Eletrophysiological Mechanism Underlying Maternal Separation Induced Deficit In Prefrontal Cognitive Function In Mice

Maternal separation(MS)refers to the separation of infants from their mothers after birth and before weaning.Absence or deprivation of maternal care severely affect the developing nervous system of infants and children,which impairs irreversibly brain development,and significantly increases the risk of developing mental illness in adolescence and early adulthood.With the accelerated pace of economic globalization and urbanization,the domestic and international migration of labors has led to the emergence of a large number of left-behind children.In China,left-behind children once accounted for 37%of the rural children population.Worldwide,the number of left-behind children has reached hundreds of millions.Due to the absence of maternal care and love,left-behind children often suffer from inattentiveness,school-grade decline,cowardice,depressed-low in emotion,and even the development of mental disorders during adolescence.All these problems suggest the functional abnormalities in the prefrontal cortex(PFC).The previous study in our laboratory showed that MS impairs PFC-dependent cognitive functions and myelination of the medial PFC(m PFC)in rats(Yang et al.Cerebral Cortex,2017),and significantly reduces dendritic spines of pyramidal neuron(PN)in layer 5(L5)of the m PFC.These results suggest that MS causes long-term and even life-long negative effects on the morphological structure of the m PFC and the cognitive behaviors mediated by the m PFC.However,it remains largely unknown how MS affects m PFC functions at electrophysiological level.The present thesis work used adolescent mice that had undergone MS experience after birth as research subject.Experiments were carried out using whole-cell patch clamp to examine synaptic transmission,suprathreshold excitability and subthreshold electrical activity on L5 PN in m PFC.The results showed that MS enhanced synaptic inhibition,increased SK(Small-conductance,calcium-activated potassium)channel currents and reduced suprathreshold excitability in L5 PN,and consistently,MS enhanced HCN(Hyperpolarization-activated cyclic nucleotide-gated)channel I_h(Hyperpolarization-activated)currents and reduced subthreshold membrane potential oscillation(MPO)in L5 PN,suggesting that an increase in SK and HCN channel currents underlies the diminished intrinsic excitability in L5 PN.In accordance,MS mice exhibited impaired working memory,increased anxiety-and depression-like behaviors,and showed diminished social competitiveness as well.The present work reveals for the first time the negative effects of MS on the intrinsic excitability of prefrontal projection neurons,demonstrates that MS causes prefrontal damage and de-inhibition of projections in adolescent mice,and provides important evidence for a comprehensive in-depth dissection of the damaging effects of maternal-infant separation on prefrontal cortex function.Given that SK and HCN channels changed in the same direction upon MS,and both channels are the co-targets of same psychotropic drugs,the present study provides potential targets of drug development for psychiatric disorders caused by early negative experiences such as MS.According to the statistics of United Nations Educational,Scientific and Cultural Organization,the Corona Virus Disease 2019(COVID-19)epidemic has caused 146 countries to suspend school,and the number of students influenced has reached 1.5 billion.Similar to Severe Acute Respiratory Syndrome(SARS),the COVID-19 outbreak and persistence also had a profound impact on the central nervous system and emotional health of social groups.How the sudden outbreak of COVID-19 affected the emotion of college students remains unknown.Chapter 2 of this study aimed to explore the influence of the beginning of the COVID-19 outbreak on the emotional state of college students.We conducted a survey among 3,092 Chinese college students who were quarantined at home as a result of the COVID-19 pandemic.The survey tools included the Generalized Anxiety Disorder 7-Item Scale(GAD-7),the Perceived Stress Scale(PSS-10),and the Self-Rating Scale of Sleep(SRSS).Of all the respondents,the prevalence of anxiety symptoms,sleep problems,any of the two,and both of the two,were 16.8,13.5,25.1,and 5.3%,respectively.During the COVID-19 outbreak,the prevalence of anxiety symptoms,and sleep problems among college students was high,as well as they experienced higher perceived stress.The persistence of COVID-19 has led to great changes in the epidemic itself,the economy,families,and social life.Nonetheless,it is still unclear how the continuing epidemic and changes in social factors influence the emotional state and related factors of college students.This study investigated anxiety,depression,and post-traumatic stress disorder(PTSD)symptoms among college students during COVID-19 persistence.The questionnaire included GAD-7,Patient Health Questionnaire-9(PHQ-9),and Impact of Event Scale(IES-R).Of 4754 participants,25.0%,29.7%,3.4%,15.3%,17.1%,and 2.9% reported anxiety,depression,PTSD symptoms,anyone,any two,and all three,respectively.Gender,household economic level,and family relationships exerted a significant influence on the occurrence of mood disorders during the COVID-19 persistence.In this study,it was found that COVID-19 outbreaks and persistence can affect the central nervous system of college students,leading to emotional problems such as anxiety,depression,and PTSD.As college students are the mainstay of social development,emotional screening and interventions for them should be given adequate attention and continued implementation as COVID-19 evolves.Our study provides a theoretical foundation for targeted solutions to the emotional problems of college students due to the COVID-19 epidemic.