Shigenobu Toda

Repeated Exposure of Adult Rats to Transient Oxidative Stress Induces Various Long-Lasting Alterations in Cognitive and Behavioral Functions

Exposure of neonates to oxidative stress may increase the risk of psychiatric disorders such as schizophrenia in adulthood. However, the effects of moderate oxidative stress on the adult brain are not completely understood. To address this issue, we systemically administrated 2-cyclohexen-1-one (CHX) to adult rats to transiently reduce glutathione levels. Repeated administration of CHX did not affect the acquisition or motivation of an appetitive instrumental behavior (lever pressing) rewarded by a food outcome under a progressive ratio schedule. In addition, response discrimination and reversal learning were not affected. However, acute CHX administration blunted the sensitivity of the instrumental performance to outcome devaluation, and this effect was prolonged in rats with a history of repeated CHX exposure, representing pro-depression-like phenotypes. On the other hand, repeated CHX administration reduced immobility in forced swimming tests and blunted acute cocaine-induced behaviors, implicating antidepressant-like effects. Multivariate analyses segregated a characteristic group of behavioral variables influenced by repeated CHX administration. Taken together, these findings suggest that repeated administration of CHX to adult rats did not cause a specific mental disorder, but it induced long-term alterations in behavioral and cognitive functions, possibly related to specific neural correlates.

Identification of an unconventional process of instrumental learning characteristically initiated with outcome devaluation-insensitivity and generalized action selection.

The distinction between goal-directed action and habitual response, particularly with respect to moderate or extended appetitive instrumental training, is well documented; however, the propensity toward instrumental behavior in the early training stage has not been elucidated. In this study, we trained Sprague Dawley rats to press a lever to obtain food as an outcome for various time periods and monitored the changes in their sensitivity to outcome devaluation and choice between the levers they had been trained with and unfamiliar levers. After the extensive training with a random interval schedule, the rats were insensitive to outcome devaluation, and exhibited a typical habit-like phenotype, as previously reported, and the untrained leverpresses were relatively rare and sporadic. During the initial stage of training (≤1 week), the rats exhibited a similar insensitivity to the devaluation; however, in contrast to the overtrained condition, they performed distinctive unbiased leverpresses on both the trained and untrained levers. Thus, we propose a possibility that, contrary to the authentic concept that instrumental learning is initiated with an outcome devaluation-sensitive goal-directed stage, under some conditions, this learning can unconventionally begin with the initial stage that is distinct from both goal-directed action and habitual response.

Pre-stress performance in an instrumental training predicts post-stress behavioral alterations in chronically stressed rats

Stress is a major factor in the development of major depressive disorder (MDD), but few studies have assessed individual risk based on pre-stress behavioral and cognitive traits. To address this issue, we employed appetitive instrumental lever pressing with a progressive ratio (PR) schedule to assess these traits in experimentally naïve Sprague-Dawley rats. Based on four distinct traits that were identified by hierarchical cluster analysis, the animals were classified into the corresponding four subgroups (Low Motivation, Quick Learner, Slow Learner, and Hypermotivation), and exposed to chronic unpredictable stress (CUS) before monitoring their post-stress responses for 4 weeks. The four subgroups represented the following distinct behavioral phenotypes after CUS: the Low Motivation subgroup demonstrated weight loss and a late-developing paradoxical enhancement in PR performance that may be related to inappropriate decision-making in human MDD. The Quick Learner subgroup exhibited a transient loss of motivation and the habituation of serum corticosterone (CORT) response to repeated stress. The Slow Learner subgroup displayed resistance to demotivation and a suppressed CORT response to acute stress. Finally, the Hypermotivation subgroup exhibited resistance to weight loss, habituated CORT response to an acute stress, and a long-lasting amotivation. Overall, we identified causal relationships between pre-stress traits in the performance of the instrumental training and post-stress phenotypes in each subgroup. In addition, many of the CUS-induced phenotypes in rats corresponded to or had putative relationships with representative symptoms in human MDD. We concluded that the consequences of stress may be predictable before stress exposure by determining the pre-stress behavioral or cognitive traits of each individual in rats.

Reconsidering Animal Models of Major Depressive Disorder in the Elderly.

Major depressive disorder (MDD) is a common psychiatric illness with high morbidity that poses a huge burden to healthcare systems worldwide. According to the World Health Organization, the lifetime prevalence of MDD is approximately 3–17% globally (Richards, 2011). However, after major, but limited, success with selective serotonin reuptake inhibitors (SSRIs) or serotonin–noradrenaline reuptake inhibitors, few promising therapeutic approaches have been developed from preclinical studies using current animal models of MDD, despite intensive research involving laborious methods and substantial costs. Traditionally, most research using rodent models of MDD has been conducted using relatively young adult animals, aged approximately 8 weeks, to avoid any involvement of aging-related biological factors. The major rationale of this strategy is based on epidemiological findings that the occurrence of MDD displays a robust peak in young adults rather than in the elderly (Jorm, 2000; Copeland et al., 2004; Blazer and Hybels, 2005). Further, the elderly may have aging-related factors rendering this group an inappropriate model of “genuine” MDD. A critical question is whether this strategy is indeed appropriate. Despite the consistent findings of a lower lifetime prevalence rate of MDD in the elderly than in young adults, there remain persistent doubts regarding the underdiagnosis of MDD in the elderly (Hoertel et al., 2013). It has been heavily argued that patients diagnosed with MDD in youth will often be rediagnosed with a bipolar disorder (Lish et al., 1994; Leonpacher et al., 2015). Thus, a considerable number of cases of MDD in young adults may be misdiagnosed. In addition, MDD in the elderly has distinct biological/environmental backgrounds and consequences compared with that in young adults. In this opinion article, we primarily shed light on the significance of MDD in the elderly (known as geriatric MDD or late-onset depression) and problems associated with the methodology of preclinical studies undertaken to investigate the characteristics and treatment of this disorder.

Effects of methamphetamine on spinophilin gene expression in the neocortex of the rat

did not affect the activities of major molecules regulating protein translation, including mTOR, ribosomal protein S6, and eIF2A. We speculated that elevation in extracellular glutamate by NAC to be responsible for rapid reductions in various proteins. However, unexpectedly, the NAC effects were not prevented by the concomitant treatment of an mGluR5 antagonist, MEPE. Moreover, an mGluR5 agonist, DHPG, did not mimic the effect of NAC at all. Thus, we conclude that the effects of NAC on synaptic protein turnover are glutamate-independent. Since NAC increases extracellular glutamate as well as intracellular glutathione, we propose that induction of glutathione by NAC might contribute to rapid protein turnover. Research fund: KAKENHI (22791114).

Upregulation of extrasynaptic GABAA receptors and PSD-95 in the nucleus accumbens may be responsible for animal model of major depressive disorder

P3-t05 Pattern separation related activity in dentate gyrus is associated with subjective mood: A functional MRI study Takeshi Fujii 1 , Daisuke N. Saito 1,2, Hisakazu T. Yanaka 1,2, Hirotaka Kosaka 3, Hiroshi Oikawa 1, Hidehiko Okazawa 1 1 Biomedical Imaging Research Center, University of Fukui, Japan 2 Research and Education Program for Life Science, University of Fukui, Fukui, Japan 3 Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

Role of PSD structure sustained by tonic dopamine in the rat nucleus accumbens in repeated cocaine administrated rats

drugs, was shown to increase extracellular levels of 5HT in the nucleus accumbens (ACC), the frontal cortex, and the ventral hippocampus in rat. For elucidation of relationship between alcohol-addiction and 5HT system, we produced chronic alcohol treatment mice by the exposure to alcohol vapor for 20 days. C57BL/6J mice showed a significant increase in alcohol drinking behavior after alcohol exposure, whereas there was no significant difference in alcohol drinking of C3H/HeJ, another inbred strain. We then examined expression levels of 5HT receptor family and found that expression of 5HT2C receptor (5HT2CR) was significantly increased in the ACC and the dorsal raphe nucleus (DRN) by chronic alcohol exposure, suggesting that 5HT2CR might be involved in alcohol addiction. 5HT2CR was known to undergo premRNA editing at five sites (site A-E) within exon 5 by deaminating enzymes. As a result of RNA-editing, amino acid substitution occurs at three sites, which alters the ability of the receptor to activate phospholipase C. Here, we investigated RNA-editing changes in alcohol vapor inhalation mice. Either C57BL/6J or C3H/HeJ was exposed to alcohol vapor, followed by the determination of 5HT2CR isoform frequency. C57BL/6J mice exhibited a 1.5-fold increase in site D editing by exposure to alcohol vapor, resulting that 5HT2CR-VXV isoforms were 92% in the ACC. On the other hand, unedited INI-isoform was the most prevalent in C3H/HeJ mice, in spite of alcohol exposure. Furthermore, it was demonstrated that an increase of RNA-editing frequency by alcohol exposure was dependent on the expression level of ADAR1 and ADAR2, RNAediting enzymes. These findings suggest that difference in RNA-editing of 5HT2CR may be associated with alcohol-addiction and -response.

Distinct subcellular distributions of GluR1 and GluR2 and their regulatory factors in the nucleus accumbens of repeatedly cocaine-administrated rats

drugs, was shown to increase extracellular levels of 5HT in the nucleus accumbens (ACC), the frontal cortex, and the ventral hippocampus in rat. For elucidation of relationship between alcohol-addiction and 5HT system, we produced chronic alcohol treatment mice by the exposure to alcohol vapor for 20 days. C57BL/6J mice showed a significant increase in alcohol drinking behavior after alcohol exposure, whereas there was no significant difference in alcohol drinking of C3H/HeJ, another inbred strain. We then examined expression levels of 5HT receptor family and found that expression of 5HT2C receptor (5HT2CR) was significantly increased in the ACC and the dorsal raphe nucleus (DRN) by chronic alcohol exposure, suggesting that 5HT2CR might be involved in alcohol addiction. 5HT2CR was known to undergo premRNA editing at five sites (site A-E) within exon 5 by deaminating enzymes. As a result of RNA-editing, amino acid substitution occurs at three sites, which alters the ability of the receptor to activate phospholipase C. Here, we investigated RNA-editing changes in alcohol vapor inhalation mice. Either C57BL/6J or C3H/HeJ was exposed to alcohol vapor, followed by the determination of 5HT2CR isoform frequency. C57BL/6J mice exhibited a 1.5-fold increase in site D editing by exposure to alcohol vapor, resulting that 5HT2CR-VXV isoforms were 92% in the ACC. On the other hand, unedited INI-isoform was the most prevalent in C3H/HeJ mice, in spite of alcohol exposure. Furthermore, it was demonstrated that an increase of RNA-editing frequency by alcohol exposure was dependent on the expression level of ADAR1 and ADAR2, RNAediting enzymes. These findings suggest that difference in RNA-editing of 5HT2CR may be associated with alcohol-addiction and -response.

Altered synaptic plasticity in the nucleus accumbens of cocaine-withdrawn rats

O3-I1-3 Important role of diacylglycerol kinase in spine formation and memory Yasuhito Shirai1, Takeshi kozuki1, Kenichi Kakefuda2, Atsushi Ohyagi2, Kyouji Horie3, Shigeki Moriguchi4, Masamitsu Simazawa2, Kohji Fukunaga4, Jyunnji Takeda3, Naoaki Saito1, Hideaki Hara2 1 Biosignal Res. Ctr., Kobe University, Japan; 2 Biofunctional Evaluation, Gifu Pharmaceutical University, Japan; 3 Social and Enviromental Med., Grad. Sch. of Med., Osaka University, Japan; 4 Pharmacol., Grad. Sch. of Pharmaceutical Sci., Tohoku University, Japan