Neuronal activity encoding temporal-order memory of visual objects in the macaque medial temporal lobe

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Abstracts / Neuroscience Research 68S (2010) e55–e108

␤-amyloid precursor protein (APP) in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. We have previously shown that the interaction between dyneindynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. Thus, in the present study, we assessed our hypothesis that the dysfunction of dyneinmediated transport would be responsible for endocytic dysfunction leading to AD pathology. First, we examined immunohistochemistry and westernblot by using young and aged monkey brains to investigate age-related endocytic pathology. Immunohistochemical and westernblot analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. We also examined RNAi studies to assess whether dynein dysfunction can reproduce endocytic pathology as seen in aged monkey brains. Evidently, we demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains. Moreover, it also resulted in endosomal APP accumulation characterized by increased ␤-site cleavage. These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the upregulation of Rab GTPases, leading to AD pathology.

an important role in the goal directed behavior. Although many advances in understanding the neural mechanisms of the goal directed behavior have been made in the last decade, it is not yet clear how an ensemble of neurons in this network would be selected to encode an appropriate behavior. A technique to observe neural activities as a neural network seems to be required to assess such question. Using transgenic zebrafish encoding the calcium indicator protein Inverse Pericam, we have identified the specific pattern of neural activity in the zebrafish telencephalon that accompanies the learning of a simple goal directed behavioral paradigm, the active avoidance. The activity spot seems to be located in the intermediate part of the pallium that has been thought to be equivalent to the mammalian cortex by comparative anatomy. Moreover, by introducing a rule change from GO to NO-GO in the active avoidance learning paradigm, we demonstrate that this activity may relate to the memory of an appropriate behavior rather than a simple motor command to swim. The activity pattern was changed when the rule of learning paradigm has been changed from GO to NO-GO suggesting that distinct neural ensembles are activated following the rule change of the goal directed behavior.

doi:10.1016/j.neures.2010.07.065

O1-7-1-2 The cholinergic medial habenulainterpeduncular pathway is critical for impulse control

O1-6-2-4 Role of vascular risk factors in the pathogenesis of Alzheimer disease: Analysis of novel mouse models of Alzheimer disease with diabetes Shuko Takeda 1,2 , Naoyuki Sato 1,2 , Kozue Uchio-Yamada 3 , Mitsuru Shinohara 1,2 , Hiromi Rakugi 2 , Ryuichi Morishita 1 1

Department of Clinical Gene Therapy, Osaka University, Japan 2 Geriatric Medicine, Osaka University, Japan 3 Laboratory of Experimental Animal Models, National Institute of Biomedical Innovation, Japan (Background)Recent epidemiological studies suggest that diabetes mellitus is a risk factor for Alzheimer disease. However, the underlying mechanisms for this association remain unknown. In this study, to better understand the pathophysiological interaction between these diseases, we generated novel animal models which reflect the pathologic conditions of both diseases.(Methods)We crossed Alzheimer APP transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and established novel diabetic Alzheimer mouse models. We examined metabolic phenotypes (body weight, blood glucose and plasma insulin levels, glucose tolerance test and insulin tolerance test) and AD-like phenotypes (cognitive function: Morris water maze, brain amyloid burden and other neuropathologies) of these animals. In some studies, mice were fed high-fat diet to induce more severe diabetic phenotypes.(Results) The onset of diabetic symptoms exacerbated Alzheimer-like cognitive dysfunction without increasing brain amyloid-beta burden. Notably, these cross-bred mice showed cerebrovascular inflammation, severe amyloid angiopathy, and impaired brain insulin signaling. On the other hand, the cross-bred mice showed more prominent diabetic phenotypes compared with original diabetic mice. We observed a significant positive correlation between brain amyloid-beta burden and severity of glucose intolerance, suggesting that amyloid pathology could aggravate diabetic conditions. In these cross-bred mice, insulin sensitivity of peripheral organs (liver and skeletal muscles) was significantly decreased.(Conclusions)Here, we created novel diabetic Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. Our findings suggest the presence of mutual interaction between Alzheimer disease and diabetes, and may reveal novel insights into this intensely debated pathological association. doi:10.1016/j.neures.2010.07.066

O1-7-1-1 Activation of distinct neural ensemble in zebrafish telencephalon following the go/no-go rule change in the goal directed active avoidance learning Tazu Aoki 1 , Ryo Aoki 1 , Masakazu Agetsuma 1 , Hidenori Aizawa 1 , Akiko Arata 2 , Shin-ichi Higashijima 3 , Hitoshi Okamoto 1 1

BSI, RIKEN 2 Division of Physiome, Department of Physiology, Hyogo College of Medicine, Kobe, Japan 3 Okazaki Institute for Integrative Bioscience, Developmental Neurophysiology, Okazaki, Japan The goal directed behavior is critical for animal’s survival in nature. In mammals, a neural circuit called “cortico-basal ganglia loop” is thought to play

doi:10.1016/j.neures.2010.07.067

Yuki Kobayashi 1 , Yoshitake Sano 1 , Veravej G. Ornthanalai 2 , Hiromichi Goto 1 , Toshio Ikeda 1 , Hitomi Suzuki 1 , Yoshikazu M Saito 1 , Hiroaki Kawasaki 3 , Niall P Murphy 2 , Shigenobu Kanba 3 1

Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako Molecular Neuropathology Group, RIKEN Brain Science Institute, Wako 3 Dept of Neuropychiatry, Graduate school of Medical Sciences, Kyushu University, Fukuoka 2

Impulsivity is a common phenomenon in various mental and personality disorders, and has a critical role in the pathogenesis of these diseases. Although the high comorbidity between tobacco abuse and various mental disorders implies an important role for nicotine in impulse control, the underlying neuronal mechanisms are poorly understood. The habenular nuclei of the epithalamus anatomically link forebrain and midbrain structures, and dysfunction of the habenula is implicated in several mental disorders, including schizophrenia and depression. The ventral medial habenula (mHb) is a cholinergic center that expresses specific nicotinic acetylcholine receptors and releases acetylcholine to the interpeduncular nucleus (IPN), the sole output region of the mHb. Here, we reveal that the cholinergic mHb-IPN pathway is a critical element in the neural circuitry underlying impulse control. We generated mice in which cells were postnatally and partially ablated in the habenula with a preference for the mHb using a genetic method. The lesion resulted in a large reduction in IPN acetylcholine content. Though home cage activity did not differ between the mutant mice and control mice, the mutant mice showed maladaptation to repeated exposure to a novel environment. In a 5-choice serial reaction time test (5CSRTT), the mutant mice had a high rate of premature responses, indicative of impulsive behaviour. The mutant mice were resistant to the sedative effect of nicotine on adaptation and rewardstimulated responding. Nicotine administration, moreover, partially rescued the impulsive phenotypes of the mutant mice. These results provide a theoretical basis for the comorbidity between high nicotine dependency and various psychiatric disorders, and demonstrate that the cholinergic mHb-IPN pathway is the central neuronal circuit responsible for impulse control. doi:10.1016/j.neures.2010.07.068

O1-7-1-3 Neuronal activity encoding temporal-order memory of visual objects in the macaque medial temporal lobe Yuji Naya , Wendy A. Suzuki Center for Neural Science, New York University The ability to recall specific temporal sequences of events in an episode is severely impaired in humans with memory impairment following medial temporal lobe (MTL) damage. In the present study, we characterize neural activity in the macaque MTL, as animals perform a temporal order memory task. The task starts with an encoding phase where the animal fixates a fixation point on a video monitor for 0.4 s. Then, a sequence of two cue stimuli (0.3 s for each) was presented with a blank delay interval (0.9 s) between them. Cue stimuli were chosen out of a pool of eight well-learned visual items. Following the presentation of the second cue stimulus, another 0.5 s of fixation was required for the animal and a single drop of water was given

Abstracts / Neuroscience Research 68S (2010) e55–e108

as a reward. The trial ended with a retrieval phase where the animal first fixated a fixation spot for 1.0 s, and then three choice stimuli were presented together; two of them were the items that had been presented as cue stimuli in the encoding phase, and another was chosen from the other six items. If the animal touched the two items in the same order as they were presented in the encoding phase, six drops of water was given as a reward. To quantify neuronal activity signaling trial-timing after the presentation of the first cue stimulus, we used a measure of distance on the population of the cells recorded in each MTL area. We found that only in hippocampus neurons but not other MTL areas the distance gradually increased during the first cue delay period between the presentations of the first and the second cue stimuli. Hippocampal gamma band activity also increased during the first cue delay period. In contrast, we saw increased activity in the beta band during the first cue delay period in the entorhinal and perirhinal cortex. These results suggest that among the MTL areas, the hippocampus plays a unique role in signaling temporal information.

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for 24 hours. Worms treated with cycloheximide or anisomycin failed to form the memory by the spaced training, whereas the memory after the massed training was not significantly affected. Furthermore, the memory after the spaced training was resistant to cold shock, while the memory after the massed training was disrupted by cold shock. Since the memory after the spaced training was consolidated by protein synthesis and was resistant to cold shock, it is classified as long-term memory. In contrast, the memory after the massed training is classified as short-term memory since it did not require protein synthesis and was sensitive to cold shock. Moreover, C. elegans mutants defective in nmr-1 encoding an NMDA receptor subunit failed to form both of the short-term and long-term memory, while mutations in crh-1 encoding the CREB transcription factor affected only on the formation of the long-term memory. These results are consistent with results previously observed in other model organisms such as Aplysia, Drosophila, and mice. doi:10.1016/j.neures.2010.07.071

doi:10.1016/j.neures.2010.07.069

O1-7-1-4 Effects of monetary reward and punishment on neural activations during successful retrieval of source memories Yayoi Shigemune 1 , Takashi Tsukiura 1 , Toshimune Kambara 1 , Ryuta Kawashima 1,2 1

O1-7-2-2 Role of kinase activity of Ca2+ /calmodulindependent protein kinase II␣ in hippocampus- and amygdala-dependent memory Yoko Yamagata 1,2 , Yuchio Yanagawa 3,4 , Keiji Imoto 1,2 1

Natl Inst for Physiol Sci, Okazaki, Japan 2 SOKENDAI, Okazaki, Japan 3 Grad Sch Med, Gunma Univ, Maebashi, Japan 4 CREST, JST, Tokyo, Japan

Dept Funct Brain Imaging, IDAC, Tohoku Univ 2 SAIRC, IDAC, Tohoku Univ Ca2+ /calmodulin-dependent protein kinase II␣ (CaMKII␣) is one of the most abundant protein kinases in the central nervous system, and is thought to be a key mediator for hippocampal synaptic plasticity. We recently generated and analyzed a kinase-dead CaMKII␣ (K42R) knock-in mouse, and found that kinase activity of CaMKII␣ is essential for hippocampal synaptic plasticity and behavioral learning. In the inhibitory avoidance task, onetrial training induced clear avoidance memory in wild-type mice, while no avoidance memory was formed in homozygous K42R mice. When training trials were repeated, K42R mice showed a certain level of avoidance, which was still impaired compared to that of wild-type mice after one-trial training. The results indicated that repeated training could not compensate for learning deficits in K42R mice, which seems to be a clear difference from previously reported phosphorylation-deficient CaMKII␣ (T286A) knock-in mice. To further examine learning deficits in K42R mice in the context of hippocampus- and amygdala-dependency, we next performed fear conditioning in wild-type and homozygous K42R mice. After 1CS/US-conditioning, both contextual and cued memories were formed in wild-type mice, while no contextual memory, but cued memory was formed in K42R mice, although to a lesser extent than in wild-type mice. When the number of CS/US paring was increased, deficits in contextual discrimination became apparent in K42R mice, but not in wild-type mice. Based on the results, we will discuss the importance of CaMKII␣ kinase activity in hippocampus- and amygdaladependent memory.

The current fMRI study investigated the effects of monetary reward and punishment on brain activations during the successful retrieval of source memories. Twenty seven college students participated in this study (mean age: 20.7). During encoding, subjects were required to memorize Japanese words (Item) and the presented locations (Left and Right) of the words (Source) under three different conditions (Reward, Punishment, and Control). During retrieval, subjects were asked to judge whether the words were old or new, and on which side of the screen the words were previously presented if the words were old. Behavioral data demonstrated that source memories encoded with rewards or punishments were remembered more accurately than those without (p < 0.05). fMRI data analyzed by parametric modulation analysis demonstrated that the medial orbitofrontal cortex (OFC) and ventral tegmental areas (VTA) showed increasing activations as linear functions of reward (Punishment: 1, Control: 2, Reward: 3), whereas activity in the lateral OFC and insula reflected the linear function of punishments (Punishment: 3, Control: 2, Reward: 1). In addition, medial temporal lobe (MTL) regions including the hippocampus and parahippocampal gyrus (PHG) showed increasing activations as a quasi-exponential function of memory (Miss: 1, Source Miss: 2, Source Hit: 9). In the correlation analysis between reward/ punishment-related and memory-related regions, activity in the hippocampus was significantly correlated with that in the VTA (r = 0.44, p < 0.05), OFC (r = 0.48, p < 0.05) and insula (r = 0.40, p < 0.05). These findings suggest that the successful encoding of source memories can be enhanced by punishments as well as rewards, and that functional connectivity between reward/ puinishment-related regions (the VTA and the insula) and memory-related regions (hippocampus and PHG) could contribute to memory enhancement.

O1-7-2-3 Endogenous hunger substance orexin impairs spatial plasticity

doi:10.1016/j.neures.2010.07.070

Yutaka Oomura 1 , Shuji Aou 2 , Koji Fukunaga 3 , Kazuo Sasaki 4

doi:10.1016/j.neures.2010.07.072

1

Dept Physiol, Graduate School of Med Sci, Kyusyu Univ, Fukuoka Department Brain Sci., Eng., Grad. Sch, Life Sci., Kyushu Inst., Technology, Kitakyushu 3 Dept Pharmacology, Faculty of Pharmacy, Tohoku University, Sendai 4 Bio-Inform. Sch. of Eng. Toyama University Toyama 2

O1-7-2-1 Associative learning and memory retention in Caenorhabditis elegans Hisayuki Amano , Ichiro Maruyama Information Processing Biology Unit, Okinawa Institute of Science and Technology Promotion Corporation Initial Research Project Animal behaviors reflect their nervous system activity, and are modified by multiple factors including environmental changes and memories of past experience. In this study, to understand cellular and molecular bases for learning and memory in C. elegans, we developed a paradigm for classical conditioning of worms with propanol, as a conditioned stimulus, and hydrochloride (HCl), as an unconditioned stimulus. Before the training, worms were attracted to propanol, an appetitive olfactory stimulus, and avoid HCl, an aversive gustatory stimulus, in chemotaxis assay. After tencycle massed (without intertrial intervals, ITI) or spaced (with 10-min ITI) training, in contrast, worms avoided propanol on the assay plate. Furthermore, interstimulus intervals (ISI) between the two stimuli were crucial for the conditioning. The memory after the massed training was extinguished within a few hours, while the memory after the spaced training was retained

The glucose-sensitive neurons in the lateral hypothalamic area of feeding center produce orexin-A (OxA) and send their axons to the CA1 neurons in the hippocampus which expresses orexin receptors (OxR1). OxA released during food intake facilitates food intake by the activation of the glucose-sensitive neurons in the lateral hypothalamic area, feeding center and inhibition of the glucoreceptor neurons in the ventromedial nucleus, satiety center. The released OxA then reaches to the hippocampus and suppresses spatial plasticity. Namely the Morris water maze tests showed that 1.0 to 10 mM OxA administered i.c.v. retarded spatial learning and memory. Probe tests after training of water maze tests also showed impairment of the spatial memory. On the same concentrations of OxA, LTP of CA1 neurons in vitro hippocampus slices was suppressed. The paired pulse facilitation tests indicated that the OxA effects were postsynaptic and not the presynaptic transmitter release. The postsynptic responces to NMDA and GABA applied electrophoretically to the apical dendrites of CA1 neurons were also suppressed. The phospho-