Disorders Of Time Cognition And Research On The Role Of Hippocampal Neurons In Schizophrenia

Aims and methods:Time cognition is an individual's reflection of the continuity and order to objective phenomena,which is a basic function of many creatures and dispensable for their survival.Schizophrenia(SCZ)is a group of severe mental diseases with unknown etiology,involving various functional disorders of perception,thinking,emotion and behavior and coordination disorders of mental activities.However,studies on time cognition in SCZ have been insufficient for a long time.Pathological and pharmacological studies of SCZ suggest that there may be some overlap between the hypothetical pathological circuit of SCZ and the functional circuits required for time cognition.It has been observed that patients with SCZ tend to overestimate the elapsed time interval.However,no direct evidence has been reported to demonstrate that the temporal cognitive impairment in patients with SCZ is a specific one rather than secondary to cognitive disorders of attention,memory and execution.Existing research models of SCZ for time cognition use tasks of time reproduction and interval judgment,in which patients are required to actively participate in the experimental process and it is difficult to exclude the involvement of complex cognitive functions.Therefore,we need to try more targeted behavioral testing to determine the specificity of temporal cognitive impairment in SCZ.Eyeblink conditioning(EBC)is a specific type of associative motor learning.For quite some time,EBC is one of the most detailed and thorough one in all types of learning and memory models(others include fear conditioning),which is characterized by simple and rapid behavior and acquired through implicit learning thus to minimize the involvement of cognitive processes such as motivation and attention during learning.EBC impairments have been found in a variety of neuropsychiatric disorders such as autism,attention deficit hyperactivity disorder and dyslexia.Therefore,using EBC behavior and its variants as the basic model,this study tested the establishment of classic EBC and temporal EBC behavior in patients with SCZ on the basis of time reproduction tasks and tried to analyze whether there is a specific temporal cognitive impairment in timing on the millisecond and second time scale.Phencyclidine(PCP),a nonspecific N-methyl-D-aspartate(NMDA)receptor antagonist,can induce schizophrenia-like symptoms in humans by blocking glutamate NMDA receptors.The SCZ model established by PCP administration has become the most successfully used pharmacological animal model of SCZ.To exclude the interference of excessive confounding factors in the clinical trial of time cognition in SCZ during experiment one,we used PCP to duplicate the SCZ model of non-human primate cynomolgus monkeys and studied the associative motor learning of EBC in cynomolgus monkeys with SCZ and its timing variability.In addition,given that sub-cortical dopaminergic dysfunction is considered as a basic condition for positive symptoms of SCZ,recent studies suggest that increased dopamine function in SCZ may be secondary to the abnormal activity in the hippocampus,a new target for SCZ treatment.Thus,in an attempt to explore the treatment of timing disorders in SCZ and their neural mechanisms,we used PCP to duplicate a rodent(rat)model of SCZ and studied the effects of inhibition of neuronal activity in the hippocampus on associative motor learning and timing function in rat models of SCZ by using optogenetics intervention technique.Results:1.The study on implicit learning behavior of EBC(including delay,trace and temporal EBC)in patients with SCZ as the basic model showed that patients with SCZ had a specific temporal cognitive impairment of timing on both the millisecond and second time scale.2.The study of the SCZ model of non-human primate cynomolgus monkeys established by PCP administration has demonstrated that in cynomolgus monkeys with SCZ,there exist impairment in the acquisition of EBC associative motor learning and in timing of EBC on the millisecond time scale.Our results suggest that under strict control and carefully controlled experimental conditions,the SCZ model of non-human primates also have a specific temporal cognitive impairment on the millisecond time scale.3.Intervention of hippocampal neurons by using optogenetics showed that selective inhibition of hippocampal neurons could alleviate the dysfunction of the associative motor learning and timing behavior in rats with SCZ established by PCP administration.Our overall experimental results show that the temporal cognitive impairment in SCZ is specific and temporal cognitive disorder may play an important role in the pathogenesis of SCZ.The results of this study will help to understand the temporal cognitive impairment in SCZ and its relationship with positive or negative symptoms of SCZ,which is of great significance for understanding the pathogenesis of SCZ.Considering that EBC has the characteristics of basically clear circuit,conservative behavioral evolution,being non-invasive and highly dependent on cerebellar function,the dEBC model should be an effective one for the research on the millisecond timing impairment in SCZ and the temporal model of dEBC could be used as a kind of detection method and practical technology to study the millisecond timing impairment in SCZ and can be used as an important tool to study the impairment of temporal processing in SCZ.The pathogenesis of the SCZ model established by PCP administration is related to the abnormal activity of hippocampal neurons.