建立新一代的精神分裂症动物模型

精神分裂症动物模型的建立与发展,是当前探索精神分裂症的神经生物学和认知心理学机制的一个关键课题。在加工-保护理论的基础上所建立起来的感觉运动门控精神分裂症模型一直受到普遍的关注。然而,高级认知活动是如何对感觉门控进行调节的这一核心问题目前还有待进一步的解决。本综述围绕着这个核心问题,系统地解释为什么惊反射前脉冲抑制成为目前最为流行的一种精神分裂症的模型,并介绍恐惧情绪学习对感觉运动门控调节作用的最新研究成果,以及阐述这种自上而下的调节作用如何受到在早期发育阶段的社会隔离的影响     

Effects of interval duration on temporal processing in schizophrenia

INTRODUCTION: Temporal processing has received scant attention in the literature pertaining to cognitive deficits in patients with schizophrenia. Previous research suggests that patients with schizophrenia exhibit temporal perception deficits on both auditory and visual stimuli. The current study investigated the effects of interval manipulation to (1) replicate the original findings with a larger sample and an increased number of trials (2) assess the degree to which both patients and controls can differentiate temporal changes in a range of experimental interstimulus intervals, and (3) explore whether different interstimulus interval durations pose different levels of difficulty for the patients with schizophrenia. METHODS: Participants were asked to decide whether temporal intervals were shorter or longer than standard intervals on a computer-based auditory temporal perception task. The standard interval remained the same duration throughout the various tasks. The interstimulus interval separating the standard and experimental intervals varied in the range of 500, 1000, or 3000 ms. Data are presented for a sample of 16 patients with schizophrenia and 15 controls. RESULTS: Data suggest that patients with schizophrenia exhibit deficits in differentiating interval durations across all paradigms compared to their control-group peers on a range of auditory tasks (p<.001). CONCLUSIONS: These results are consistent with a general temporal deficit in schizophrenia. However, the roles of medication and localization are also addressed.     

Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats

Recent data showed that neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia symptoms in rodents, produce premature deficits of working memory believed to be associated with early medial prefrontal cortex (mPFC) maldevelopment. This experiment expands the investigation of mPFC integrity in juvenile rats with neonatal VH lesions by assessing behavioral flexibility and dendritic spine density. Sixteen Sprague-Dawley male pups received bilateral microinjections of ibotenic acid in the VH or SHAM surgery on postnatal day (PND) 6. On PND 29 and 30, rats were subjected to a spatial shift task in a cross-maze; an attentional set-shifting task was then administered on two consecutive days, between PND 33 and PND 35. Rats were sacrificed at PND 36 and dendritic spine density in the mPFC was assessed using Golgi-Cox staining procedure. Results revealed impaired extra-dimensional shift in VH-lesioned rats and inconsistent reversal discrimination outcomes. Although lesioned animals displayed intact performance in the spatial shift, rates of perseverative responses were higher than normal in this task. Neonatal VH damage resulted in lower dendritic spine density in the mPFC than measured in control brains; however, no significant correlation was found between this outcome and behavioral data. Juvenile morphological and cognitive perturbations are consistent with the early emergence of mPFC anomalies following neonatal VH lesions. Results are discussed in relation with potential common mechanisms linking pre- and post-pubertal onsets of behavioral dysfunction.     

对听感觉运动门控自上而下调节的动物模型和神经机制

对惊反射的前脉冲抑制是减少干扰影响、保护脑内信息加工的重要机制。它既是研究感觉运动门控的模型, 也是探究精神分裂症机制的模型。前脉冲抑制可被选择性注意和情绪等高级认知活动所调节。本论文工作围绕着恐惧条件化和知觉空间分离去掩蔽(空间选择性注意)对听觉前脉冲抑制多层次化的自上而下调节, 在大鼠行为模型、神经通路、神经电生理机制等几个层次上开展了系统性研究, 并引入了精神分裂症的神经发育模型, 证实早期社会隔离饲养对前脉冲抑制注意调节的破坏影响。本论文研究成果不仅对认识正常情况下脑在复杂刺激场景中的信息加工机制有重要意义, 以感觉运动门控认知调节功能缺失为基础的动物模型也将推动精神分裂症心理学和神经生物学机制的研究。     

大鼠注意定势转移任务模型的深入研究：种系和检测程序的影响

注意定势转移任务(attentional set-shifting task, AST)可用于特异性检测啮齿类动物前额叶皮层及其皮层下神经通路介导的认知灵活性, 是目前研究认知灵活性及其障碍神经基础的重要模型。本研究系统调查了大鼠种系和检测程序差异对AST结果的影响。通过比较Wistar和Sprague Dawley (SD)两个种系大鼠在七阶段和五阶段两种AST检测程序中的认知表现, 研究发现：(1) SD和Wistar大鼠前额叶认知功能存在差异, 后者的总体认知表现优于前者。尤其是Wistar大鼠在逆反学习阶段的达标训练次数及错误率显著低于SD大鼠, 表明Wistar大鼠具有更高的策略转换灵活性。(2)在AST测试中逆反学习和外维度定势转移是认知灵活性评价的核心指标。这两种认知转换过程分别以前期策略和注意定势建立为基础。结果显示在两种AST检测程序中Wistar和SD大鼠在逆反学习和/或外维度定势转移等复杂学习阶段的达标训练次数和错误率均高于其它简单关联学习阶段, 表明在目前实验条件下大鼠均表现出定势形成和转换困难的反应模式, 不同认知反应间的结构关系具有稳定性。这些结果提示大鼠前额叶皮质介导的认知灵活性存在种系差异, AST各阶段认知反应间的结构效度不受目前使用的大鼠种系和检测程序差异的影响, 扩展了对AST模型的认识。     

Trait “pessimism” is associated with increased sensitivity to negative feedback in rats

Several cognitive theories of depression have proposed that cognitive judgment bias determines individual vulnerability to this disorder. Indeed, we have recently demonstrated a relationship between pessimistic judgment bias and vulnerability of rats to the stress-induced anhedonia, and a negative correlation between the level of pessimism and motivation. To further characterize the effects of trait pessimism on cognitive processes associated with depression, in the present study we compared the sensitivity of rats displaying optimistic and pessimistic traits to positive and negative feedback. The animals were initially trained and tested in the rat version of the probabilistic reversal-learning (PRL) task, which allowed for the assessment of feedback sensitivity in individual animals. Subsequently, the rats were re-trained and tested in a series of ambiguous-cue interpretation (ACI) tests, which allowed for the classification of animals displaying “optimistic” and “pessimistic” traits. The “pessimistic” rats were significantly more sensitive to negative feedback than their “optimistic” conspecifics, as indicated by an increased proportion of lose-shift behaviors. The results of our study demonstrate the interrelation and co-existence of two cognitive biases that may predict vulnerability to depressive disorder.     

Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats

Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition effectively, animal models of addiction must utilize self-administration procedures in which drug is earned contingently; thus, it remains unclear whether reversal-learning deficits caused by noncontingent cocaine exposure are relevant to addiction. To test whether reversal learning deficits are caused by contingent cocaine exposure, we trained rats to self-administer cocaine, assessed cue-induced cocaine seeking in extinction tests after 1 and 30 d of withdrawal, and then tested for reversal learning more than a month later. We found robust time-dependent increases in cue-induced cocaine seeking in the two extinction tests (incubation of craving) and severe reversal-learning impairments.     

Qualitative evaluation of divergent thinking in patients with schizophrenia

Patients with schizophrenia show deficits across a broad spectrum of neurocognitive domains. In particular, deficits in verbal fluency are common. Verbal fluency tests are neuropsychological tests that assess frontal lobe function or executive function but also assess divergent thinking. However, few studies have considered the impairment of verbal fluency from the viewpoint of divergent thinking. To consider the structure of divergent thinking, not only verbal assessments but also non-verbal assessments are indispensable. We administered several fluency tests, the idea fluency test, the design fluency test, and word (letter and category) fluency tests to 26 patients with schizophrenia and 26 healthy control subjects to evaluate divergent thinking in both groups and assessed their responses qualitatively. An acceptable minimal level of intelligence was maintained in the patient group. Although attention and executive functioning were relatively preserved in the subjects with schizophrenia, they demonstrated significant deficits in divergent thinking and had particular difficulty in producing ideas and designs requiring concept flexibility, a conversion of viewpoint, originality, or novelty. Research on deficits in divergent thinking in patients with schizophrenia may contribute to the development of cognitive and behavioral rehabilitation programs.     

A contribution of cognitive decision models to clinical assessment: decomposing performance on the Bechara gambling task

The Bechara simulated gambling task is a popular method of examining decision-making deficits exhibited by people with brain damage, psychopathology, antisocial personality, or drug abuse problems. However, performance on this task is confounded by complex interdependencies between cognitive, motivational, and response processes, making it difficult to sort out and identify the specific processes responsible for the observed behavioral deficits. The authors compare 3 competing cognitive decision models of the Bechara task in terms of their ability to explain the performance deficits observed in Huntington's disease patients as compared with healthy populations and people with Parkinson's disease. The parameters of the best fitting model are used to decompose the observed performance deficit of the Huntington patients into cognitive, motivational, and response sources.     

Aggression and social experience in domesticated rats.

Small colonies of rats were established, using adult animals that had either received continuous social experience or had been isolated since weaning. Unfamiliar "intruder" rats--with or without postweaning social experience--were exposed individually to the colonies for a 21-hr. period. Behavioral observations and an assessment of the intruder's physical condition indicated that serious fighting, physical injuries, and large weight losses occurred only when an isolation-reared intruder was placed into a colony of socially experienced rats. These results demonstrate that aggression is a joint function of the rearing history of both the colony and the intruder and that social experience plays an important role in the behavioral development of this species.     

Strategy-dependent changes in memory: Effects on behavior and brain activity

In the present study, an implicit strategy manipulation was used to explore the contribution of memory strategy to brain activation and behavioral performance. Participants were biased to use either a short-term (maintenance-focused) or long-term (retrieval-focused) memory strategy within a single memory task through manipulation of task context. In comparing directly matched trials across the different task contexts, we observed clear changes in both behavioral performance and brain activity across a network of regions located primarily within lateral and medial frontal cortex. These effects of the memory strategy manipulation suggest that when a retrieval-focused strategy is induced, mnemonic processes are preferentially engaged during the encoding period. In contrast, when a maintenance-focused strategy is induced, mnemonic processes are preferentially engaged during the delay and response periods. Taken together, the results imply that covert cognitive strategies play an important role in modulating brain activation and behavior during memory tasks.     

Precedence-effect-induced enhancement of prepulse inhibition in socially reared but not isolation-reared rats

Attention to a prepulse presented shortly before a startling stimulus enhances prepulse inhibition (PPI) of startle in normal people, but not in schizophrenics. Fear conditioning for the prepulse enhances PPI in socially reared, but not isolation-reared, rats. In humans, selective attention to acoustic signals against masking can be facilitated by precedence-effect-induced perceived spatial separation between the signal and the masker. This study investigated whether perceived spatial separation between a prepulse and a noise masker enhances PPI in socially reared rats and isolation-reared rats. The results show that both PPI and conditioning-induced PPI enhancement were larger in socially reared rats than in isolation-reared rats. More important, in socially reared, but not isolation-reared, rats, a further PPI enhancement was induced by precedence-effect-induced perceived separation between a prepulse and a masker only after the prepulse became fear conditioned. Thus, perceived separation facilitates normal rats’ attention to a conditioned prepulse and enhances PPI. Isolation rearing impairs rats’ ability to attend to ecologically significant acoustic events.     

Perceptual training strongly improves visual motion perception in schizophrenia

Schizophrenia patients exhibit perceptual and cognitive deficits, including in visual motion processing. Given that cognitive systems depend upon perceptual inputs, improving patients’ perceptual abilities may be an effective means of cognitive intervention. In healthy people, motion perception can be enhanced through perceptual learning, but it is unknown whether this perceptual plasticity remains in schizophrenia patients. The present study examined the degree to which patients’ performance on visual motion discrimination can be improved, using a perceptual learning procedure. While both schizophrenia patients and healthy controls showed decreased direction discrimination thresholds (improved performance) with training, the magnitude of the improvement was greater in patients (47% improvement) than in controls (21% improvement). Both groups also improved moderately but non-significantly on an untrained task—speed discrimination. The large perceptual training effect in patients on the trained task suggests that perceptual plasticity is robust in schizophrenia and can be applied to develop bottom-up behavioral interventions.     

Episodic Memory in Schizophrenia

Episodic memory impairments in individuals with schizophrenia have been well documented in the literature. However, despite the abundance of findings, constituent cognitive, neural, behavioral, and genetic components of the deficits continue to elude full characterization. This review provides a characterization of these deficits by organizing findings within three frameworks of interest: 1) neuroanatomical; 2) genetic; and 3) behavioral. Within each approach, evidence from imaging studies as well as behavioral studies is examined. The hope is that by synthesizing the cognitive science paradigms, molecular genetic neurophysiological findings, and computational algorithms applied to medial temporal lobe subregions, we will be able to expand our understanding of the types of compromises in episodic memory systems of individuals with schizophrenia.     

Identification of tone duration, line length, and letter position: an experimental approach to timing and working memory deficits in schizophrenia

Patients with schizophrenia display numerous cognitive deficits, including problems in working memory, time estimation, and absolute identification of stimuli. Research in these fields has traditionally been conducted independently. We examined these cognitive processes using tasks that are structurally similar and that yield rich error data. Relative to healthy control participants (n = 20), patients with schizophrenia (n = 20) were impaired on a duration identification task and a probed-recall memory task but not on a line-length identification task. These findings do not support the notion of a global impairment in absolute identification in schizophrenia. However, the authors suggest that some aspect of temporal information processing is indeed disturbed in schizophrenia.     

Examining the Link Between Hoarding Symptoms and Cognitive Flexibility Deficits

Executive functioning deficits have been found to underlie primary symptoms of hoarding, such as difficulty discarding belongings and significant clutter. Cognitive flexibility—the ability to inhibit irrelevant material and attend flexibly between different mental sets—may be impaired as well, as individuals experience difficulty staying on task and are often distracted by specific possessions that tend to evoke an exaggerated emotional response. The present study investigated cognitive flexibility deficits via eye-tracking technology as a novel approach. Participants (N = 69) with high and low self-reported hoarding symptoms were asked to respond to a series of auditory cues requiring them to categorize a small target number superimposed on one of three distractor image types: hoarding, nature, or a blank control. Across a range of behavioral and eye-tracking outcomes (including reaction time, accuracy rate, initial orientation to distractors, and viewing time for distractors), high hoarding participants consistently demonstrated greater cognitive inflexibility compared to the low hoarding group. However, high hoarding participants did not evidence context-dependent deficits based on preceding distractor types, as performance did not significantly differ as a function of hoarding versus nature distractors. Current findings indicate a pervasive, more global deficit in cognitive flexibility. Those with hoarding may encounter greater difficulty disengaging from previous stimuli and attending to a given task at hand, regardless of whether the context of the distractor is specifically related to hoarding. Implications and future directions for clarifying the nature of cognitive inflexibility are discussed.     

Does social environment influence learning ability in a family-living lizard?

Early developmental environment can have profound effects on individual physiology, behaviour, and learning. In birds and mammals, social isolation during development is known to negatively affect learning ability; yet in other taxa, like reptiles, the effect of social isolation during development on learning ability is unknown. We investigated how social environment affects learning ability in the family-living tree skink (Egernia striolata). We hypothesized that early social environment shapes cognitive development in skinks and predicted that skinks raised in social isolation would have reduced learning ability compared to skinks raised socially. Offspring were separated at birth into two rearing treatments: (1) raised alone or (2) in a pair. After 1 year, we quantified spatial learning ability of skinks in these rearing treatments (N = 14 solitary, 14 social). We found no effect of rearing treatment on learning ability. The number of skinks to successfully learn the task, the number of trials taken to learn the task, the latency to perform the task, and the number of errors in each trial did not differ between isolated and socially reared skinks. Our results were unexpected, yet the facultative nature of this species’ social system may result in a reduced effect of social isolation on behaviour when compared to species with obligate sociality. Overall, our findings do not provide evidence that social environment affects development of spatial learning ability in this family-living lizard.     

Risky decision making and cognitive flexibility among online sports bettors in Nigeria

Online sports betting is a popular recreational activity in Nigeria. Like other forms of gambling, risk of pathological progression exists for gamblers who continue betting despite severe financial and psychosocial consequences. In the present study, we examined whether this population of gamblers shows deficits in decision making and cognitive flexibility that have been documented in Western gambling populations. Thirty-six online sports bettors and 42 non-gambling participants completed a version of the Iowa gambling task (IGT) and an established set-shifting task for the assessment of cognitive flexibility. The two groups did not differ significantly in the selection of disadvantageous decks on the IGT. In contrast, sports bettors committed significantly more errors on the set-shifting task than non-gambling control participants. As this performance deficit was not specific to trials requiring a set shift, it most likely resulted from gambling-related changes in general cognitive or motivational abilities that are required to successfully complete challenging mental tasks. While our results illustrate that findings from Western populations cannot automatically be generalised to other contexts, it should be noted that we focused on only one particular type of gambling and included mostly participants with mild gambling-related problems.     

The effects of cross-fostering on inherent sensorimotor gating deficits exhibited by Brattleboro rats

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating, a process critical to normal cognitive function. Researchers (D. Feifel & K. Priebe, 2001) have identified PPI deficits in the Brattleboro rat, a genetically vasopressin-deficient strain that is derived from the Long Evans rat. The absence of vasopressin, a neuropeptide involved in affiliative behaviors, may adversely affect the rearing of offspring by Brattleboro dams, perhaps accounting for their attenuated PPI. Cross-fostering of Long Evans and Brattleboro pups did not alter the PPI deficits in Brattleboro rats. However, the magnitude and habituation of the startle response, which normally differs between Brattleboro and Long Evans rats, was not different in cross-fostered rats. The authors' results indicated that abnormal rearing by Brattleboro dams may contribute to the startle magnitude and habituation abnormalities in Brattleboro Rats but not to their PPI deficits, suggesting that their sensorimotor gating deficits result from their genetic deviation from Long Evans rats.     

Imagining the future: degraded representations of future rewards and events in schizophrenia

Over the course of life, most people work toward temporally distant rewards such as university degrees or work-related promotions. In contrast, many people with schizophrenia show deficits in behavior oriented toward long-term rewards, although they function adequately when rewards are more immediately present. Moreover, when asked about possible future events, individuals with schizophrenia show foreshortened future time perspectives relative to healthy individuals. Here, we take the view that these deficits are related and can be explained by cognitive deficits. We compared the performance of participants with schizophrenia (n = 39) and healthy participants (n = 25) on tasks measuring reward discounting and future event representations. Consistent with previous research, we found that relative to healthy participants, those with schizophrenia discounted the value of future rewards more steeply. Furthermore, when asked about future events, their responses were biased toward events in the near future, relative to healthy participants' responses. Although discounting and future representations were unrelated in healthy participants, we found significant correlations across the tasks among participants with schizophrenia, as well as correlations with cognitive variables and symptoms. Further analysis showed that statistically controlling working memory eliminated group differences in task performance. Together these results suggest that the motivational deficits characteristic of schizophrenia relate to cognitive deficits affecting the ability to represent and/or evaluate distant outcomes, a finding with important implications for promoting recovery from schizophrenia.