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Impairment of learning and memory by transient reduction of synaptic zinc in the hippocampus
Abstracts / Neuroscience Research 71S (2011) e108–e415
array with 6 colored discs by trial and error. In this task, the relevant color was not informed and changed into another color when the trial block was unexpectedly alternated. So the subject was required to seek the relevant color by TE search in several trials after every color change and then to maintain KB search within a block after the detection of the relevant color. The subject successfully performed this task by switching TE- and KB-search strategies flexibly. We conducted the single-unit recording from the dorsolateral prefrontal cortex (DLPFC) and found that DLPF neurons showed a significant difference in their sustained activity before response depending on the ongoing search strategy. Interestingly, some of those neurons also showed transient activity at the timing of the feedback on the first error trial after a color change and/or on the first successful trial after a color change. This transient activity presumably acted as the command signal for a switching of the search strategies. Thus, DLPF neurons reflected the ongoing search strategy and/or the switching command with the differential time courses in their activities. These results suggested that DLPF neurons play a crucial role for a flexible switching of the search strategies based on the contextdependent feedback (first error/success after a color change) at adapting to the changing environment. Research fund: KAKENHI 20500283, 20033010, 22120507. doi:10.1016/j.neures.2011.07.1208
P3-o05 Impairment of learning and memory by transient reduction of synaptic zinc in the hippocampus Shunsuke Takada , Atsushi Takeda, Masatoshi Nakamura, Masaki Ando, Naoto Oku Dept. of Med. Biochem., Grad. Sch. of Pharm. Scis., Univ. of Shizuoka, Shizuoka, Japan The hippocampus plays an important role for learning and memory. Longterm potentiation (LTP) is one of synaptic plasticity and a cellular model for memory. The hippocampus is enriched with histochemically reactive (chelatable) zinc, which predominately exists in the presynaptic vesicles. Chelatable zinc released from glutamatergic neurons may multi-functionally participate in LTP induction in the hippocampus. However, the role of chelatable zinc in memory processing, i.e., encoding, storage, and expression of memory, is poorly understood. To examine the role of chelatable zinc in cognitive function, in the present study, hippocampal LTP induction and object recognition memory were examined in young rats after i.p. injection of clioquinol (CQ, 30 mg/kg), a lipophilic chelator for zinc. In vivo LTP induction was performed under conscious condition, because LTP induced under conscious condition, unlike anesthetized condition, is maintained for more than 24 h after the induction. Hippocampal slices were prepared 2–72 h after CQ injection and chelatable zinc was stained by Timm’s sulfide-silver method and by using ZnAF-2, a membrane-impermeable zinc indicator. Chelatable zinc was transiently decreased after CQ injection and the decreased rate was maximally reached 6 h after injection. LTP induction at the perforant path-granule cell synapse was suppressed 6 h after injection and restored 72 h after injection. In the training of object recognition memory 6 h after injection, the time exploring the objects was decreased in CQ-administered rats. One hour later, CQ-administered rat showed object recognition memory deficit in the test. In contrast, in the training 72 h after injection, CQ-administered rat showed normal object recognition memory in the test. The present study suggests that transient reduction of histochemically reactive (chelatable) zinc significantly attenuates dentate gyrus LTP, followed by object recognition memory deficit. doi:10.1016/j.neures.2011.07.1209
P3-o06 Enhancement of hippocampal adult neurogenesis by memantine treatment improves hippocampusdependent learning and memory Rie Ishikawa 1 , Ryang Kim 1 , Tetsuo Okugawa 1 , Takashi Namba 2 , Shinichi Kohsaka 2 , Shigeo Uchino 2 , Satoshi Kida 1,3 1
Dep. of Bioscience, Tokyo Univ. of Agriculture, Tokyo, Japan 2 National Institute of Neuroscience, NCNP, Tokyo, Japan 3 CREST, JST, Saitama, Japan
Adult neurogenesis occurs in the subgranular zone of the dentate gyrus (DG) in the hippocampus. Abundant studies have shown that adult hippocampal neurogenesis contributes to hippocampus-dependent learning and memory. However, effects of enhanced adult hippocampal neurogenesis on learning and memory still remain unclear. Previous studies have shown that a single treatment with memantine, an antagonist for N-methyl-D-aspartate (NMDA) glutamate receptor, by a systemic injection promotes cell proliferation in the DG during adult neurogenesis. In this current study, we examined effects of
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enhanced adult hippocampal neurogenesis by the treatment with memantine on hippocampus-dependent learning and memory. We examined social recognition and spatial learning/memories 1 or 3 weeks after the memantine treatment. Memantine-treated mice displayed enhancements of long-term recognition and spatial memories in social recognition and Morris water maze tasks, respectively, 3, but not 1, weeks after the memantine treatment, suggesting that mature, but not immature, neurons generated following the memantine treatment contributed to improvement of memory performance. Consistent with previous observations, we observed that the treatment with memantine led to significant and drastic enhancement of cell proliferation in the DG of the hippocampus, indicating that the treatment with memantine promoted adult neurogenesis. More importantly, memantine-treated mice revealed a significant positive correlation between the number of BrdU positive cells and memory performance in Morris water maze task. These results suggest that enhancement of hippocampal adult neurogenesis by treatment with memantine improves hippocampus-dependent learning and memory. doi:10.1016/j.neures.2011.07.1210
P3-o07 Positive regulation of memory formation by retinoic acid receptors in the hippocampus Masanori Nomoto 1,2 , Yohei Mitsuda 1 , Satoshi Kida 1,2 1
Takeda 1 , Ryang
Kim 1 , Koji
Dept. of Bio., Tokyo Univ. of Agri., Tokyo, Japan 2 CREST, JST, Japan
Retinoic acid (RA), a metabolite of Vitamin A, functions as a specific ligand for retinoic acid receptors (RARs) and regulates various biological phenomena through transcriptional regulation. RARs ubiquitously express in brain. Previous studies have shown that RA-deficient mice and RARs-knockout mice exhibit impairments of LTP and spatial memory, suggesting that RARs may play an important role in hippocampal synaptic plasticity and memory. However, mechanisms by which RARs in the hippocampus regulate synaptic plasticity and memory still remain unclear. To ask this, we have examined effects of loss-of-functions or gain-of-function of RARs on memory and LTP by generating and analyzing conditional mutant mice that enable to regulate forebrain-specific expression of a dominant negative RARalpha mutant (dnRAR) or wild type RARalpha, respectively. We have shown that dnRAR mice display impairments of AMPA receptor-mediated excitatory postsynaptic potentials and LTP in the hippocampus and hippocampus-dependent memory formation. In this study, we examined effects of pharmacological loss-of-function or gain-of-function of hippocampal RARs on memory performance. An infusion of Ro41-5253 (RARalpha antagonist) into the hippocampus 4 hrs before the training impaired the formation of social recognition memory in a dose-dependent manner. In contrast, an infusion of all-trans RA (RARs agonist) into the hippocampus 4 hrs before the training improved the formation of social recognition memory. These results suggest that inactivating or activating hippocampal RARalpha impairs or improves, respectively, social recognition memory. Taken together, these results strongly suggest that retinoid signaling pathway in the hippocampus positively regulates memory formation as well as synaptic plasticity. Research fund: CREST Grant-in-Aid for Scientific Research (B) 20380078. doi:10.1016/j.neures.2011.07.1211
P3-o08 Roles of transcription factor CREB in learning and short-term memory Tatsurou Serita 1 , Hotaka Fukushima 1,2 , Satoshi Kida 1,2 1
Dep. of Bioscience, Tokyo Univ. of Agriculture, Tokyo, Japan 2 JST, CREST, Saitama, Japan Previous findings that loss-of-function of CREB leads to an impairment of long-term memory (LTM) suggest that CREB positively regulates the formation of LTM. To further understand roles of CREB in memory formation, we have examined effects of gain-of-CREB function on memory formation by generating and analyzing transgenic mice expressing a constitutively active CREB mutant (C REB DIEDML) in the forebrain. Interestingly, these transgenic mice displayed enhancements of STM as well as LTM. We also found that up-regulation of BDNF by a constitutive increase in CREB activity contributes to this enhancement of STM. In this current study, to further understand effects of gain-of-CREB function, we examined learning performance of DIEDML mice using trace fear conditioning task. In the trace fear conditioning, mice learn association between the conditioning stimulus (CS; tone) and the unconditioning stimulus (US; footshock) separated from temporal gap (the trace interval). During training consisting of 8 CS-traceUS-intertrial interval (ITI), mice were assessed average freezing for each trace interval as a learning indicator. DIEDML mice displayed comparable learning
array with 6 colored discs by trial and error. In this task, the relevant color was not informed and changed into another color when the trial block was unexpectedly alternated. So the subject was required to seek the relevant color by TE search in several trials after every color change and then to maintain KB search within a block after the detection of the relevant color. The subject successfully performed this task by switching TE- and KB-search strategies flexibly. We conducted the single-unit recording from the dorsolateral prefrontal cortex (DLPFC) and found that DLPF neurons showed a significant difference in their sustained activity before response depending on the ongoing search strategy. Interestingly, some of those neurons also showed transient activity at the timing of the feedback on the first error trial after a color change and/or on the first successful trial after a color change. This transient activity presumably acted as the command signal for a switching of the search strategies. Thus, DLPF neurons reflected the ongoing search strategy and/or the switching command with the differential time courses in their activities. These results suggested that DLPF neurons play a crucial role for a flexible switching of the search strategies based on the contextdependent feedback (first error/success after a color change) at adapting to the changing environment. Research fund: KAKENHI 20500283, 20033010, 22120507. doi:10.1016/j.neures.2011.07.1208
P3-o05 Impairment of learning and memory by transient reduction of synaptic zinc in the hippocampus Shunsuke Takada , Atsushi Takeda, Masatoshi Nakamura, Masaki Ando, Naoto Oku Dept. of Med. Biochem., Grad. Sch. of Pharm. Scis., Univ. of Shizuoka, Shizuoka, Japan The hippocampus plays an important role for learning and memory. Longterm potentiation (LTP) is one of synaptic plasticity and a cellular model for memory. The hippocampus is enriched with histochemically reactive (chelatable) zinc, which predominately exists in the presynaptic vesicles. Chelatable zinc released from glutamatergic neurons may multi-functionally participate in LTP induction in the hippocampus. However, the role of chelatable zinc in memory processing, i.e., encoding, storage, and expression of memory, is poorly understood. To examine the role of chelatable zinc in cognitive function, in the present study, hippocampal LTP induction and object recognition memory were examined in young rats after i.p. injection of clioquinol (CQ, 30 mg/kg), a lipophilic chelator for zinc. In vivo LTP induction was performed under conscious condition, because LTP induced under conscious condition, unlike anesthetized condition, is maintained for more than 24 h after the induction. Hippocampal slices were prepared 2–72 h after CQ injection and chelatable zinc was stained by Timm’s sulfide-silver method and by using ZnAF-2, a membrane-impermeable zinc indicator. Chelatable zinc was transiently decreased after CQ injection and the decreased rate was maximally reached 6 h after injection. LTP induction at the perforant path-granule cell synapse was suppressed 6 h after injection and restored 72 h after injection. In the training of object recognition memory 6 h after injection, the time exploring the objects was decreased in CQ-administered rats. One hour later, CQ-administered rat showed object recognition memory deficit in the test. In contrast, in the training 72 h after injection, CQ-administered rat showed normal object recognition memory in the test. The present study suggests that transient reduction of histochemically reactive (chelatable) zinc significantly attenuates dentate gyrus LTP, followed by object recognition memory deficit. doi:10.1016/j.neures.2011.07.1209
P3-o06 Enhancement of hippocampal adult neurogenesis by memantine treatment improves hippocampusdependent learning and memory Rie Ishikawa 1 , Ryang Kim 1 , Tetsuo Okugawa 1 , Takashi Namba 2 , Shinichi Kohsaka 2 , Shigeo Uchino 2 , Satoshi Kida 1,3 1
Dep. of Bioscience, Tokyo Univ. of Agriculture, Tokyo, Japan 2 National Institute of Neuroscience, NCNP, Tokyo, Japan 3 CREST, JST, Saitama, Japan
Adult neurogenesis occurs in the subgranular zone of the dentate gyrus (DG) in the hippocampus. Abundant studies have shown that adult hippocampal neurogenesis contributes to hippocampus-dependent learning and memory. However, effects of enhanced adult hippocampal neurogenesis on learning and memory still remain unclear. Previous studies have shown that a single treatment with memantine, an antagonist for N-methyl-D-aspartate (NMDA) glutamate receptor, by a systemic injection promotes cell proliferation in the DG during adult neurogenesis. In this current study, we examined effects of
e277
enhanced adult hippocampal neurogenesis by the treatment with memantine on hippocampus-dependent learning and memory. We examined social recognition and spatial learning/memories 1 or 3 weeks after the memantine treatment. Memantine-treated mice displayed enhancements of long-term recognition and spatial memories in social recognition and Morris water maze tasks, respectively, 3, but not 1, weeks after the memantine treatment, suggesting that mature, but not immature, neurons generated following the memantine treatment contributed to improvement of memory performance. Consistent with previous observations, we observed that the treatment with memantine led to significant and drastic enhancement of cell proliferation in the DG of the hippocampus, indicating that the treatment with memantine promoted adult neurogenesis. More importantly, memantine-treated mice revealed a significant positive correlation between the number of BrdU positive cells and memory performance in Morris water maze task. These results suggest that enhancement of hippocampal adult neurogenesis by treatment with memantine improves hippocampus-dependent learning and memory. doi:10.1016/j.neures.2011.07.1210
P3-o07 Positive regulation of memory formation by retinoic acid receptors in the hippocampus Masanori Nomoto 1,2 , Yohei Mitsuda 1 , Satoshi Kida 1,2 1
Takeda 1 , Ryang
Kim 1 , Koji
Dept. of Bio., Tokyo Univ. of Agri., Tokyo, Japan 2 CREST, JST, Japan
Retinoic acid (RA), a metabolite of Vitamin A, functions as a specific ligand for retinoic acid receptors (RARs) and regulates various biological phenomena through transcriptional regulation. RARs ubiquitously express in brain. Previous studies have shown that RA-deficient mice and RARs-knockout mice exhibit impairments of LTP and spatial memory, suggesting that RARs may play an important role in hippocampal synaptic plasticity and memory. However, mechanisms by which RARs in the hippocampus regulate synaptic plasticity and memory still remain unclear. To ask this, we have examined effects of loss-of-functions or gain-of-function of RARs on memory and LTP by generating and analyzing conditional mutant mice that enable to regulate forebrain-specific expression of a dominant negative RARalpha mutant (dnRAR) or wild type RARalpha, respectively. We have shown that dnRAR mice display impairments of AMPA receptor-mediated excitatory postsynaptic potentials and LTP in the hippocampus and hippocampus-dependent memory formation. In this study, we examined effects of pharmacological loss-of-function or gain-of-function of hippocampal RARs on memory performance. An infusion of Ro41-5253 (RARalpha antagonist) into the hippocampus 4 hrs before the training impaired the formation of social recognition memory in a dose-dependent manner. In contrast, an infusion of all-trans RA (RARs agonist) into the hippocampus 4 hrs before the training improved the formation of social recognition memory. These results suggest that inactivating or activating hippocampal RARalpha impairs or improves, respectively, social recognition memory. Taken together, these results strongly suggest that retinoid signaling pathway in the hippocampus positively regulates memory formation as well as synaptic plasticity. Research fund: CREST Grant-in-Aid for Scientific Research (B) 20380078. doi:10.1016/j.neures.2011.07.1211
P3-o08 Roles of transcription factor CREB in learning and short-term memory Tatsurou Serita 1 , Hotaka Fukushima 1,2 , Satoshi Kida 1,2 1
Dep. of Bioscience, Tokyo Univ. of Agriculture, Tokyo, Japan 2 JST, CREST, Saitama, Japan Previous findings that loss-of-function of CREB leads to an impairment of long-term memory (LTM) suggest that CREB positively regulates the formation of LTM. To further understand roles of CREB in memory formation, we have examined effects of gain-of-CREB function on memory formation by generating and analyzing transgenic mice expressing a constitutively active CREB mutant (C REB DIEDML) in the forebrain. Interestingly, these transgenic mice displayed enhancements of STM as well as LTM. We also found that up-regulation of BDNF by a constitutive increase in CREB activity contributes to this enhancement of STM. In this current study, to further understand effects of gain-of-CREB function, we examined learning performance of DIEDML mice using trace fear conditioning task. In the trace fear conditioning, mice learn association between the conditioning stimulus (CS; tone) and the unconditioning stimulus (US; footshock) separated from temporal gap (the trace interval). During training consisting of 8 CS-traceUS-intertrial interval (ITI), mice were assessed average freezing for each trace interval as a learning indicator. DIEDML mice displayed comparable learning