Research Report Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats Koutaro Kudo a,b , Henny Wati a , Chunxiang Qiao a , Jun Arita c , Shigenobu Kanba d, * a Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, Yamanashi University, Yamanashi, Japan b Department of Psychiatry, Graduate School of Medical Sciences, Tokyo University, Tokyo, Japan c Department of Physiology, Interdisciplinary Graduate School of Medicine and Engineering, Yamanashi University, Yamanashi, Japan d Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan Accepted 5 June 2005 Available online 27 July 2005 Abstract In the early process of long-term memory formation, cyclic AMP response element-binding protein (CREB), a transcription factor on which multiple signal transduction pathways converge, has been implicated. We examined whether the age difference in the performance of contextual fear conditioning (CFC) is associated with a change in activation of CREB in the hippocampus which is an important neural structure for long-term memory. The activation of CREB in the hippocampus in young (15 weeks old) and old (120 weeks old) male rats was determined immunohistochemically with an antibody that specifically recognizes the phosphorylated form of CREB (pCREB). Young rats exhibited better performance than old rats with respect to the freezing time in CFC. Phosphorylation of CREB as revealed by the ratio of the pCREB-immunoreactive cell number to the CREB-immunoreactive cell number was increased in the CA1 region, but not in other hippocampal regions following training for CFC. The close relationship between behavioral performance and CREB phosphorylation in the CA1 region suggests that hippocampal CREB is involved in age-related decline of learning and memory. D 2005 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Aging Keywords: Aging; Memory disturbance; Neural plasticity; Hippocampus; CREB 1. Introduction Impairment of learning and memory in the aging process has been widely studied in various animal models as well as in humans. The hippocampus is well known to play a significant role in the process of learning and/or memory [4,18,20]. In aged rats, there is evidence of marked impairment of hippocampus-dependent tasks, such as spatial memory tasks [7,36], Morris water-maze [9,21,27], con- textual fear conditioning (CFC), radial maze [22], and passive avoidance [27]. There is, on the other hand, no impairment in solving a simple cued discrimination task [22] or immediate memory even though short-term memory is impaired [33]. To understand the molecular mechanisms of the impairment of learning and memory in the aging process, rat hippocampus-dependent tasks are reasonably valid and useful animal models. Previous studies have suggested some mechanisms underlying the aging-related cognitive changes in the rat brain. One of the mechanisms is a reduction in the duration of experimentally induced long-term potentiation (LTP) of hippocampal synapses [16,17], which is correlated with faster forgetting of spatial information [4]. The impairment of LTP was thought to be caused by an increase of intracellular calcium by aging [6,17]. Another is loss of synaptic connectivity and integration among hippocampal 0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2005.06.045 * Corresponding author. Fax: +81 92 642 6544. E-mail address: skanba@npsych.med.kyushu-u.ac.jp (S. Kanba). Brain Research 1054 (2005) 30 – 37 www.elsevier.com/locate/brainres