Developmental Delay Of Ocular Dominance Plasticity After Early Adverse Experiences And Reactivation Of Ocular Dominance Plasticity During Adulthood In Mouse

Development of the nervous system refers to the processes that generate,shape,and reshape the nervous system of animals,from the earliest stages of embryogenesis to adulthood.Experience-dependent plasticity is an important research area related to visual system development.Ocular dominance plasticity(ODP)is a classical model to study experience-dependent plasticity.In early stage of development called critical period,brief monocular deprivation can cause significant ocular dominance shift.This kind of plasticity declines quickly during late postnatal development,leaves adult amblyopia incurable.Therefore,it is important to study the mechanisms underlying the onset and closure of the critical period and to explore how to restore ODP in adult animals.This thesis explores the effect of two early adverse experience models:early maternal separation and early chronic mild stress(ECMS),on the onset and closure of the critical period of ODP,and studies the restoration of adult visual plasticity through pharmacological approaches.The first part of the thesis focuses on exploring the effects of external environment on ODP in the developing mouse visual cortex.Early life experiences have profound effects on brain development and behavior.In mammals,postnatal mother-infant interaction is an important constitute of early life experiences.Therefore,we use repeated maternal separation(RMS)model in our study.We found that in female mice,but not in male mice,early RMS of 1 hr/day from P2-8 delayed the onset of ODP critical period.In both male and female mice,early RMS prevented the closure of ODP critical period,but only female adult mice showed juvenile-like ODP after early RMS.We use intrinsic signal optical imaging to measure the visual acuity at different ages.No significant differences were found in visual acuity between early RMS mice and control mice at any age.The visual water task for visual acuity assessment in adult mice demonstrates consistent results.These results suggest that RMS has no significant effects on other aspects of visual system development.Prior research shows that early RMS possibly induces changes in HPA axis and monoamine system,along with depression-like and/or anxiety-like behavior in rat.We use sucrose preference test to measure the depression-like behavior,open field and elevated plus-maze test for anxiety-like behavior in mice.Early RMS in our model did not induce depression-or anxiety-like behavior in mice.Preliminary exploration of the underlying mechanisms excludes the changes of glutamic acid decarboxylase(GAD)65 and N-methyl-Daspartate receptor subtype 2B(NR2B)expression level.Besides RMS,we used another model of early adverse experiences:ECMS.One hour/day(P2-8)of unpredictable stress stimuli(including tilting of the cage,keeping lights on for a short period of the time during the dark phase,etc.)were given to the mice.Both male and female mice subjected to this stress model showed delayed onset and closure of ODP critical periods,and only female mice exhibited juvenile-like ODP in adulthood.Meanwhile,ECMS induced a reduction in the expression of corticotropinreleasing factor(CRF)mRNA in adult mouse V1.Further studies reveal that CRFCRFR1 signaling pathway in the visual cortex mediates this sex-specific effect.Wholecell recordings show that CRFR1 antagonists and agonists can sex-specifically attenuate and enhance short-term inhibition of inhibitory postsynaptic current(IPSCs)in female mouse visual cortex layer II/III,respectively,which indicates that the CRFCRFR1 pathway can enhance GABA release probability in female mouse visual cortex.Our findings enhance the knowledge in the effects of early RMS on neural system development,and moreover,provide inspiration to the mechanism of the activation and decline of the critical period.Restoration of ODP in adult visual cortex is another important research topic related to ODP.The decline of ODP in adult is due to the maturation of inhibition system according to the mainstream view.In previous studies,reactivating ODP in adult visual cortex by environmental enrichment or through some pharmacological methods is accompanied with reduced inhibitory level and increased BDNF expression level.To explore how brain derived neurotrophic factor(BDNF)/TrkB pathway participates in plasticity of adult mouse visual cortex,we use a TrkB agonist 7,8-DHF,which can pass blood-brain barrier,to pharmacologically activate TrkB.Our research suggests that 7,8DHF can not only reactivate juvenile-like ODP in adult mice,but also promote the function recovery of visual cortex in adult amblyopia mice.These findings provide possible noninvasive treatment for amblyopia without disturbance in binocular vision.Additionally,our study in ALK5 Inhibitor II,an inhibitor of transforming growth factorβ type Ⅰ receptor ALK5,shows systemic administration of ALK5 Inhibitor II can restore juvenile-like ocular dominance plasticity in adult mouse visual cortex too.This phenomenon was accompanied by a significant decrease of GAD67 protein expression in visual cortex,and can be blocked by GABAA receptor agonist DZ,which suggests that the ODP induced by ALK5 Inhibitor Ⅱ at least partially depends on changes in inhibitory neural transmission.In summary,this study used environmental modulation and pharmacological approach to regulate ODP in mouse visual cortex at different developmental stages.The results reveal for the first time that the long-term effects of early adverse experiences on ODP in the visual cortex,and that the effect in the two models is modulated by different mechanisms.This study provides a new animal model for future research on the effects of early adverse experiences on the development of the visual system.The study of restoration of ODP in adult animals provides new insights into the mechanisms of adult visual cortex plasticity and provides potential treatments for adult amblyopia.