Normal cognitive and social development require posterior cerebellar activity

23.09.2021 12:38
avatar  Alex84
#1 Normal cognitive and social development require posterior cerebellar activity

Normal cognitive and social development require posterior cerebellar activity

Human capacities for cognition and flexible behavior unfold rapidly in the first six years of life. During this period, subcortical processing helps refine connections in the developing forebrain (Knudsen, 2004; Wang et al., 2014; Wiesel, 1982). Even though the cerebellum is best known as a structure that guides movement and action (Dean et al., 2010), it is also likely to regulate cognitive and emotional processing (Reeber et al., 2013; Snow et al., 2014), a role that may extend to early development. Cerebellar projections to and from the forebrain are extensive (Figure 1A; Altman and Bayer, 1997; Buckner et al., 2011; Diamond, 2000; Sokolov et al., 2017; Wang et al., 2014) and are present in early life (Altman and Bayer, 1997; Buckner et al., 2011; Diamond, 2000; Sokolov et al., 2017; Wang et al., 2014). The cerebellum communicates with midbrain and neocortical targets (Strick et al., 2009), providing a means for guiding the brainwide maturation of flexible and social behaviors.

Our findings show that the cerebellum exerts substantial influence over the development of social and flexible behavior. These results could be explained if the cerebellum plays a preprocessing role that, over time, guides the long-term maturation of novelty-seeking and flexible cognition. Cerebellar function and structure are aberrant in the majority of people with autism (Wang et al., 2014), a disorder that arises in the first few years of life (Courchesne et al., 1988; Kates et al., 2004; Schumann and Nordahl, 2011; Wang et al., 2014). We perturbed in the second month of rodent postnatal life, which approximately corresponds to the first several years of human life as defined by neocortical growth and plasticity (Bayer et al., 1993; Liscovitch and Chechik, 2013). Many autism susceptibility genes are coexpressed in the cerebellum during postnatal development (Menashe et al., 2013; Wang et al., 2014; Willsey et al., 2013) and are required for the normal expression of cerebellum-dependent associative learning (Kloth et al., 2015). Our chemogenetic approach provides a means of disrupting cerebellar circuit function independent of specific genes, thereby allowing relatively direct perturbation of activity as well as the exploration of specific sites within the cerebellum.

How might the cerebellum provide guidance to behavioral development? The cerebellum’s circuit architecture allows it to carry out certain types of information processing with exceptionally high computational power. Over half of the mammalian brain’s neurons are cerebellar granule cells. Granule cells provide a wide range of efference, sensory, and other signals (Giovannucci et al., 2017; Huang et al., 2013; Wagner et al., 2017) for use in driving Purkinje cell output, which in turn guides action on subsecond time scales. The cerebellum may provide continual feedback to shape nonmotor function, while simultaneously receiving both external information and the brain’s own efforts to control behavior (Wolpert et al., 1998).

In rodents, juvenile life is a period of behavioral maturation (Spear, 2000) and neocortical dendritic spine plasticity (Alvarez and Sabatini, 2007). Our experiments have identified juvenile life as a period when disruption of cerebellar output is sufficient to alter the adult expression of cognitive and social capacities. Further experiments are necessary to determine the minimum effective duration of cerebellar disruption, to test whether vulnerability is restricted to specific developmental time periods, and to determine if the long-term behavioral consequences are accompanied by functional or structural alterations in distal brain structures.

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