海洛因成瘾脑灰质密度和结构网络研究

Behavioral and functional imaging studies consistently show that heroin abuse leads to various cognitive impairments, while brain structural changes associated with heroin use remain poorly understood. In the current study, we used voxel-based morphology (VBM), a method sensitive to structural changes of the brain, to investigate the gray concentration in MRI structure images of heroin addicts. Results show that the concentration of the temporal cortex and frontal cortex of heroin users significantly decreased as compared to age/education matched normal controls. Further analysis revealed that this brain structure change was detectable only in the users who had used heroin more than 5 year, but not in the remaining users. These results converge to the abnormality of the brain structure in heroin users and this abnormality is clearly associated with duration of drug use. We then analyzed the large-scale brain structure network in the heroin addicts. As compared to the normal controls, there was significant difference in interregional correlation between the temporal cortex, hippocampus, thalamus, and frontal cortex. Importantly, two major indices of the small-world properties, Clustering coefficient(Cp) and shortest path length (Lp), which are thought to reflect the local specialty and global integrity, were marginal-significantly larger than the normal controls, especially for Lp. These results suggest that chronic use of heroin results in the reorganization of the brain system. Taken together, this thesis has provided compelling evidence for brain structure impairments in chronic heroin users and further characterized the large-scale brain structure network in the same population.

阿片药物依赖的神经机制---内侧前额叶与药物的心理依赖

Mental dependence, characterized by craving and impulsive seeking behavior, is the matter of intensive study in the field of drug addiction. The mesolimbic dopamine system has been suggested to play an important role in rewarding of drugs and relapse. Although chronic drug use can induce neuroadaptations of the mesolimbic system and changes of drug reinforcement, these mechanisms cannot fully account for the craving and the compulsive drug-using behavior of addicts. Acknowledging the reinforcement effects of drugs, most previous studies have studied the impact of environmental cues and conditioned learning on addiction behavior, often using established classical or operant conditioning model. These studies, however, paid little attention to the role of cognitive control and emotion in addiction. These mental factors that are believed to have an important influence on conditioned learning. The medial prefrontal cortex (mPFC) has close anatomic and functional connections with the mesolimbic dopamine system. A number of the cognitive neurological studies demonstrate that mPFC is involved in motivation, emotional regulation, monitoring of responses and other executive functions. Thus we speculated that the function of abnormality in mPFC following chronic drug use would cause related to the abnormal behavior in addicts including impulse and emotional changes. In the present study of a series of experiments, we used functional magnetic resonance imaging to examine the hemodynamic response of the mPFC and related circuits to various cognitive and emotional stimuli in heroin addicts and to explore the underlying dopamine neuromechnism by microinjection of tool drugs into the mPFC in laboratory animals. In the first experiment, we found that heroin patients, relative to the normal controls, took a much shorter time and committed more errors in completing the more demanding of cognitive regulation in the reverse condition of the task, while the neural activity in anterior cingulate cortex (ACC) was attenuated. In the second experiment, the scores of the heroin patients in self-rating depression scale (SDS) and Self-rating anxiety scale (SAS) were significantly higher than the normal controls and they rated the negative pictures more aversive than the normal controls. Being congruent with the behavioral results, hemodynamic response to negative pictures showed significant difference between the two groups in bilateral ventral mPFC (VMPFC), amygdala, and right thalamus. The VMPFC of patients showed increased activation than normal controls, whereas activation in the amygdala of patients was weaker than that in normal subjects. Our third experiment showed that microinjection of D1 receptor agonist SKF38393 into the mPFC of rats decreased hyperactivity, which was induced by morphine injection, in contrast, D1 receptor antagonist SCH23390 increased the hyperactivity, These findings suggest: (1) The behavior and neural activity in ACC of addicts changed in chronic drug users. Their impulsive behavior might result from the abnormal neural activity in the mPFC especially the ACC. (2) Heroine patients were more depress and anxiety than normal controls. The dysfunction of the mPFC---amygdala circuit of heroine addicts might be related to the abnormal emotion response. (3) Dopamine in the mPFC has an inhibitory effect on morphine induced behavior. The hyperactivity induced by chronic morphine was reduced by dopamine increase with D1 receptor agonist, confirm the first experiment that the neuroadaption of mPFC system induced by chronic morphine administration appears to be the substrate the impulse behavior of drug users.

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.

左侧梭状回内文字的字形加工：中文正常阅读者，中文文盲、非中文母语被试的对比研究

Reading is an important human-specific skill obtained through extensive learning experience and is reliance on the ability to rapidly recognize single words. According to the behavioral studies, the most important stage of reading is the representation of “visual word form”, which is independent on surface visual features of the reading materials. The prelexical visual word form representation is characterized by the abstractive and highly effective and precise processing. Neuroimaging and neuropsychological studies have investigated the neural basis underlying the visual word form processing. On the basis of summary of the existing literature, the current thesis aimed to address three fundamental questions involving neural basis of word recognition. First, is there a dedicated neural network that is specialized for word recognition? Second, is the orthographic information represented in the putative word/character selective region (VWFA)? Third, what is the role of reading experience in the genesis of the VWFA, is experience a main driver to shape VWFA instead of evolutionary selectivity? Nineteen Chinese literate volunteers, 5 Chinese illiterates and 4 native English speakers participated in this study, and performed perceptual tasks during fMRI scanning. To address the first question, we compared the differential responses to three categories of visual objects, i.e., faces, line drawings of objects and Chinese characters, and defined the region of interesting (ROI) for the next experiment. To address the second question, Chinese character orthography was manipulated to reveal possible differential responses to real characters, false characters, radical combinations, and stroke combinations in the regions defined by the first experiment. To examine the role of reading experience in genesis of specialization for character, the responses for unfamiliar Chinese characters in Chinese illiterates and native English speakers were compared with that in the Chinese literates, and tracked the change in cortical activation after a short-term reading training in the illiterates. Data were analyzed in two dimensions. Both BOLD signal amplitude and spatial distribution pattern among multi-voxels were used to systematically investigate the responsiveness of the left fusiform gyrus to Chinese characters. Our results provide strong and clear evidence for the existence of functionally specialized regions in the human ventral occipital-temporal cortex. In the skilled readers a region specialized for written words could be consistently found in the lateral part of the left fusiform gyrus, line drawings in the median part and faces in the middle. Our results further show that spatial distribution analysis, a method that was not commonly used in neuroimaging of reading, appears to be a more effective measurement for category specialization for visual objects processing. Although we failed to provide evidence that VWFA processes orthographic information in terms of signal intensitiy, we do show that response pattern of real characters and radical collections in this area is different from that of false characters and random stroke combinations. Our last set of experiments suggests that the selective bias to reading material is clearly experience dependent. The response to unknown characters in both English speakers/readers and Chinese illiterates is fundamentally different from that of the skilled Chinese readers. The response pattern for unknown characters is more similar to that for line drawings rather as a weak version of character in skilled Chinese readers. Short-term training is not sufficient to produce VWFA bias even when tested with learned characters, rather the learned characters generated a overall upward shift of the activation of the left fusiform region. Formation of a dedicated region specialized for visual word/character might depend on long-term extensive reading experience, or there might be a critical period for reading acquisition.

左中部梭状回枕颞沟内皮质对汉字加工的必要性、选择性和作用性质

A number of functional neuroimaging studies with skilled readers consistently showed activation to visual words in the left mid-fusiform cortex in occipitotemporal sulcus (LMFC-OTS). Neuropsychological studies also showed that lesions at left ventral occipitotemporal areas result in impairment in visual word processing. Based on these empirical observations and some theoretical speculations, a few researchers postulated that the LMFC-OTS is responsible for instant parallel and holistic extraction of the abstract representation of letter strings, and labeled this piece of cortex as “visual word form area” (VWFA). Nonetheless, functional neuroimaging studies alone is basically a correlative rather than causal approach, and lesions in the previous studies were typically not constrained within LMFC-OTS but also involving other brain regions beyond this area. Given these limitations, it remains unanswered for three fundamental questions: is LMFC-OTS necessary for visual word processing? is this functionally selective for visual word processing while unnecessary for processing of non-visual word stimuli? what are its function properties in visual word processing? This thesis aimed to address these questions through a series of neuropsychological, anatomical and functional MRI experiments in four patients with different degrees of impairments in the left fusiform gyrus. Necessity: Detailed analysis of anatomical brain images revealed that the four patients had differential foci of brain infarction. Specifically, the LMFC-OTS was damaged in one patient, while it remained intact in the other three. Neuropsychological experiments showed that the patient with lesions in the LMFC-OTS had severe impairments in reading aloud and recognizing Chinese characters, i.e., pure alexia. The patient with intact LMFC-OTS but information from the left visual field (LVF) was blocked due to lesions in the splenium of corpus callosum, showed impairment in Chinese characters recognition when the stimuli were presented in the LVF but not in the RVF, i.e. left hemialexia. In contrast, the other two patients with intact LMFC-OTS had normal function in processing Chinese characters. The fMRI experiments demonstrated that there was no significant activation to Chinese characters in the LMFC-OTS of the pure alexic patient and of the patient with left hemialexia when the stimuli were presented in the LVF. On the other hand, this patient, when Chinese characters were presented in right visual field, and the other two with intact LMFC-OTS had activation in the LMFC-OTS. These results together point to the necessity of the LMFC-OTS for Chinese character processing. Selectivity: We tested selectivity of the LMFC-OTS for visual word processing through systematically examining the patients’ ability for processing visual vs. auditory words, and word vs. non-word visual stimuli, such as faces, objects and colors. Results showed that the pure alexic patients could normally process auditory words (expression, understanding and repetition of orally presented words) and non-word visual stimuli (faces, objects, colors and numbers). Although the patient showed some impairments in naming faces, objects and colors, his performance scores were only slightly lower or not significantly different relative to those of the patients with intact LMFC-OTS. These data provide compelling evidence that the LMFC-OTS is not requisite for processing non-visual word stimuli, thus has selectivity for visual word processing. Functional properties: With tasks involving multiple levels and aspects of word processing, including Chinese character reading, phonological judgment, semantic judgment, identity judgment of abstract visual word representation, lexical decision, perceptual judgment of visual word appearance, and dictation, copying, voluntary writing, etc., we attempted to reveal the most critical dysfunction caused by damage in the LMFC-OTS, thus to clarify the most essential function of this region. Results showed that in addition to dysfunctions in Chinese character reading, phonological and semantic judgment, the patient with lesions at LMFC-OTS failed to judge correctly whether two characters (including compound and simple characters) with different surface features (e.g., different fonts, printed vs. handwritten vs. calligraphy styles, simplified characters vs. traditional characters, different orientations of strokes or whole characters) had the same abstract representation. The patient initially showed severe impairments in processing both simple characters and compound characters. He could only copy a compound character in a stroke-by-stroke manner, but not by character-by-character or even by radical-by-radical manners. During the recovery process, namely five months later, the patient could complete the abstract representation tasks of simple characters, but showed no improvement for compound characters. However, he then could copy compound characters in a radical-by-radical manner. Furthermore, it seems that the recovery of copying paralleled to that of judgment of abstract representation. These observations indicate that lesions of the LMFC-OTS in the pure alexic patients caused several damage in the ability of extracting the abstract representation from lower level units to higher level units, and the patient had especial difficulty to extract the abstract representation of whole character from its secondary units (e.g., radicals or single characters) and this ability was resistant to recover from impairment. Therefore, the LMFC-OTS appears to be responsible for the multilevel (particularly higher levels) abstract representations of visual word form. Successful extraction seems independent on access to phonological and semantic information, given the alexic patient showed severe impairments in reading aloud and semantic processing on simple characters while maintenance of intact judgment on their abstract representation. However, it is also possible that the interaction between the abstract representation and its related information e.g. phonological and semantic information was damaged as well in this patient. Taken together, we conclude that: 1) the LMFC-OTS is necessary for Chinese character processing, 2) it is selective for Chinese character processing, and 3) its critical function is to extract multiple levels of abstract representation of visual word and possibly to transmit it to phonological and semantic systems.

精神分裂症患者及其未患病一级亲属的面孔情绪知觉研究

Schizophrenia is a heritable disorder. However, molecular genetics and related research area have not unmasked the nature and mechanisms of this disorder. Therefore, many researchers begin to explore the pathology mechanism from other approaches. High-risk study is one of the promising approaches. In this study, we mainly focused on facial emotion perception in schizophrenia and their non-psychotic first-degree relatives, and attempted to explore whether facial emotion perception is the potential biological marker of schizophrenia. This dissertation comprises 4 studies. In the first study, we conducted a meta-analysis on behavioral data of facial emotion perception in schizophrenia. Our findings showed that patients demonstrated general deficits in both facial emotion perception and facial processing tasks. In the second study, sixty-nine patients with schizophrenia and 56 of their first-degree relatives (33 parents and 23 siblings), and 92 healthy controls (67 younger and 25 older healthy controls) completed a set of facial emotion perception tasks. The results validated that patients with schizophrenia displayed general deficits in facial emotion perception. Study two also demonstrated that siblings of patients performed equally well compared to the corresponding younger healthy controls in all the facial emotion perception tasks, while the parents of patients behaved significantly worse than the corresponding older healthy controls in the composite index of facial emotion perception tasks. The results suggest that relatives of patients display more severely declining in facial emotion perception with the increasing of age. In the third study, we used an automated voxel-wise technique, activation likelihood estimation (ALE) to provide an objective, quantitative evaluation of facial emotion processing in schizophrenia. Our findings demonstrated a marked under-recruitment of the amygdala, accompanied by a substantial limitation in activation in schizophrenia throughout a ventral temporal-basal ganglia-prefrontal cortex ‘social-brain’ system may be central to the difficulties patients experience when processing facial emotion. In the last study, we did an fMRI study about facial emotion perception in 12 patients with schizophrenia, 12 non-psychotic siblings of patients and 12 healthy controls. The results suggest that siblings of patients demonstrate abnormal activation in a variety of brain areas, including prefrontal gyrus, insula, parahippocampal gyrus and superior temporal gyrus. Taken together, the current findings suggest facial emotion perception may be a potential biological marker of schizophrenia.

PLCß介导的钙调腺苷酸环化酶在突触可塑性相关基因转录中的作用和FE65对海马依赖学习及LTP的调节

Gene regulation is required for activity-dependent changes in synaptic plasticity and remodeling. The metabotropic glutamate receptors (mGluRs) contribute to different brain functions, including learning/memory, mental disorders, drug addiction, and persistent pain in the CNS. We found that Gp I mGluRs activate PLCß through Gq and then lead to activation of several calcium-dependent signaling pathways, including ERK, which play an important role in gene transcription. These findings support a calcium-dependent role for Gq in release of Calcium and activation of calcium-stimulated adenylyl cyclases I in activity-dependent transcription in response to application of group I metabotropic glutamate receptors agonist and may provide insights into group I mGluRs-dependent synaptic plasticity through MAP kinases signaling. Moreover, the present study investigated the transcription-dependent changes of Arc in response to the activation of group I mGluRs and suggested the central role of ERK1/2 in group I mGluR-mediated Arc transcription. Further, we selected APP-interaction protein FE65 to investigate the mechanism of transcription-related process in synaptic plasticity. FE65 is expressed predominantly in the brain, and interacts with the C-terminal domain of β-amyloid precursor protein (APP). We examined hippocampus-dependent memory and in vivo long-term potentiation (LTP) at the CA1 synapses with the isoform-specific FE65 knock-out (p97FE65-/-) mice. p97FE65 knock-out mice showed impaired short-term memory for both TDPA and CFC when tested 10min after training, which is transcription-independent. Consistently, at the Schaffer collateral-CA1 synapses, p97FE65 knock-out mice showed defective early phase LTP. These results demonstrate novel roles of FE65 in synaptic plasticity, acquisition, and retention for certain forms of memory formation.

条件反射性免疫抑制及其脑机制的c-fos研究

To explore the neural mechanisms underlying conditioned immunomodulation, this study employed the classical taste aversion (CTA) behavioral paradigm to establish the conditioned humoral and cellular immunosuppression (CIS) in Wistar rats, by paring saccharin (CS) with intraperitoneal (i.p.) injection of an immunosuppressive drug cyclophophamide (UCS). C-fos immunohistochemistry method was used to observe the changes of the neuronal activities in the rat brain during the acquisition, expression and extinction of the conditioned immunosuppression (CIS). The followings are the main results: 1. Five days after one trial of CS-UCS paring, reexposure to CS alone significantly decreased the level of the anti-ovalbumin (OVA) IgG in the peripheral serum. Two trials of CS-UCS paring and three reexposures to CS not only resulted in further suppression of the primary immune response, but also reduced the numbers of peripheral lymphocytes and white blood cells. This finding indicates that CS can induce suppression of the immune function, and the magnitude of the effects is dependent on the intensity of training. 2. On day 5 following two trials of CS-UCS pairing, CS suppressed the spleen lymphocytes responsiveness to mitogens ConA, PHA and PWM, and decreased the numbers of peripheral lymphocytes and white blood cells. On day 15, only PHA induced lymphocyte proliferation was suppressed by CS. On day 30, presentation of CS did not have any effect on these immune parameters. These results suggest that the conditioned suppression of the cellular immune function can retain 5-15 days, and extinct after 30 days. 3. CTA was easily induced by one or two CS-UCS parings, and remained robust even after 30 days. These data demonstrate that CIS can be dissociated from CTA, and they may be mediated by different neural mechanisms. 4. Immunohistochemistry assays revealed a broad pattern of c-fos expression throughout the rat brain following the CS-UCS pairing and reexposure to CS, suggesting that many brain regions are involved in CIS. Some brain areas including the solitary tract nucleus (Sol), lateral parabrachial nucleus (LPB) and insular cortex (IC), showed high level c-fos expressions in response to both CS and UCS, suggesting that they may be involved in the transmission and integration of the CS and UCS signals in the brain. There were dense c-FOS positive neurons in the paraverntricular nucleus (PVN) and supraoptic nucleus (SO) of hypothalamus, subfornical organ (SFO) and area postrema (AP) etc. after two trials of CS-UCS paring and after the reexposure to CS 5 days later, but not in the first training and after the extinction of CIS (30 days later). The results reflect that these nuclei may have an important role in CIS expression, and may also response to the immunosuppression of UCS. The conditioned training and reexposure to CS 5 days later induced high level c-fos expression in the cingulate cortex (Cg), central amygdaloid nucleus (Ce), intermediate part of lateral septal nucleus (LSI) and ventrolateral parabrachial nucleus (VLPB) etc. But c-fos induction was not apparent when presenting CS 30 days later. These brain regions are mainly involved in CIS, and may be critical structures in the acquisition and expression of CIS. Some brain regions, including the frontal cortex (Fr), ventral orbital cortex (VO), IC, perirhinal cortex (PRh), LPB and the medial part of solitary nucleus (SolM), showed robust c-FOS expression following the conditioning training and reexposure to CS both on day 5 and day 30, suggesting that they are critically involved in CTA.

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.

基底神经节的认知和记忆功能研究

The cognition and memory functions of the Basal Ganglia have been the focus of contemporary cognitive neuroscience researches. This study, from neuroanatomical and neurophysiological point of view, thoroughly surveyed the recent relevant research progress, carefully examined the evidences of the neurological basis for the Basal Ganglia possessing or participating cognition or memory functions. Moreover, it reviewed recent achievements on the cognitive functions of the basal ganglia based on researches on rodent animals, primate animals and human beings. Then it presented a series of experiments conducted, by neuropsychological and cognitive psychological methods, on neurological patients with focal lesions to the basal ganglia or combining with bilateral hippocampus or thalamus impaired to explore what the role of the basal ganglia play in human explicit and implicit memory. It was found that the lesions to the basal ganglia partially handicapped explicit verbal memory and completely impaired perceptual priming. It was also found that right cerebral cortex dysplasia but basal ganglia spared had no effects on priming tasks performances. The results suggested that the basal ganglia contain or accommodate higher cognitive functions and further suggested that priming be irrelevant to right cerebral cortex. It was posited that the basal ganglia, on the basis of interaction with prefrontal or temporal cortices, mediate movement function as well as cognition and memory functions.