Mechanisms On Striatum-associated Decision-making Dysfunction Provoked By Early-life Stress

Background: The adverse stress events and chronic stress that occur in the early stages of life have a life-long impact on cognitive function and have been associated with many neuropsychiatric diseases.During the development stage of rural left-behind children,most of them live in a long-term environment full of unpredictable events and harmful stimulation,that is,the growth environment of chronic early stress,and show psychological and emotional problems as well as memory and cognitive impairment.The dorsal striatum is the largest heterogeneous structure in the brain,which plays an important role in decision-making.At present,how stress in early life affects the development of striatal neurons and associated behavior have not been systematically reported.Objective: To investigate the effects of early-life stress on the differentiation and maturation of dendritic spines as well as excitatory synapses of the striatal neurons,and to test whether the changes of dendritic spines and excitatory synapses are the basis of early-life stress-provoked damage of striatal dependent decision-making.Methods: C57BL/6J mice were assigned to early-life stress and control groups.The early-life stress animal model was created by changing the rearing environment of mice from postnatal day 2(P2)to day 9(P9).The main methods were as follows:(1)After establishing early-life stress animal models,we record the body weight of mice at P2,P9,P21,P56,and P90 five time points.(2)A cohort of mice from each group was sacrificed at P9,P21,and P90 to collect blood(morning time),and the blood was used for the detection of plasma levels of corticosterone via ELISA CORT kit.(3)The brain tissues of mice were harvested at P9,P21,and P90 days for Golgi staining and immunohistochemical experiments to quantitatively analyze the effects of early-stress on the structure and function of dendritic spines and synapses of medium spiny neurons.(4)Behavioral experiments were carried out before P90 to detect the changes of goal-directed behavior,habitual behavior,and emotional state of early-life stressed mice in adulthood.(5)Analyze the relationship between the behavioral changes after early life stress and the structure and function of dendritic spines and synapses of striatal medium spiny neurons.Results:(1)The body weights of mice in early-life stress group decreased significantly on P21,P56,and P90 days when compared with their age-matched controls(P < 0.05,P < 0.01,P < 0.05,respectively).(2)The levels of corticosterone in stressed mice increased significantly at P9 and P21 when compared with age-matched controls(P< 0.05,P < 0.05,respectively).(3)In the early devaluation test,the number of lever pressing decreased significantly in both early-life stress group and control group(P <0.05 for both).In the late devaluation test,the number of pressing levers decreased significantly in the control group(P < 0.05),however,the number did not decrease significantly in the early-life stress group(P > 0.05).Compared with controls,mice in early-life stress group had increased total distance in the open field and distance in the central area(P < 0.01),increased times of crossing the central area and of standing(P <0.01),increased number of feces,increased latency of tail suspension(P < 0.001),but decreased number of grooming(P < 0.001)and decreased immobility time(P < 0.001).In addition,the immobility latency of forced swimming was increased and the immobility time was shortened(P < 0.001).(4)Golgi staining experiment showed that the number of dendrites in the DLS area of stressed mice increased significantly within 100 μ m from the cell body at P9,P21,and P90 compared with their age-matched controls(P < 0.05).The stressed mice also had increased total length of dendritic branches(P < 0.05),but decreased density of dendritic spines(P < 0.05).Conclusion:(1)The weight of mice that experienced stress early in life decreased and continued to adulthood,accompanied by an increase in the level of corticosterone.(2)In the stage of growth and development,environmental changes affect the development of striatal medium spiny neurons,resulting in an increase in dendritic branches,an increase in dendritic length,and a decrease in the density of dendritic spines.(3)This was accompanied by a decrease in the volume of postsynaptic dense zone(PSD-95)and a decrease in the expression of Glu R1 and VGlu T1.(4)At the age of about 2months,individuals who had experienced nociceptive stimulation in childhood had obvious decision-making dysfunction,and tended to habitual behavior,increased emotional sensitivity and increased anxiety level.