Effects Of Early Chronic Mild Stress On Ocular Dominance Plasticity And Visual Perception Learning In Visual Cortex Of Mice

During the early life,the nervous system is gradually developed into a mature,well-functioning system with the stimulation of the environment.This specific time window is called critical period.Adverse childhood experiences affect the structure and function of brain region,resulting in irreversible physical,physiological and psychological consequences in childhood,adolescence and even adulthood.Previous studies have shown that early adverse experiences lead to structural abnormalities or decreased adult neurogenesis in hippocampus,prefrontal cortex,amygdala or other brain regions,both of which may relate to increased susceptibility to mental illness.However,the influence of early adverse experiences on the development of the perceptual cortex(such as visual cortex)has rarely been studied.In order to avoid the interference of mental disorders such as depression and anxiety,we established an early chronic mild stress(ECMS)model in C57BL/6 mice,and studied the response characteristics and visual plasticity of visual cortex.Corticosterone levels in the serum of ECMS mice were significantly elevated at an early age and returned to normal after adulthood.In addition,adult ECMS mice did not show anxiety-like or depression-like behavior.We used the intrinsic signal optical imaging to measure the visual acuity of the mice at different ages(Early-CP,Peak-CP,Late-CP,Adult).Results manifested that the visual acuity of ECMS mice did not change,confirmed by T-Water Maze test in adulthood.In vivo single-unit electrophysiological recordings exhibited that primary visual cortex neurons in ECMS mice did not alter significantly the orientation and direction selectivity,but did show a preference to lower spatial frequency and higher temporal frequency.We further induced visual plasticity by monocular deprivation.Compared to control mice,ECMS mice had lower plasticity in the early critical phase and higher plasticity in Late-CP.In adult ECMS mice,we observed juvenile plasticity.Interestingly,this phenomenon only occurs in female mice.Fluoxetine treatment did not impair the plasticity in adult ECMS mice,indicating that depression was not involved.Western blot results showed that the expression level of GAD65 protein(GABA synthase)in the visual cortex was not affected by ECMS at all tested ages,but GAD67 protein level was significantly reduced in Early-CP.Diazepam which could increase the cortical GABA inhibition enhanced the ocular dominance plasticity of ECMS mice in Early-CP.Moreover in late development stages(Late-CP and adult),NR2B subunit levels of NMD A receptors were significantly increased in famale mice with ECMS,but back to normol level in adult male ECMS mice.Infusion of Ro 25-6981(NR2B inhibitor)into visual cortex with osmotic minipump could block ECMS-induced juvenile plasticity in adult female mice.These results indicated that ECMS reduced inhibition levels and plasticity in early development stages,however it might delay the closure of critical period through the NR2B pathway in late development stages.The CRH signaling pathway is a crucial part of the stress system.We found that CRH neurons are widely distributed in visual cortex.Most of CRH positive neurons were inhibitory neurons,while few of them were excitatory neurons.Furthermore,CRH neurons colocalized with VIP/SST but not PV neurons.Results of real-time PCR indicated that the expression level of CRH mRNA in the visual cortex was lower in adult ECMS mice than control mice.Visual perceptual learning improves the performance of tasks through repeated learning and training,reflecting the plasticity of visual cortex.We found that ECMS males reached higher visual acuity after visual perceptual learning.Visual perception training itself could suppress the expression of CRH mRNA in visual cortex.Moreover,ECMS and visual perception learning had a superposition effect.The chemogenetic downregulation of the CRH neurons' activity in visual cortex of control mice mimicked the visual perceptual learning curve in ECMS mice.However,increasing the activity of CRH neurons with the same techniques did not evoke significant effects,suggesting that CRH neurons kept active in perceptual learning.Finally,down-regulation of CRH neuronal activity could induce visual plasticity in adult mice.Enhancing the CRH neuronal activity of visual cortex did not reverse the juvenile-like plasticity in ECMS females.Our results indicate that early chronic mild stress has a long-lasting effect on visual development in mice.That is,changing in ocular dominance plasticity of mice caused by abnormalities in excitation/inhibition levels and changing in CRH neuron-dependent visual perception learning.This part of work provided experimental data about the impact of early experience on the perceptual cortex,and a reference for the differences between females and males induced by early stress.