Fear learning transiently impairs hippocampal cell proliferation

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Abstract

We sought to determine whether contextual fear conditioning, a hippocampal-dependent task, would affect neurogenesis in the dentate gyrus of the hippocampus, and if so, to identify which aspect of the training experience accounts for the change. The immediate shock deficit paradigm was used, together with bromodeoxyuridine immunohistochemistry, to isolate the contribution of different aspects of contextual fear conditioning to neurogenesis. Contextual fear learning caused a 33% decrease in the number of proliferating cells that was anatomically restricted to the dentate gyrus with no change in cell survival or differentiation. This attenuation was not related to exposure to the conditioned stimulus alone, the footshock unconditioned stimulus alone, or the expression of fear to the context after training. Instead, the effect of context conditioning on cell proliferation appears to be specifically due to the formation of an association between the context and shock during training, an amygdala dependent function.

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Animals

All experiments were performed on adult male Sprague–Dawley rats (3 months old) and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the New York University Institutional Animal Care and Use Committee. Rats were individually housed in 10 inch wide×16 inch long×12 inch high cages, had unlimited access to food and water, and were maintained on a 12-h light/dark cycle with lights on from 7:00 a.m. to 7:00 p.m.

Acquisition of contextual fear conditioning decreases cell proliferation

Animals that received both conditioning chamber pre-exposure (CS) and shock (US) demonstrated robust freezing (78±3.7%; Fig. 1b). In contrast, rats that received the US in the absence of CS pre-exposure demonstrated marginal levels of freezing (9.2±2.7%), consistent with previous demonstration of the ISD (Blanchard et al., 1976; Fanselow, 1986). A planned comparison ANOVA comparing the CS P or NP versus the US S or NS revealed a significant interaction between pre-exposure and shock [F(1,20)

Discussion

We have shown an inverse correlation between learning and cell proliferation such that acquisition of contextual fear conditioning leads to a 33% transient reduction in proliferation in the DG, but not in the subventricular zone, while leaving cell survival and differentiation unaffected. Furthermore, by adjusting the parameters of the ISD paradigm, we asked whether it was the CS representation, the US in the absence of learning, the formation of a context-shock association or its expression

Acknowledgments

Supported by NIH grants MH41256 and MH58911 (B.S.M. and J.E.L.), NRSA training grant GM07524 (K.P.), and EJLB Foundation and NSERC grants (K.N.).

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