Forced swimming evokes a biphasic response in CREB phosphorylation in extrahypothalamic limbic and neocortical brain structures in the rat.
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-kappaB 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.
Bilang-Bleuel
A
A
Max Planck Institute of Psychiatry, Section of Neuropsychopharmacology, Kraepelinstrasse 2, D-80804 Munich, Germany.
Rech
J
J
De Carli
S
S
Holsboer
F
F
Reul
J M H M
JM
D051697:Activating Transcription Factor 1; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003080:Cold Temperature / Q000009:adverse effects; D003348:Cortisone / Q000097:blood; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004986:Ether / Q000009:adverse effects; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007150:Immunohistochemistry; D007858:Learning / Q000502:physiology*; D008032:Limbic System / Q000166:cytology / Q000378:metabolism*; D008297:Male; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D013550:Swimming / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D004986:Ether; D000324:Adrenocorticotropic Hormone; D003348:Cortisone