weeks. CA1 pyramidal neurons expressing YFP (n = 10 per group) are shown in control condition (A) and in cultures grown with CRH (B). C, Sholl analysis of both apical dendrites (left panel; F(1,16) = 26.99; p < 0.0001) and basal dendrites (right panel; F(1,6) = 18.35; p < 0.0001) revealed significant reductions in dendritic complexity induced by CRH exposure. Error bars indicate SEM. Scale bar, 70 μm.
Figure 3.
Figure 3.
Hippocampus-dependent learning and memory were preserved in early-life stress rats treated systemically with a blocker of CRF1, NBI30775, during P10–P17. A, During the first 2 training days, all groups successfully learned to find the hidden platform (effect of trial: F(11,539) = 7.73, p < 0.001). Early-life stress impaired acquisition of the water maze (effect of stress condition: F(1,49) = 11.09, p < 0.005), and CRF1 blocker treatment improved performance regardless of stress exposure (F(1,49) = 5.7, p < 0.05). Compared to CTL middle-aged rats (n = 20), age-matched CES rats (n = 13) required more time on the last trial of each water maze training day (trials 6 and 12) to find a hidden platform (*p < 0.05, CES vs CTL). At the end of training (trial 12), this deficit was completely abolished in the stressed group that received CRF1 antagonist (CES+ANT; n = 8; #p < 0.05, vs CES; p > 0.05, vs CTL). B, On day 3 of the water maze, the platform was moved to a new quadrant and rats relied on strategically placed spatial cues to learn the new platform location. Untreated control rats, as well as control (CTL+ANT; n = 4) and early-stressed groups treated with a CRF1 blocker, successfully learned the task, whereas untreated stressed rats had significantly higher escape latencies (*p < 0.05, CES vs all other groups). Analysis of the last trial of the reversal procedure indicated that by the end of testing, CES rats had not learned the new platform location as well as controls (t(40) = 3.26, p < 0.05), and CRF1 antagonist treatment reversed this deficit (CES vs CES+ANT: t(23) = 3.34, p < 0.005; CES+ANT vs CTL: t(31) = 1.33, p = 0.19). C, On day 1 of the object recognition task, exploration times of both objects were similar among the four experimental groups. D, On day 2, preferential exploration of the novel object (apparent from the increased ratio of time spent with novel versus the familiar objects) was observed in untreated control rats (ratio: 2.14), as well as CRF1 blocker-treated controls (ratio: 1.75). The cohort of middle-aged CES rats given the CRF1 receptor blocker also discriminated between the novel and familiar objects (ratio: 1.84), evidenced by a significantly higher mean exploration ratio compared to untreated CES rats (ratio: 0.99; p < 0.0001) (*p < 0.05, CES vs all other groups). Error bars indicate SEM.
Figure 4.
Figure 4.
Hippocampal LTP was attenuated by chronic early-life stress and rescued by a CRF1 blocker given during the week that followed the stress. Acute hippocampal slices were prepared from middle-aged rats killed without any early-life manipulation (CTL) or exposed to CES without or with CRF1 blocker administration (ANT). A, Field EPSP amplitudes (±SEM) plotted as a function of input stimulus duration within a range subthreshold for eliciting a population spike revealed no differences between the three groups. B, Inset: Representative fEPSP traces collected during baseline (black, labeled “1”) or 40 min after HFS (gray overlay, labeled “2”) from controls (left), CES (middle), and CES+ANT (right) rats illustrate the greater potentiation of the fEPSP in the control and CES+ANT rats as compared to the stressed rats. Calibration: 0.5 mV, 5 ms. Plot, fEPSP slopes measured from 10 min before to 1 h after HFS (arrow). LTP in the stressed rats (open triangles) stabilized at significantly lower levels than did potentiation in controls (open circles; p < 0.05 vs control; repeated measure ANOVA) or CES+ANT rats (gray triangles; p < 0.05); values from control and CES+ANT rats were not significantly different. C, Bar graph shows group mean slope values for the final 10 min of recording (*p = 0.02 vs CTL).
Figure 5.
Figure 5.
Administration of the CRF1 antagonist directly into the cerebral ventricles (intracerebroventricularly) sufficed to prevent late-onset cognitive impairments after chronic early-life stress. A, Deficits in spatial learning were found in early-life stressed (CES; n = 15) rats during the 2 d of Morris water maze training, evidenced by higher escape latencies when compared to control (p < 0.001 vs CTL; n = 23). B, The effects of intracerebroventricular CRF1 antagonist treatment surfaced during the water maze tests in which the platform was moved to a new quadrant (reversal). By the last trial of reversal testing (trial 18), the untreated CES rats took significantly longer to find the platform compared to control rats or early-stressed rats given intracerebroventricular CRF1 blocker treatment (CES+ANT; n = 5) (*p < 0.05, CES vs CTL, CES vs CES+ANT). Antagonist treatment of control rats (CTL+ANT; n = 4) had no effect on escape latencies (p > 0.05, vs CTL). C, In the novel-object recognition task, rats from all groups explored two separate objects equally on day 1 of the task, eliminating the possibility of differences in motivation to explore. D, The ratio of time spent with a novel versus a familiar object, a measure of 24 h recognition memory, was significantly lower in early-stressed rats compared to controls (*p < 0.05). CRF1-blocker treatment significantly increased this ratio (*p < 0.05, vs CES), and had little effect on recognition memory in control rats (p > 0.05, vs untreated controls). E, A similar pattern of results was found when the novel objects were counterbalanced across groups. The ratio of time spent exploring a novel versus a familiar object was again lower in untreated early-stressed rats, and CRF1-blocker treatment significantly increased this ratio (*p < 0.05, CES vs all other groups). Data indicate mean ± SEM.
Figure 6.
Figure 6.
CA1 dendritic atrophy in middle-aged, early-life stressed rats was prevented by treatment with a blocker of CRF1 during the week following the stress. A, Golgi-impregnated CA1 pyramidal cells from control, CES, CES+ANT, and CTL+ANT groups were reconstructed using camera lucida. Representative neurons from each group illustrate the reduction in dendritic branching in neuron from the stress group, and the normalization of dendritic arborization of neurons from CES+ANT rats (n = 5–8 neurons per animal, 3–5 animals per group; scale bar, 60 μm). B, Complexity of dendritic arbors was quantified using Sholl analyses, counting the number of dendritic intersections in apical (left) and basal (right) dendritic regions. Significantly reduced dendritic complexity was found in the proximal stratum radiatum of neurons from early-stress rats when compared to either controls (p < 0.05) or CES+ANT (p < 0.05). C, Total apical dendritic length was significantly reduced in the early stress group, but not in stressed rats given the CRH receptor blocker NBI30775. Error bars indicate SEM. *p < 0.05 versus CTL, p < 0.05 versus CES+ANT.
Figure 7.
Figure 7.
CRF1 blocker treatment during P10–P17 prevented augmentation of CRH-immunoreactive (IR) cells in middle-aged rats that had experienced CES. A, CRH-IR neurons in hippocampal CA1 of CTL, early-stressed, antagonist-treated CTL (CTL+ANT), and antagonist-treated early-stressed (CES+ANT) rats. Arrows point to CRH-positive interneurons in the pyramidal cell layer. B, Representative images from hippocampal CA3 region of the same groups. C, Numbers of CRH-IR neurons in areas CA1 and CA3 of NBI30775-treated early-stressed rats were significantly lower than in untreated stressed littermates, and were comparable to controls. *p < 0.05 versus CTL, **p < 0.05 versus CTL+ANT, p < 0.05 versus CES+ANT.

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