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 naive 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. ©2015 Iguchi, Kosugi, Lin, Nishikawa, Minabe and 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

動物脳内redox反応を検出するin situ技術の開発と精神医学研究への応用

金沢大学医薬保健研究域医学系酸化ストレスは、精神疾患への関与が指摘されているが、動物研究でも有効な実験系が確立されていない。そこで本研究では、コカインによって誘導されるラット線条体でのredox反応をin situで確認する系の確立を目指した。まず、慢性コカイン投与の結果、側坐核で抗酸化剤N-acetylcysteineがシナプス関連タンパク質量を減少させることを確認した。続いて脳内主要抗酸化物質、グルタチオンの産生能の変化を検討したところ、側坐核ではグルタチオン産生がグリアから神経細胞にシフトすることが強く示唆された。その結果、細胞型特異的なグルタチオン代謝変化の検出系が必要なことがわかった。It is postulated that oxidative stress may be involved in the pathophysiology of some psychiatric disorders, however, sophisticated method to investigate redox status in brain is lacking even in animal studies. In this study, we aimed to confirm the alteration in redox status induced by repeated cocaine administration in situ in the rat striatum. First, we found that an anti-oxidative stress compound, N-acetylcysteine, reduced many synaptic proteins in the nucleus accumbens as the consequence of repeated cocaine administration. Second, it appeared that the production of glutathione, the major endogenous antioxidant, shifted from astroglias to neurons. These results suggest a necessity of more cell-type-specific approach to detect the alteration of glutathione metabolism.研究課題/領域番号:22791114, 研究期間(年度):2010-2011出典：研究課題「動物脳内redox反応を検出するin situ技術の開発と精神医学研究への応用」課題番号22791114（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-22791114/22791114seika/）を加工して作

大うつ病におけるアリピプラゾールによる増強療法の分子機序

金沢大学医薬保健研究域医学系①慢性ストレス負荷後の動物に、生食、SSRI あるいはアリピプラゾールを慢性投与した後、側坐核の興奮性シナプス関連タンパク質に対する影響について検討したところ、２つの薬剤は全く異なる作用を有することが確認された。②対照動物のドパミン依存性行動の個体差を知る目的にて、意欲ならびにコスト/利益バランスに応じた意思決定の個体差に基づく亜群分けを試みたところ、大きく４つの亜群に分けられた。さらに慢性ストレス負荷後にそれぞれの亜群が異なるストレス誘導性の表現型を示した。従って、ストレス負荷後のうつ病様表現型の発現は、病前の個体差に大きく依存し、そこからストレス負荷後の反応も予測できることが示唆された。We found that SSRI and dopamine partial agonist aripiprazole have distinct effects on the regulations of synaptic proteins in the rat nucleus accumbens after chronic stress. To investigate if we could predict the responses to chronic unpredictable stress of each individual based on the pre-stress individual differences, we next aimed to classify several subgroups from naive rats based on their performance of food-instrumental training with progressive ratio schedule. We succeeded to classify 4 from a group of original naive into 4 subgroups that represent distinctive response in motivation or reactions in cost/benefit decision-making. In addition, each 4 subgroups demonstrated distinct phenotypes after 3-weeks chronic unpredictable stress. These data implicate that the phenotypes induced after chronic stress in rats largely depend on individual differences that exist at pre-stress stages, and it would be possible to predict the responses to stress of each by taking advantage of it.研究課題/領域番号:24791208, 研究期間(年度):2012-04-01 – 2014-03-3

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

<div><p>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.</p></div

Effects of repeated 2-cyclohexen-1-one (CHX) administration on behavioral responses to an acute cocaine injection.

<p>(A) Locomotor activity (distance traveled in cm), (B) number of rearings, and (C) number of stereotypic movements before and after an acute injection of cocaine (15 mg/kg intraperitoneally; arrow). The test was conducted 26 days after repeated CHX or vehicle administration (N = 9/each). Data represent the mean ± SEM. *<i>p</i> < 0.05, **<i>p</i> < 0.01, ^#<i>p</i> < 0.005, ^##<i>p</i> < 0.001 compared with control (Veh).</p

Principal component scores derived from principal component analysis (PCA) of the behavioral variables.

<p>The scores were calculated for individual animals administrated saline or 2-cyclohexen-1-one (N = 9/each) using loadings derived from PCA. Data represent the mean ± SEM. *<i>p</i> < 0.05 (Bonferroni’s corrected <i>α</i>-value of 0.01) compared with control (Veh).</p

Effects of 2-cyclohexen-1-one (CHX) on immobility during the forced swimming test.

<p>The test was conducted 35 days after repeated CHX or vehicle administration control (N = 9/each). Data represent the mean + SEM. *<i>p</i> < 0.05 compared with control (Veh).</p