The Role And Mechanism Of Orbitofrontal-striatal Circuit Abnormalities In Motor Skill Learning Impairment In Fragile X Syndrome

Background: Motor skill learning is one of the basic functions of the nervous system in animals or humans,and it is included in the learning and execution of motor skills throughout the entire life course of an individual,from birth,development,maturation,and the completion of daily behavioral activities,and at the same time,motor and cognitive-such as vocabulary learning,social-such as the full understanding of emotional expression and other neurological functions are closely interrelated and mutually reinforcing,so as to achieve a series of complex behavioral activities of higher life individuals.In the process of motor skill learning,multiple brain regions are involved and coordinated with each other.The current research on motor skill learning have established the general framework of cortico-basal ganglia-cerebellar network,however,cortical,basal ganglia(BG),and cerebellum as broad,aggregated heterogeneous brain regions are divided,and the connection patterns and coordination relationships bet ween each specific structure and subregion in which they function need to be further explored and clarified.Previous researches on the orbitofrontal cortex(OFC)in mice have demonstrated its breadth and diversity of functions,including emotion,cognitio n,memory,social and behavioral decision-making,while the striatum as both a major structure of the BG and one of the downstream projections of the OFC,the role of the orbitofrontal cortex striatum circuit in motor skill learning needs to be further cla rified.In the classic neurodevelopmental disorder-fragile X syndrome(FXS),motor skill learning deficits are one of its common manifestations,however,the specific loop mechanisms underlying the motor skill learning deficit in FXS are not yet known,and its association with the orbitofrontal-striatal circuit urgently needs to be studied.Objective: This study focuses on FVB WT(wild type)and FVB Fmr1 KO(Fragile X messenger riboprotein 1 knock out)mice as the main research subjects to clarify the characterization of motor skill learning deficits in FXS disease animal models,further reveal the role of OFC in motor skill learning,and explore the relevance and mechanism between the orbitofrontal striatal circuit and FXS motor skill learning disorders.Methods: 1.6-8 weeks old FVB WT and FVB Fmr1 KO mice were selected to test the presence of deficient motor skill learning phenotypes in Fmr1 KO mice by performing movement-related behavioral experiments such as open field,balance beam,and rotating rod;2.Clarification of brain regions associated with motor skill learning by detecting early immediate gene c-Fos expression using immunofluorescence staining,with a focus on OFC;3.Utilizing fiber optic recording and Tetanus Neurotoxin(Te NT)neuron-inhibiting viruses to clarify the role of OFC in motor skill learning;4.Probing whole-brain upstream and downstream connectivity of the OFC by neuronal trac er virus and validating orbitofrontal cortico-striatal neural circuit;5.Using chemical genetic modulation techniques to clarify the role of the orbitofrontal cortico-striatal neural circuit in motor skill learning.Results: 1.The Fmr1 KO mice showed deficits in motor skill learning compared to the WT mice group;2.c-Fos expression is significantly enhanced in OFC brain regions of WT mice after motor skill learning;3.Fiber optic recordings in WT mice show that OFC neurons are significantly activated in motor skill learning behavior,injection of Te NT in the OFC reduce motor skill learning ability in WT mice;4.The neural circuit relationship between OFC and striatum caudate putamen(CPu)was verified by using anterograde and retrograde neuronal tracing virus;5.In WT mice using chemical genetic inhibition(h M4D)virus and Fmr1 KO mice using chemical genetic activation(h M3D)virus to modulate the OFC-CPu neural circuit,respectively,WT mice showed reduced motor skill learning compared to the unmodulated group and Fmr1 KO mice showed enhanced motor skill learning compared to the unmodulated group.Conclusion: The OFC brain region is involved in the motor skill learning process,and the abnormal function of the OFC-CPu neural circuit may be one of the mechanisms underlying the motor skill learning deficit in FXS.