Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.
 ...
PMID:Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function. 2357 23

Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA)- receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Evidence has shown that MK-801 increases the probability of operant responding during extinction, possibly modeling perseveration, as would be seen in patients with schizophrenia. This MK-801-induced behavioral perseveration is reversed by dopamine receptor antagonism. To further explore the role of dopamine in this behavioral change, the current study sought to determine if the MK-801-induced increase in non-rewarded operant responding could be mimicked by dopamine agonism and determine how it was related to locomotor activity. Male Long Evans rats were treated systemically with MK-801, cocaine, GBR12909 or apomorphine (APO) and given a single trial operant extinction session, followed by a separate assessment of locomotor activity. Both MK-801 (0.05 mg/kg) and cocaine (10 mg/kg) significantly increased responding during the extinction session and both increased horizontal locomotor activity. No dose of GBR-12909 (5, 10 or 20 mg/kg) was found to effect non-rewarded operant responding or locomotor activity. APO (0.05, 0.5, 2 or 5 mg/kg) treatment produced a dose-dependent decrease in both operant responding and locomotor activity. These results suggest the possibility that, rather than a primary influence of increased dopamine concentration on elevating bar-pressing responses during extinction, other neurotransmitter systems may be involved.
...
PMID:Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats. 2376 88

A number of psychiatric illnesses have been associated with prenatal disturbance of brain development, including autism, attention deficit hyperactivity disorder, and schizophrenia. Individuals afflicted with these disorders exhibit both repetitive motor and cognitive behavior. The potential role that environmental insult to the developing brain may play in generating these aberrant behaviors is unclear. Here we examine the behavioral consequences of an early gestational insult in the non-human primate. Rhesus macaques were exposed to x-irradiation during the first trimester of development to disrupt neurogenesis. The behavior of five fetally irradiated monkeys (FIMs) and five control monkeys (CONs) was observed as they matured from juvenile (1.5 years) to adult ages (4-5 years). Home-cage behavior was indistinguishable in the two groups. In the testing cage, circling was prevalent in both groups at juvenile ages, persisting to adulthood in three of the five FIMs. One FIM executed a ritualized motor sequence marked by semi-circling and undulating head movements. Seven macaques (4 FIMs, 3 CONs) were tested on a spatial Delayed Alternation (DA) task as adults. Perseverative errors and non-perseverative errors were recorded in early stages of the testing, at the 0 delay interval. While performing DA, FIMs made more errors of perseveration than CONs yet the number of total errors committed did not differ between groups. The presence of motor stereotypies and cognitive perseveration in fetally irradiated non-human primates suggests that environmental insult to the embryonic brain may contribute to repetitive motor and cognitive behaviors in neuropsychiatric diseases.
 ...
PMID:Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation. 2376 11

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.
 ...
PMID:Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation. 2419 46

A neurocognitive model of thought disorder is proposed that links: (1) impaired ability to establish set with poverty of speech; (2) impaired ability to maintain set with positive thought disorder; and (3) impaired ability to shift sets with perseveration in speech. The aim of this study is to examine performance on tests sensitive to set ability in patients prone to thought disorder. Patients with schizophrenia (n = 36), mania (n = 18) and a well control group (n = 20) were assessed on two occasions separated by 4 weeks. Testing included: a free speech sample, Controlled Oral Word Association test, Stroop test, Wisconsin Card Sort test, and the Trail Making test. Impaired ability to maintain set in the face of interference was correlated with positive thought disorder, impaired ability to establish set was correlated with poverty of speech, and impaired ability to shift set was associated with perseveration in speech. The associations between impaired set ability and types of thought disorder support a neurocognitive model implicating impaired executive ability in the pathogenesis of thought disorder.
...
PMID:Thought disorder and executive ability. 2541 96

Abnormalities in the dopamine system have long been implicated in explanations of reinforcement learning and psychosis. The updated reward prediction error (RPE)-a discrepancy between the predicted and actual rewards-is thought to be encoded by dopaminergic neurons. Dysregulation of dopamine systems could alter the appraisal of stimuli and eventually lead to schizophrenia. Accordingly, the measurement of RPE provides a potential behavioral index for the evaluation of brain dopamine activity and psychotic symptoms. Here, we assess two features potentially crucial to the RPE process, namely belief formation and belief perseveration, via a probability learning task and reinforcement-learning modeling. Forty-five patients with schizophrenia [26 high-psychosis and 19 low-psychosis, based on their p1 and p3 scores in the positive-symptom subscales of the Positive and Negative Syndrome Scale (PANSS)] and 24 controls were tested in a feedback-based dynamic reward task for their RPE-related decision making. While task scores across the three groups were similar, matching law analysis revealed that the reward sensitivities of both psychosis groups were lower than that of controls. Trial-by-trial data were further fit with a reinforcement learning model using the Bayesian estimation approach. Model fitting results indicated that both psychosis groups tend to update their reward values more rapidly than controls. Moreover, among the three groups, high-psychosis patients had the lowest degree of choice perseveration. Lumping patients' data together, we also found that patients' perseveration appears to be negatively correlated (p = 0.09, trending toward significance) with their PANSS p1 + p3 scores. Our method provides an alternative for investigating reward-related learning and decision making in basic and clinical settings.
...
PMID:Inferring reward prediction errors in patients with schizophrenia: a dynamic reward task for reinforcement learning. 2542 91

The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-10-imine maleate (MK-801) has been shown to increase the probability of operant responding during extinction and reduce infralimbic prefrontal cortical activation, possibly modeling the cognitive dysfunction symptomology, and underlying cause, in patients with schizophrenia. The present study sought to determine if typical and/or atypical antipsychotics would attenuate the MK-801-induced behavioral perseveration and whether this would be associated with concomitant changes in phosphorylated ERK1/2 (pERK1/2) labeling in the infralimbic cortex (IL). Male, Long Evans rats were pretreated with the typical antipsychotic, Flupenthixol (0, 0.125, 0.25 or 0.5 mg/kg) or the atypical antipsychotic, aripiprazole (0, 0.3, 1.0, 3.0 mg/kg), then given 0.1 mg/kg MK-801 followed by a 60-min appetitive operant extinction session. Flupenthixol produced a dose-dependent decrease in MK-801-induced bar pressing behavior and locomotor activity and a dose-dependent increase in IL pERK1/2 labeling. Aripiprazole produced a U-shaped dose-response curve on MK-801-induced bar pressing behavior, a dose-dependent decrease in locomotor activity but no changes in IL pERK1/2 labeling. The attenuation of the MK-801-induced behavioral (bar pressing, locomotion) profile by Flupenthixol indicates a clear dopaminergic contribution to this behavior. The behavioral effect of aripiprazole may be due to its a) binding to presynaptic dopamine receptors at the midrange dose decreasing dopamine output and b) binding to postsynaptic dopamine receptors at the higher dose increasing dopamine tone. While both classes of antipsychotics can normalize perseverative behavioral symptoms, the underlying prefrontal cortical dysregulation seems to persist.
 ...
PMID:Attenuation of MK-801-induced behavioral perseveration by typical and atypical antipsychotic pretreatment in rats. 2605 91

Perseveration is a core symptom of schizophrenia, the cause, however, is unknown. It has been shown that for people with frontal lobe lesions, perseveration can be explained with a set-maintenance problem. Perseveration in Parkinson's disease can be explained with problems shifting from one set to another without cues (set-shifting). These disorders can be distinguished using a two-choice task and the Wisconsin Card Sorting Test, that is analysed in phases. Analogs of these tests can be used in animal research. By adding an animal part to the human research, more insight can be gained into the role of specific brain areas in set-maintenance and set-shifting.
...
PMID:Perseveration in schizophrenic patients: a neuropsychological approach for research. 2697 82

Research with patients suffering from Parkinson's disease and frontal lobe lesions has shown that disturbances in the fronto-striatal loops in the brain can cause perseveration. Perseveration is a core symptom of schizophrenia, yet the cause is not known. For schizophrenic patients disorders of many parts of the fronto-striatal loops are found, for example disturbances of the prefrontal cortex and the striatum. Perseveration in schizophrenia can be explained with set-maintenance problems, related to dysfunction of the prefrontal cortex, or with set-shifting problems that are related to disorders in the striatum. These set-maintenance and set-shifting problems can be distinguished with neuropsychological tests. Regarding the bloodflow patterns for the different subtypes of schizophrenia three problems are expected as explanations for perseveration: set-maintenance problems concerning abstract information, set-maintenance problems shifting between stimuli and enhanced set-shifting with cues.
...
PMID:Set-maintenance and set-shifting problems in schizophrenic subtypes: relationship to dysfunctions of the fronto-striatal loops. 2697 83

Formal thought disorder (FTD) is one of the fundamental symptom clusters of schizophrenia and it was found to be the strongest predictor determining conversion from first-episode acute transient psychotic disorder to schizophrenia. Our goal in the present study was to compare a first-episode psychosis (FEP) sample to a healthy control group in relation to subtypes of FTD. Fifty six patients aged between 15 and 45years with FEP and forty five control subjects were included in the study. All the patients were under medication for less than six weeks or drug-naive. FTD was assessed using the Thought and Language Index (TLI), which is composed of impoverishment of thought and disorganization of thought subscales. FEP patients showed significantly higher scores on the items of poverty of speech, weakening of goal, perseveration, looseness, peculiar word use, peculiar sentence construction and peculiar logic compared to controls. Poverty of speech, perseveration and peculiar word use were the significant factors differentiating FEP patients from controls when controlling for years of education, family history of psychosis and drug abuse.
 ...
PMID:Formal thought disorder in first-episode psychosis. 2756 75


<< Previous 1 2 3 4 5 6 7 8 Next >>