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BMAL1 plays a role in circadian regulation of memory retrieval
Abstracts / Neuroscience Research 71S (2011) e108–e415
e373
coding neurons. Neurons whose phasic or tonic response to the CS presentation was positively correlated with the reward probability were classified as stimulus value coding neurons. Neurons whose activity increased before the delivery of an expected reward were classified as reward expectation coding neurons. We then examined sensitivity to time discounting for these neurons by increasing the duration of the delay period. With increasing delay, the CS response decreased and the reward response increased in the RPE coding neurons, which may be due to an increase of unpredictability of the reward; the CS response decreased in the stimulus value coding neurons, which may be due to a decrease of the stimulus value, and the activity decreased and its peak latency shifted toward the new time of the reward delivery in the reward expectation coding neurons, which may be due to the animal’s adaptation to the new time of the reward delivery. These results suggest that the CS, delay, and reward-related activities of striatal neurons can be affected by time discounting.
complexity increases. The high temporal resolution provided by the optical inhibition of NAcc and VTA neurons (via halorhodopsin) will provide us with answers about the importance of feedback information when an error is made. Research fund: OIST.
doi:10.1016/j.neures.2011.07.1636
Reversal learning has been widely used to assess the reward sensitivity in both human and nonhuman animals. In this task the subjects have to attend to the relevant stimulus dimension (e.g., size, color, and shape of the stimuli) for reward, so it is also used to evaluate the categorical ability of the subjects. Reward sensitivity and categorical ability are highly important for adaptive behavior, which is known to require intact brain function in orbitofrontal cortex. To establish the marmoset model of the cognitive abilities, we trained the common marmosets to perform simple discrimination using visual stimuli on the touch monitor screen and evaluated their learning of repeated reversals of the reward contingency. After habituated to the apparatus, the subjects were required to select one out of two visual stimuli which differed in terms of the size. The subjects were trained to select, for example, the smaller stimulus of the two until their performance met the learning criterion. Once they met the criterion, the reward contingency of the stimulus was reversed in the next session (i.e. now the larger stimulus leads to the reinforcement). After several contingency reversals, they showed quick recovery of the performance in the first session of the reversal. Then, using the novel stimulus sets, we tested their generalization performance whether they based their responses on the absolute or the relative stimulus size (i.e. transposition). Performance in the test trials suggested that they learned not only specific stimulus characteristics leading to the reinforcement, but the relative size of the stimulus combinations which was applicable to the novel situations. Research fund: The study was supported by the Centre for Advanced Research on Logic and Sensibility, The Global COE Program, at Keio University, Japan, and the Funding Program for World-leading Innovative R&D on Science and Technology, at RIKEN, Japan.
P4-m19 Cognitive control of response inhibition in the primate Kazuko Hayashi 1 , Atsushi Noritake 1 , Kae Nakamura 1,2 1 2
Department of Physiology, Kansai Medical University, Osaka, Japan PRESTO, JST
The dorsal raphé nucleus (DRN) is a major source of serotonin. Many studies suggest that serotonergic neurotransmission is involved in emotional, cognitive and behavioral control processes. We have previously shown that the primate DRN neurons code both rewarding and aversive information during Pavlovian conditioning task. To further investigate the role of DRN in behavioral impulsivity, especially regulation of response inhibition, we used an operant conditioning procedure. In this study, a monkey (Macaca fascicularis) was trained using Go/No-go paradigm. On each trial, a fixation point appeared at the center of the screen. After the fixation, a cue was presented to the left or right of the fixation point. Each cue was associated with different action (Go/No-go). If the cue indicated “Go”, the monkey made saccade to the left or right. If “No-go”, the monkey had to inhibit saccade to the target and continue to gaze at the central fixation point. A liquid reward was delivered after the appropriate generation or inhibition of saccade. The monkey showed differential behavior depending on the cue and successfully learned the association of each cue with the action. The result suggests that this paradigm is useful for the electrophysiological evaluation of DRN function in regulating response inhibition. We will record single-unit activity in the DRN of monkeys performing the Go/No-go saccade task in future studies. Research fund: PRESTO, HFSP, KAKENHI (20020028), KAKENHI (20300139). doi:10.1016/j.neures.2011.07.1637
P4-m20 VTA and NAcc neurons inhibition during reversal learning: A pharmacological and an optogenetic approach Luca Aquili , Jeffrey Wickens Okinawa Institute of Science and Technology Purpose: The aim of this study was to understand the contribution of VTA and Nacc cells in reversal learning performance by using two approaches. First, inhibition of VTA and Nacc cells using a Gaba-a agonist (Muscimol). Second, inhibition of VTA and Nacc cells using light-sensitive opsins (halorhodopsin). The prediction from this investigation was that neuronal suppression of Nacc neurons would have a greater impact on reversal learning performance than suppression of VTA cells, as task complexity increased. Methods: Rats (Muscimol group) (n = 15) were implanted with bilateral guide cannulae above the VTA and Nacc. Another group of rats (n = 15) received injections of lentivirus (halorhodopsin) in the VTA and Nacc, and were implanted with a fiber guide system that would deliver a yellow light to target neurons via an optical fiber. After surgery, rats were trained to complete an FR1 discrimination, and then tested in a between reversal and a within session reversal task. Results: VTA (n = 5) and Nacc (n = 5) implanted rats that received muscimol injections made significantly fewer errors during the between reversal session than the control group (saline, n = 5): F(1,14) = 42.885, p < 0.001. VTA rats also took significantly longer than the control group to reach criterion: F(1,14) = 4.933, p < 0.05. However, Nacc rats made significantly more errors than the control group during the more complex within session reversal F(1,14) = 7.031, p < 0.05. Conclusion: Our preliminary results suggest that NAcc neurons play an instrumental role in reversal learning performance, especially when task
doi:10.1016/j.neures.2011.07.1638
P4-v13 Reversal learning and generalization in the common marmosets (Callithrix jacchus) Yumiko Yamazaki 1,2 , Masakado Shigeru Watanabe 1,3 , Atsushi Iriki 2
Saiki 2 , Masayuki
Inada 2 ,
1
Grad. Sch. of Human Relations, Keio Univ., Tokyo, Japan 2 Lab. for Symbol. Cogn. Devel., RIKEN BSI, Saitama, Japan 3 Faculty of Letters, Keio Univ
doi:10.1016/j.neures.2011.07.1639
P4-m21 BMAL1 plays a role in circadian regulation of memory retrieval Shunsuke Hasegawa 1,2 , Miho Ohta 1 , Kaori Nakamura 1 , Hiroshi Hosoda 1 , Satoshi Kida 1,2 1
Saito 1 , Azumi
Dept. of Biosci., Tokyo Univ. of Agri., Tokyo, Japan 2 CREST, JST
bHLH-PAS transcription factor BMAL1 has been shown to play essential roles in circadian rhythm. BMAL1 functions by forming a heterodimer with either CLOCK or NPAS2 and regulates circadian transcriptional rhythms. Importantly, previous studies have shown that BMAL1 ubiquitously expresses in the brain and other peripheral tissues, thereby regulating circadian transcription rhythms in not only the SCN but also other cells including neurons in the forebrain. In this study, we have tried to understand roles of BMAL1 in the forebrain in learning and memory. To do this, we have derived conditional mutant mice that enable to induce the inhibition of BMAL1 function in the forebrain by regulating expression of a dominant negative mutant of BMAL1 (BMAL1 R91A; dnBMAL1) that forms a heterodimer with CLOCK but loses the binding activity with E-box (Hosoda et al., 2004). Biochemical analyses showed that dnBMAL1 mice exhibit disruptions of circadian expression cycle of BAML1-target genes in the forebrain, but not in the hypothalamus. In addition, dnBMAL1 mice displayed normal circadian rhythms at the behavioral level. These results indicated that inhibition of BMAL1 activity forebrain-specifically impairs circadian transcription rhythms without affecting behavioral circadian rhythms. Behavioral analyses using social recognition, novel object recognition and contextual fear conditioning tasks showed that these mutant mice displayed normal memory retrieval tested at ZT4, 16, or 22. In contrast, interestingly, these mutant mice exhibited impairments of memory retrieval tested at ZT10 in a dnBMAL1 expressiondependent manner. These findings indicate that CLOCK/BMAL1 signaling pathway in the forebrain contributes to circadian regulation of memory retrieval. doi:10.1016/j.neures.2011.07.1640
e373
coding neurons. Neurons whose phasic or tonic response to the CS presentation was positively correlated with the reward probability were classified as stimulus value coding neurons. Neurons whose activity increased before the delivery of an expected reward were classified as reward expectation coding neurons. We then examined sensitivity to time discounting for these neurons by increasing the duration of the delay period. With increasing delay, the CS response decreased and the reward response increased in the RPE coding neurons, which may be due to an increase of unpredictability of the reward; the CS response decreased in the stimulus value coding neurons, which may be due to a decrease of the stimulus value, and the activity decreased and its peak latency shifted toward the new time of the reward delivery in the reward expectation coding neurons, which may be due to the animal’s adaptation to the new time of the reward delivery. These results suggest that the CS, delay, and reward-related activities of striatal neurons can be affected by time discounting.
complexity increases. The high temporal resolution provided by the optical inhibition of NAcc and VTA neurons (via halorhodopsin) will provide us with answers about the importance of feedback information when an error is made. Research fund: OIST.
doi:10.1016/j.neures.2011.07.1636
Reversal learning has been widely used to assess the reward sensitivity in both human and nonhuman animals. In this task the subjects have to attend to the relevant stimulus dimension (e.g., size, color, and shape of the stimuli) for reward, so it is also used to evaluate the categorical ability of the subjects. Reward sensitivity and categorical ability are highly important for adaptive behavior, which is known to require intact brain function in orbitofrontal cortex. To establish the marmoset model of the cognitive abilities, we trained the common marmosets to perform simple discrimination using visual stimuli on the touch monitor screen and evaluated their learning of repeated reversals of the reward contingency. After habituated to the apparatus, the subjects were required to select one out of two visual stimuli which differed in terms of the size. The subjects were trained to select, for example, the smaller stimulus of the two until their performance met the learning criterion. Once they met the criterion, the reward contingency of the stimulus was reversed in the next session (i.e. now the larger stimulus leads to the reinforcement). After several contingency reversals, they showed quick recovery of the performance in the first session of the reversal. Then, using the novel stimulus sets, we tested their generalization performance whether they based their responses on the absolute or the relative stimulus size (i.e. transposition). Performance in the test trials suggested that they learned not only specific stimulus characteristics leading to the reinforcement, but the relative size of the stimulus combinations which was applicable to the novel situations. Research fund: The study was supported by the Centre for Advanced Research on Logic and Sensibility, The Global COE Program, at Keio University, Japan, and the Funding Program for World-leading Innovative R&D on Science and Technology, at RIKEN, Japan.
P4-m19 Cognitive control of response inhibition in the primate Kazuko Hayashi 1 , Atsushi Noritake 1 , Kae Nakamura 1,2 1 2
Department of Physiology, Kansai Medical University, Osaka, Japan PRESTO, JST
The dorsal raphé nucleus (DRN) is a major source of serotonin. Many studies suggest that serotonergic neurotransmission is involved in emotional, cognitive and behavioral control processes. We have previously shown that the primate DRN neurons code both rewarding and aversive information during Pavlovian conditioning task. To further investigate the role of DRN in behavioral impulsivity, especially regulation of response inhibition, we used an operant conditioning procedure. In this study, a monkey (Macaca fascicularis) was trained using Go/No-go paradigm. On each trial, a fixation point appeared at the center of the screen. After the fixation, a cue was presented to the left or right of the fixation point. Each cue was associated with different action (Go/No-go). If the cue indicated “Go”, the monkey made saccade to the left or right. If “No-go”, the monkey had to inhibit saccade to the target and continue to gaze at the central fixation point. A liquid reward was delivered after the appropriate generation or inhibition of saccade. The monkey showed differential behavior depending on the cue and successfully learned the association of each cue with the action. The result suggests that this paradigm is useful for the electrophysiological evaluation of DRN function in regulating response inhibition. We will record single-unit activity in the DRN of monkeys performing the Go/No-go saccade task in future studies. Research fund: PRESTO, HFSP, KAKENHI (20020028), KAKENHI (20300139). doi:10.1016/j.neures.2011.07.1637
P4-m20 VTA and NAcc neurons inhibition during reversal learning: A pharmacological and an optogenetic approach Luca Aquili , Jeffrey Wickens Okinawa Institute of Science and Technology Purpose: The aim of this study was to understand the contribution of VTA and Nacc cells in reversal learning performance by using two approaches. First, inhibition of VTA and Nacc cells using a Gaba-a agonist (Muscimol). Second, inhibition of VTA and Nacc cells using light-sensitive opsins (halorhodopsin). The prediction from this investigation was that neuronal suppression of Nacc neurons would have a greater impact on reversal learning performance than suppression of VTA cells, as task complexity increased. Methods: Rats (Muscimol group) (n = 15) were implanted with bilateral guide cannulae above the VTA and Nacc. Another group of rats (n = 15) received injections of lentivirus (halorhodopsin) in the VTA and Nacc, and were implanted with a fiber guide system that would deliver a yellow light to target neurons via an optical fiber. After surgery, rats were trained to complete an FR1 discrimination, and then tested in a between reversal and a within session reversal task. Results: VTA (n = 5) and Nacc (n = 5) implanted rats that received muscimol injections made significantly fewer errors during the between reversal session than the control group (saline, n = 5): F(1,14) = 42.885, p < 0.001. VTA rats also took significantly longer than the control group to reach criterion: F(1,14) = 4.933, p < 0.05. However, Nacc rats made significantly more errors than the control group during the more complex within session reversal F(1,14) = 7.031, p < 0.05. Conclusion: Our preliminary results suggest that NAcc neurons play an instrumental role in reversal learning performance, especially when task
doi:10.1016/j.neures.2011.07.1638
P4-v13 Reversal learning and generalization in the common marmosets (Callithrix jacchus) Yumiko Yamazaki 1,2 , Masakado Shigeru Watanabe 1,3 , Atsushi Iriki 2
Saiki 2 , Masayuki
Inada 2 ,
1
Grad. Sch. of Human Relations, Keio Univ., Tokyo, Japan 2 Lab. for Symbol. Cogn. Devel., RIKEN BSI, Saitama, Japan 3 Faculty of Letters, Keio Univ
doi:10.1016/j.neures.2011.07.1639
P4-m21 BMAL1 plays a role in circadian regulation of memory retrieval Shunsuke Hasegawa 1,2 , Miho Ohta 1 , Kaori Nakamura 1 , Hiroshi Hosoda 1 , Satoshi Kida 1,2 1
Saito 1 , Azumi
Dept. of Biosci., Tokyo Univ. of Agri., Tokyo, Japan 2 CREST, JST
bHLH-PAS transcription factor BMAL1 has been shown to play essential roles in circadian rhythm. BMAL1 functions by forming a heterodimer with either CLOCK or NPAS2 and regulates circadian transcriptional rhythms. Importantly, previous studies have shown that BMAL1 ubiquitously expresses in the brain and other peripheral tissues, thereby regulating circadian transcription rhythms in not only the SCN but also other cells including neurons in the forebrain. In this study, we have tried to understand roles of BMAL1 in the forebrain in learning and memory. To do this, we have derived conditional mutant mice that enable to induce the inhibition of BMAL1 function in the forebrain by regulating expression of a dominant negative mutant of BMAL1 (BMAL1 R91A; dnBMAL1) that forms a heterodimer with CLOCK but loses the binding activity with E-box (Hosoda et al., 2004). Biochemical analyses showed that dnBMAL1 mice exhibit disruptions of circadian expression cycle of BAML1-target genes in the forebrain, but not in the hypothalamus. In addition, dnBMAL1 mice displayed normal circadian rhythms at the behavioral level. These results indicated that inhibition of BMAL1 activity forebrain-specifically impairs circadian transcription rhythms without affecting behavioral circadian rhythms. Behavioral analyses using social recognition, novel object recognition and contextual fear conditioning tasks showed that these mutant mice displayed normal memory retrieval tested at ZT4, 16, or 22. In contrast, interestingly, these mutant mice exhibited impairments of memory retrieval tested at ZT10 in a dnBMAL1 expressiondependent manner. These findings indicate that CLOCK/BMAL1 signaling pathway in the forebrain contributes to circadian regulation of memory retrieval. doi:10.1016/j.neures.2011.07.1640