Regulation Of Prefrontal Cortical Working Memory And Risk Decision-Making

Epidermal growth factor receptor 4(ErbB4)is a tyrosine kinase receptor specifically expressed in parvalbumin(PV)positive GABAergic interneurons.The kinase activity of ErbB4 is mediated by binding neuregulin 1(NRG1),which is involved in regulating the presynaptic release of GABA in interneurons.A great many studies have identified the genes of ErbB4 and its legend NRG1 as susceptibility genes for schizophrenia.In mice,abnormal NRG1/ErbB4 signaling disrupts GABA synaptic transmission in the hippocampus and the prefrontal cortex(PFC)and results in severe deficits in learning,memory and cognitive functions,leading to schizophrenia-like behavioral phenotypes.Working memory is an important function executed by the PFC,and disorder of working momery function is a typical manifestation of schizophrenia.In monkeys,pyramidal neurons and interneurons in dorsolateral PFC(dl PFC)maintain spatial working memory: pyramidal neurons with similar spatial tuning characteristics are connected each other to achieve excitation during the delay period,whereas those with different or opposite spatial tuning characteristics maintain their spatial tuning characteristics by inhibiting each other through PV-positive interneurons.An unpublished work in our laboratory reveals that ErbB4 receptor is highly and specifically expressed in PV-positive interneurons in the monkey dl PFC.The present work aims to answer the scientific question: whether and how ErbB4 receptor in dl PFC is involved in regulating spatial working memory,from behavioral and neurophysiological perspectives.In the present study,behavioral pharmacological method was used to determine whether local microinjection of the ErbB4 receptor antagonist AG1478 into the dl PFC affects the performance of the delayed response task(DR)and the level of prepulse inhibition(PPI)in rhesus monkeys.Electrophysiological method was employed to record firing activities of pyramidal neurons in the dl PFC when the monkeys were performing the oculomotor delayed response(ODR)task,and to examine the effect of AG1478 on firing of pyramidal neurons during delay period.The results showed that: 1)correct rate of performance for the DR task was reduced upon blocking the ErbB4 receptors of dl PFC;2)sensory gating was impaired upon ErbB4 receptor blockade;3)directional selectivity in pyramidal cell firing during the delay period was reduced upon ErbB4 receptor blockade,resulting in "generalization" of spatial memory field.These results demonstrate for the first time that ErbB4 receptor in the monkey dl PFC is involved in regulating working memory and sensory gating functions,and plays a key role in maintaining the spatial memory fields of pyramidal cells,suggesting that abnormal NRG1/ErbB4 signaling in PV-positive interneurons in the PFC may be an important mechanism for schizophrenia.The present study provides a new perspective for elucidating the mechanism of ErbB4 receptor in regulating PFC function.Risk decision-making(RDM)is that individuals make choices based on the definite cognition for the probabilities of the options.Risk is embodied in the certainty of reward,and the smaller the probability is,the greater the risk will be.It is important for individuals to evaluate the risk in life to survive in an unpredictable environment.Individuals have different attitudes toward risk in daily life,but most of them tend to take risk,and prefer lager reward but ignore the risk involved.Previous studies have shown that the prefrontal cortex(PFC)plays a key role in RDM.The PFC receives projections of dopamine(DA)system from the ventral tegmental area of the midbrain.Mesocorticolimbic DA system regulates the judgments of reward and value in RDM.However,the specific receptor mechanism for prefrontal DA regulation of RDM behavior remains unclear.Here we established a RDM behavioral paradigm to detect the behavior of rats making decision between a small certain reward and a large uncertain reward.The reward probability and reward amount of risk option were adjusted to observe the change of RDM strategy.The D1 receptor antagonist SCH-23390(5 m M)or agonist SKF-82958(5 m M),and the D2 receptor antagonist thioridazine hydrochloride(5 m M)or agonist MLS-1547(5 m M)was injected into the m PFC,respectively,to investigate how the RDM behavior was changed.The results showed that: 1)Rats were able to master the operation of the RDM task;2)Most rats were inclined to choose risk rather than safe option when the reward expectations were equal;3)Rats were able to adjust the decision strategy in time upon change in risk,suggesting that they have the ability to perceive risk;and 4)risk selection was reduced upon inhibition of D1 receptors or stimulation of D2 receptors,but increased upon stimulation of D1 receptors or inhibition of D2 receptors,suggesting that RDM performance is regulated by D1 and D2 receptors in the m PFC.The present results suggest that DA receptors in the m PFC of rats are involved in regulating RDM behavior,with differential involvement of D1 and D2 receptors in the regulation.