Nature Sub-journal: Cerebellum destroys cortex "family harmony" causing autism disorders.

The cerebellum accounts for 80% of the neurons in the human brain, including five types of neurons: granulosa cells, Purkinje cells, Golgi cells, astrocytes and basket cells, but their volume accounts for only 10% of the total human brain.it has been thought that the cerebellum mainly controls motor functions, but with the deepening of research, there are more and more new cerebellar functions, one of which is autism.there is cerebellar dysfunction in autism disorder - specific knockout of TSC1 on cerebellar Purkinje cells (PC) causes autism like social disorder and stereotyped repetitive behavior.inhibition of Purkinje cell activity in the cerebellum right crus 1 (rcrus1) region resulted in autism like behavior disorder, and activation of Purkinje cells in rcrus1 region could alleviate autism like behavior induced by TSC1 knockout (1).in addition, significant changes in the functional connectivity of the cerebellar prefrontal cortex in autistic patients suggest that the neural circuits between the two brain regions may be involved in autism.on July 13, 2020, the research team of Professor Peter T. Tsai of Southwest Medical Center of University of Texas published an article in the journal Nature Neuroscience, and found that there is an inhibitory neural loop in cerebellum and prefrontal cortex to regulate autistic like behavior (2).through electrophysiological experiments, the researchers found that the firing frequency of neurons in the left mPFC brain area of TSC1 knockout mice was increased. In addition, the discharge frequency of neurons in the left mPFC brain area was also significantly increased after chemical genetics chronic inhibition of Purkinje cells in the rcrus1 region, indicating that neurons in the mPFC brain area were hyperactivated in the autism model mice, and there may be rcrus1 region mPFC brain area Functional connectivity is impaired.can inhibition of mPFC activity improve the autistic behavior of TSC1 knockout mice? They used chemical genetics to chronically inhibit neuronal activity in the mPFC brain region, which alleviated the social disorder and repetitive stereotyped behavior of TSC1 knockout mice, and improved the spatial memory ability of mice.in order to further confirm the functional connectivity of rcrus1 mPFC in mice, researchers injected CRE enzyme dependent inhibitory chemical genetic virus into rcrus1 of PC CRE mice, which could specifically inhibit the neuronal activity of Purkinje cells in this brain area. Subsequently, electrophysiological experiments showed that the firing frequency of neurons in mPFC brain area increased, indicating that there was a strong functional connection in rcrus1 mPFC brain area This connection may be impaired in autism.subsequently, the researchers found that the above-mentioned functional connectivity disorder did exist in 94 strains of autism model mice, and the functional connectivity of these two brain regions was also found in autistic patients.there is no direct neural projection between rcrus1 and mPFC. It is necessary to find out the brain regions that regulate the functional connection between rcrus1 and mPFC. After injecting anterograde virus into the rcrus1 brain region, there were neural projections in the lateral / dentate nucleus (LN) of the cerebellum.therefore, after further inhibition of neuronal activity in the LN brain area, they found that the mPFC brain area could detect a decrease in neuronal discharge activity.is this brain region involved in the regulation of ASD like behavior? The researchers showed that suppression of right LN in TSC1 knockout mice by chemical genetics significantly improved social disorder, suggesting that ln brain regions play a "bridge" role between the two brain regions.based on the above results, is there a neural connection between the right LN and the left mPFC? The researchers injected AAV anterograde tracing virus into the right ln brain region and found fluorescence expression in the downstream thalamus and cortex, and the ventromedial thalamic (VM thalamic) may be the relay station of LN mPFC loop.after the axon of VM thalamic projecting to the mPFC brain area (VM thalamic mPFC neural circuit for short) was activated by photogenetic technology, which led to the increase of neuronal discharge activity in the brain region and the occurrence of social disorder and repetitive stereotyped behavior in mice.however, the VM thalamic mPFC neural circuit in TSC1 knockout mice was significantly improved by photoinhibition.the hypothesis of excitability / inhibition balance is an important theory in the pathogenesis of autism (3). the cerebellum is mainly composed of inhibitory Purkinje cells, which makes the cerebellum the main source of inhibition. in general, this study revealed that the dysfunction of cerebellar Purkinje cells exerted a de inhibitory effect on the mPFC brain region, which caused the neurons in this brain area to become hyperactive, and a neural loop was found to regulate this de inhibition effect. References: 1. Tsai, P. T. et al. Aesthetic like behavior and cerebellar dysfunction in Purkinje cell TSC1 mutant Mie. Nature 488, 647 – 651 (2012). 2. Regulation of audit related behaviors by cerebellar – anterior continental circuits, J. L. & amp; Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).