吗啡奖赏效应及其敏化与空间学习能力的关系

Rewarding experience after drug use is one of the mechanisms of substance abuse. Previous evidence indicated that rewarding experience was closely related to learning processes. Neuroscience studies have already established multiple-mode learning model. Reference memory system and habit memory are associated with hippocampus and dorsa striatum respectively, which are also involved in the rewarding effect of morphine. However, the relationship between spatial/habit learning and morphine reward property is still unclear. After drug use, with sensitization to rewarding effect, spatial learning is also changed. To study the mechanism of increment of spatial learning would provide new perspective about reward learning. Based on the individual difference between spatial learning and reward learning, the experiments studied relationship between the two leaning abilities and tested the function of dorsal hippocampus and dorsal striatum in morphine-induced CPP. The results were summarized below： 1 In a single－rule learning water maze task, subjects better in spatial learning also excelled in rewarding learning. In a multi-rule learning task, morphine administration was more rewarding to subjects of use place strategy. 2 Treatment potentiating the rewarding effect of morphine also increased place-rule learning, with no significant improvement in habit learning. 3 Intracranial injections into CA1 of hippocampus or dorsal striatum of M1 antagonist, Pirenzepine, could block the establishment of morphine CPP after three days morphine treatment. In contrast, the antagonist of D1 receptor SCH23390 had no blocking effect. Both Pirenzepine and SCH23390 blocked the locomotor-stimulating effect of morphine. In summary, spatial learning stimulated the behavioral expression of morphine’s rewarding effect, in which CA1 of hippocampus was critically involved. On the other side, a pretreatment schedule of morphine, while increased the rewarding effect, improved place-rule learning, indicating that spatial learning might be one chain of sensitization to drug rewards effects

细胞外信号调节蛋白激酶-cAMP反应元件结合蛋白信号通路在应激所致抑郁行为障碍中的作用

Stress is the most important factor in the vulnerability to depression and other behavioral disorders, but the mechanisms that stress signals are transferred into depression are far from understanding. To date, the neurotransmitters, neurotrophins and signal pathway have been concerned in the topic focusing on the pathophysiology of depression, but there are still many puzzles. Increasing evidence has indicated that the alteration in neuronal plasticity is the “trace” of stress-induced damages. The extracellular signal-regulated protein kinase(ERK)-cyclic-AMP-responsive element（CRE）-binding protein(CREB)signal pathway is a powerful intracellular signal transduction pathway participating in neuronal plasticity which is involved in higher brain cognitive functions such as learning and memory. However, so far, little is known about the role of the ERK-CREB signal pathway in response to stress and emotional modulations. Thus the aim of the study was to systematically investigate the role of the ERK-CEB signal pathway in depressive-like behaviors induced by stress. Depression animal models, antidepressant agent treatment and disruption of signal pathway in specific brain regions were applied. In the present study, three experiment sessions were designed to make sure whether the ERK-CREB signal pathway was indeed one of pathophysiological mechanisms of depressive-like behaviors induced by stress. In experiment one, two different stress animal models were applied, chronic forced swim stress and chronic empty water bottle stress. After stress, all animals were tested behaviorally using open-field, elevated-plus maze and saccharine preference test, and brain samples were processed for determination of ERK, P-ERK, CREB and P-CREB using western blot. The relationships between the proteins of ERK, P-ERK, CREB and P-CREB in the brain and the behavioral variables were also analyzed. In experiment two, rats were treated with antidepressant agent fluoxetine once a day for 21 consecutive days, then the brain levels of ERK, P-ERK, CREB and P-CREB was determined, the depressive-like behaviors were also examined. In experiment three, mitogen activated extracellular-signal-regulated kinase kinase (MEK) inhibitor U0126 was administrated to inhabit the activation of ERK in the hippocampus and prefrontal cortex respectively, then behavioral measurements and protein detection were conducted. The main results of the study were as the following: (1) Chronic forced swim stress induced animals to suffer depression and disrupted the ERK-CREB signal pathway in hippocampus and prefrontal cortex. There were significant correlations between P-ERK2, P-CREB and multiple variables of depressive-like behaviors. (2) Chronic empty water bottle stress did not induce depressive-like behaviors. Such stress decreased the brain level of P-ERK2 in hippocampus and prefrontal cortex, but the level of P-CREB in the hippocampus was increased. (3) The antidepressant agent fluoxetine relieved depressive-like behaviors and increased the activities of the ERK-CREB signal pathway in stressed animals. (4) Animals treated with U0126 injection into hippocampus showed decreased activities of the ERK-CREB signal pathway in the hippocampus, and suffered depression comorbid with anxiety. (5) Animals treated with U0126 injection into prefrontal cortex showed decreased activities of the ERK-CREB signal pathway in the prefrontal cortex, and exhibited depressive-like behaviors. In conclusion, The ERK-CREB signal pathway in the hippocampus and prefrontal cortex was involved in stress responses and significantly correlated with depressive-like behaviors; The ERK-CREB signal pathway in the hippocampus and prefrontal cortex participated in the mechanism that fluoxetine reversed stress-induced behavioral disorders, and might be the target pathway of the therapeutic action of antidepressants; The disruption of the ERK-CREB signal pathway in the hippocampus or prefrontal cortex led to depressive-like behaviors in animals, suggesting that disruption of ERK-CREB pathway in the hippocampus or prefrontal cortex was involved in the pathophysiology of depression, and might be at least one of the mechanisms of depression induced by stress.

细胞因子对大鼠抑郁样行为的影响

Depression is one of the most important psychological diseases to threaten human health. “Cytokine theory of depression” suggests that cytokines may play an important role in depression, which provided a new perspective in the study the mechanism and the therapy of depressive symptoms. This view is supported by various findings. Administration of pro-inflammatory cytokine or lipoposaccharide in animal induces depressive-like behavior such as anhedonia and low locomotion, which is very similar to the behavioral symptoms of depression in humans. However, the earlier researches may only pay attention to the short-time behavior effects; the effects of long-time behavior changes have not been clearly reported. In addition, there are few reports about the effects of pro-inflammatory cytokine or anti-inflammatory cytokine on the depressive-like behavior induced by chronic stressors. To further understand the role of cytokines in depression, the purpose of the present study is to investigate the dose and time effects of pro-inflammatory cytokines induced by lipoposaccharide on depressive-like behavior, sensitization effect of pro-inflammatory and blockage effect of anti-inflammatory on depressive-like behavior induced by chronic cold swimming stress. The behavioral observation was carried out using sacharin preference test, open field test and elevated-plus maze. The results indicated that: 1) The activated immunity induced by LPS i.p administration could induce significant depressive-like behavior, but these behaviors had no long-term effect; 2)The depressive-like behaviors induced by stress could be elicited earlier and kept longer by the activated immunity induced by LPS ip ; 4) The chronic activated immunity induced by LPS icv administration could provoke significant depressive-like behavior, and the depressive-like behaviors induced by stress could be enhanced by icv LPS, LPS and stress had certain interact-sensitization effect on depressive-like behavior； 5) Anti-inflammatory cytokines IL-10 icv reversed the depressive-like behaviors induced by the stress. In conclusion, cytokines play an important role in the depressive-like behavior. Both peripheral and central administration of LPS induced a certain depressive-like behavior and enhanced stress-induced depressive behavior. The anti-inflammatory cytokine IL-10 icv could reverse the depressive-like behaviors induced by the stress. Keywords: lipoposaccharide, depressive-like behavior, anhedonia, locomotion, chronic cold swimming stress

抑郁行为及不同抑郁亚型的多巴胺机制研究

The conceptualization of “depression” as a heterogenous disease has been widely accepted by most researchers. However, controlled experiments are rather sparse. To date, most studies demonstrated that animals with helplessness, a widely recognized behavioral index of “depression” also show varied comobidity expressions of other emotional behaviors, such as hightened or lightened anxiety level compared with controls. This means that distinct subtypes of “depression” may exist, in which different neural mechanisms may play roles. The present study aims to explore the possibility of behaviorally categorizing two depressive subtypes, referred as anxious helplessness and non-anxious helplessness, respectively. Then, by using RT-PCR, the dopamine D1, D2, D3 receptors mRNA expressions in medial prefrontal cortex (mPFC) and nucleus accubems (NAc) were quantified. The main findings are described as belows: 1. Uncontrollable shock could readily induce helpless behavior in shocked animals as a whole but with salient individual differences. Prior inescaoable shock induces subsuquent helplessness in approximately 40% shocked animals, while the other animals showed no sign of helpless expression, and were classified as non-helplessness. 2. Among helpless animals, the “subtype” of anxious helpless and non-anxious helpless could be identified according to the anxiety level evaluated by elevated plus maze. 3. D3 receptors mRNA expressions in the mPFC and NAc were increased in stressed animals after uncontrollable shock treatment. At the meanwhile, significant lower expressions of D2 receptors in the mPFC and NAc, and much lower expressions of D1 receptors in the mPFC were found in rats that did not become helpless after stress. In contrast, no significant difference between helpless and control animals was found in D1/D2 receptors mRNA expressions. 4. Based on above mentioned results, the up-regulation of D3 receptors in the mPFC and NAc may reflect a generalized effect of exposure to uncontrollalbe shock. While the down-regulation of D1\D2 receptors in the mPFC and decreased expression of D2 receptors in the NAc may be associated with adaptive or protective mechnisms which protecting animals from helplessness after uncontrollable shock treatment. 5. Futhermore, a significant negative relationship was found between anxiety level and D1 receptors expressions in the mPFC in helpless animals. Compared to the non-anxious helpless and control rats, the D1 receptors mRNA of anxious helpless rats were down-regulation in the mPFC. The present study indicated that the D1 dopamine receptor gene is associated with co-morbid depression and anxiety.

影响吗啡动物行为效应的因素及其机制

Credible and stable animal behavioral models are necessary to research the mechanisms of addiction in vivo, especially to study the relationship between memory or stress and drug addiction, which has been one of the focuses in this field. So the object of this study was to observe the influences of several factors on the behavioral effects of morphine shown in the paradigms of conditioned place preference (CPP) and locomotor activity (LA), and to explore the effects of adrenalectomy on LA induced by morphine in rats. In addition, the cortexes of rats were examined, which were exposed to chronic administration of several doses of morphine with or without foot shock. Moreover, a new behavioral model was built to quantify the motivation of drug seeking. The results showed that CPP was more sensitive to low dose of morphine than to high dose. The period of experiment could be shortened by increasing the training times everyday, whereas in this way the dose of morphine should be low enough to avoid the impact between the near two exposures to morphine. Effects of chronic administration of morphine on LA in rats were dose- and time- dependent, which supplied evidence to choose parameters in other behavioral models. The results obtained by the simplified LA paradigm showed that hyperactivity of low dose of morphine following hypoactivity, and naloxone had no effects on LA but blocked the locomotion effects of morphine. Obvious effects of morphine on LA of rats might depend on a reasonable level of plasma corticosterone, which may determine individual vulnerability to drug addiction. Stress may also potentiate the vulnerability by aggravating damage to cortex of rats induced by drug dose-dependently, which is suggested by the results of histological examination. The result that frontal and temporal cortexes and hippocampus were injured suggests that there may be a close relationship between memory and drug addiction. It was showed that the new behavioral model on the basis of Morris water maze might be used to quantify the motivation of drug-craving.

隔区损毁对大鼠空间认知能力的影响及其在Morris迷宫中搜索策略的比较

Separate groups of rats with bilateral or unilateral lesions in septum were tested for acquisition and retention of the Morris water maze spatial cognitive task. Some of the animals in each lesion group received preoperative training in the task. Other animals in each group received no preoperative training. The results indicate that although both lesions lead to a spatial cognitive impairment in both the acquisition and retention of the task, the animals with bilateral lesions were more severely impaired than were the animals with unilateral, as indicated by quantitative measure. Searching strategies were used as an index to eximine the qualitative difference in the animals swim be havior, we found that the unilateral damaged animals still tend to use "mapping" strategies to solve the task as in the case of control groups but the accuracy is lower. The searching strategies used by the bilateral damaged animals showed complex patterns. The acquisition group with bilateral tend to use random and paratic strategies, however, the retention group with bilateral had a tendacy to use paratic and taxic strategies. The difference between searching strategies and its dynamic, change possibly suggest that other cognitive processing systems play an role in the processing of information about the task.

樟柳碱和石杉碱甲对学习和记忆的影响及其有关机制的研究

Two experiments were designed to examine the role of the cholinergic agents, anisodine and huperzine A, and related mechanisms. In experiment 1, the effects of anisodine and huperzine A on rat performance in Morris water maze were observed. It was found that the drugs injected before daily training had significant effect on performance of place navigation task and transfer test, while the drugs injected after daily training, before retest and overtraining had no such effect. the results indicated that the drugs, which only have effects on reference memory related to cognitive mapping strategy, may mediate the acquisition process of memory. In experiment 2, the spontaneous hippocampol neuronal activities and the effects of the drugs on them in awake rabbits were observed. The results showed that anisodine had significant inhibitory effect on the activities, the opposite effect was found in huperzine A. Furthermore, sensory stimulation and administration of huperzine A have similar effects. It was sujested that hipppocampus be directly relavent to transmission of information to memory storage system, in which the role of central cholinergic system is critical.

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The Effects of Insulin-Induced Moderate Hypoglycemia on Hippocampal Plasticity

Self-regulation of blood glucose in diabetics via insulin administration introduces the risk of hypoglycemia. Previous studies have shown hypoglycemia damages the dentate gyrus, an area of the hippocampus associated with anxiety- and depressive-like behavior. To date, only depressive-like behaviors have been observed following moderate hypoglycemia. This study sought to examine whether acute moderate hypoglycemia induces both behaviors due to high clinical comorbidity. One episode of moderate hypoglycemia was induced in a male Sprague-Dawley rat. Twenty-four hours later, hippocampal function was evaluated via the elevated plus maze and the forced swim test to assess anxiety-like and depressive-like behavior. Results, though not statistically significant, suggested that acute moderate hypoglycemia may increase anxiety- and depressive-like behavior. These findings may elucidate hypoglycemia-related behavioral changes.

Anterior thalmic lesions stop immediate early gene activation in selective laminae of the retrosplenial cortex: evidence of covert pathology in rats

Lesions involving the anterior thalamic nuclei stopped immediate early gene (IEG) activity in specific regions of the rat retrosplenial cortex, even though there were no apparent cytoarchitectonic changes. Discrete anterior thalamic lesions were made either by excitotoxin (Experiment 1) or radiofrequency (Experiment 2) and, following recovery, the rats foraged in a radial-arm maze in a novel room. Measurements made 6-12 weeks postsurgery showed that, in comparison with surgical controls, the thalamic lesions produced the same, selective patterns of Fos changes irrespective of method. Granular (caudal granular cortex and rostral granular cortex), but not dysgranular (dysgranular cortex), retrosplenial cortex showed a striking loss of Fos-positive cells. While a loss of between 79 and 89% of Fos-positive cells was found in the superficial laminae, the deeper layers appeared normal. In Experiments 3 and 4, rats 9-10 months postsurgery were placed in an activity box for 30 min. Anterior thalamic lesions (Experiment 3) led to a pronounced IEG decrease of both Fos and zif268 throughout the retrosplenial cortex that now included the dysgranular area. These IEG losses were found even though the same regions appeared normal using standard histological techniques. Lesions of the postrhinal cortex (Experiment 4) did not bring about a loss of retrosplenial IEG activity even though this region is also reciprocally connected with the retrosplenial cortex. This selective effect of anterior thalamic damage upon retrosplenial activity may both amplify the disruptive effects of anterior thalamic lesions and help to explain the posterior cingulate hypoactivity found in Alzheimer's disease.

Changes in fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

Fos imaging reveals that lesions of the anterior thalamic nuclei produce widespread limbic hypoactivity in rats

Activity of the immediate early gene c-fos was compared in rats with neurotoxic lesions of the anterior thalamic nuclei and in surgical controls. Fos levels were measured after rats had been placed in a novel room and allowed to run up and down preselected arms of a radial maze. An additional control group showed that in normal rats, this exposure to a novel room leads to a Fos increase in a number of structures, including the anterior thalamic nuclei and hippocampus. In contrast, rats with anterior thalamic lesions were found to have significantly less Fos-positive cells in an array of sites, including the hippocampus (dorsal and ventral), retrosplenial cortex, anterior cingulate cortex, and prelimbic cortex. These results show that anterior thalamic lesions disrupt multiple limbic brain regions, producing hypoactivity in sites associated in rats with spatial memory. Because many of the same sites are implicated in memory processes in humans (e.g., the hippocampus and retrosplenial cortex), this hypoactivity might contribute to diencephalic amnesia.

Effect of chronic angiotensin converting enzyme inhibition on spatial memory and anxiety-like behavours in rats

Angiotensin converting enzyme inhibitors (ACEis) are widely used anti-hypertensive agents that are also reported to have positive effects on mood and cognition. The present study examined the influence of the ACEi, perindopril, on cognitive performance and anxiety measures in rats. Two groups of rats were treated orally for one week with the ACEi, perindopril, at doses of 0.1 and 1.0mg/kg/day. Learning was assessed by the reference memory task in the water maze, comparing treated to control rats. Over five training days both perindopril-treated groups learnt the location of the submerged platform in the water maze task significantly faster than control rats. A 60s probe trial on day 6 showed that the 1.0mg/kg/day group spent significantly longer time in the training quadrant than control rats. This improved performance in the swim maze task was not due to the effect of perindopril on motor activity or the anxiety levels of the rats as perindopril-treated and control animals behaved similarly in activity boxes and on the elevated+maze. These results confirm the anecdotal human studies that ACEis have a positive influence on cognition and provide possibilities for ACEis to be developed into therapies for memory loss.

Using idiothetic cues to swim a path with a fixed trajectory and distance: Necessary involvement of the hippocampus but not the retrosplenial cortex.

Rats rapidly learned to find a submerged platform in a water maze at a constant distance and angle from the start point, which changed on every trial. The rats performed accurately in the light and dark, but prior rotation disrupted the latter condition. The rats were then retested after receiving cytotoxic hippocampal or retrosplenial cortex lesions. Retrosplenial lesions had no apparent effect in either the light or dark. Hippocampal lesions impaired performance in both conditions but spared the ability to locate a platform placed in the center of the pool. A hippocampal deficit emerged when this pool-center task was run in the dark. The spatial effects of hippocampal damage extend beyond allocentric tasks to include aspects of idiothetic guidance.

Del Fichero supremo a la Biblioteca de Babel: Salaverría, precursor de Borges

A juzgar por alguna declaración más bien negativa de Borges sobre la literatura española, se podría creer que esta no influyó demasiado en él. Sin embargo, existen indicios de que pudo haberse inspirado también en determinados escritores españoles coetáneos hoy casi olvidados. Uno de ellos pudo ser José María Salaverría, entre cuyos relatos destaca “El fichero supremo” (1926), del que se ha dicho que “anticipa algunas de las preocupaciones características de un tipo de relato que Jorge Luis Borges elevará años después a la máxima categoría estética”. De hecho, recuerda a “La biblioteca de Babel” (1941) borgiana por su planteamiento hasta el punto de que podría pensarse que el maestro argentino pudo tener presente, a la hora de escribir esa obra maestra, ese cuento de Salaverría, el cual se publicó por primera vez en Caras y Caretas, una revista porteña que Borges reconoció “devorar” en su juventud. Sin embargo, el interés mayor de la comparación entre “El fichero supremo” y “La biblioteca de Babel” no radica tanto en el carácter de posible fuente del primero como en el contraste entre sus formas de presentación narrativa: desde fuera y en tercera persona en Salaverría, en un marco realista; y desde dentro y en primera persona, prácticamente sin marco, en Borges. Este parece desarrollar, en el registro propio de la “imaginación razonada” descrito por él mismo, una virtualidad presente en el relato de Salaverría, cuya comparación con “La biblioteca de Babel” puede suscitar también alguna reflexión sobre el enigma de la identidad y el carácter de la voz enunciadora de la biblioteca universal de Babel. Al menos, esta parece haber hecho realidad en cierto modo, de forma sublime, el patético sueño divino del archivero imaginado por Salaverría.