Forced swimming evokes a biphasic response in CREB phosphorylation in extrahypothalamic limbic and neocortical brain structures in the rat

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Abstract
The transcription factor cAMP response element‐binding protein (CREB) plays a critical role in plasticity processes underlying learning and memory. We investigated the phosphorylation of CREB in rat brain after forced swimming, a stressor known to impact on higher limbic and neocortical brain areas. As shown by immunohistochemistry, forced swimming increased phosphorylated CREB (P‐CREB) levels in the dentate gyrus, all neocortical areas, the medial, lateral and basolateral nuclei of the amygdala, cerebellum but not in the hypothalamic paraventricular nucleus. Distinct differences in the P‐CREB pattern were observed in the deeper vs. superficial layers of the neocortex. The response in P‐CREB was stressor type‐specific because exposure to either ether or a cold environment was ineffective. The forced swimming‐induced changes in P‐CREB levels showed a biphasic time‐course: an early peak detected at 15 min was followed by a marked drop at 60 min; a second rise starting after 1–2 h, reached maximal values between 6 and 8 h, and remained elevated for at least 48 h. Examination of the neuroanatomical induction pattern of the CRE‐inducible immediate early gene product c‐fos revealed that it was only partly overlapping with that of P‐CREB. Western analyses showed that only the 43‐kDa CREB protein (an enhancer of CRE‐containing promotors) was phosphorylated after forced swimming, while other members of the CREB/ATF family (CREM, ATF‐1 and ATF‐2) remained unaffected. The NF‐κB pathway was not activated, indicating that forced swimming does not unspecifically evoke transcription factor activation. Thus, in contrast to physical stressors, such as ether or cold exposure, forced swimming, a stressor with a strong psychological component, elicits the recruitment of the CREB pathway in a widespread manner in the limbic system and neocortex; brain regions known to be implicated in various forms of (stress‐related) learning and memory.