ABSTRACT
Social isolation (SI) during childhood increases the susceptibility to neuropsychiatric disorders, including anxiety
disorders, depression, and cognitive impairments. Limited treatment for these disorders highlights the
importance of identifying new therapeutic targets. Recent evidence has underscored the role of the cerebellum
in early-life stress. For example, the neonatal cerebellum contains the highest level of glucocorticoid receptor
(GR) in the entire brain, indicating that the cerebellum is enriched in the molecular machinery for processing the
stress response. The cerebellum is extensively connected to brain networks that are sensitive to psychological
stress. However, whether and how SI stress regulates gene expression in the cerebellum to result in cerebellar
dysfunction and maladaptive behaviors remain elusive. To address the knowledge gap, we isolated experimental
mice in singly housed cages. They displayed behavioral changes reminiscent of high anxiety, depression, and
social memory loss. Moreover, we found that SI impaired intrinsic excitability of Purkinje cells (PCs), the sole
output neurons in the cerebellar cortex. And cerebellar gene expression was highly responsive to stress stimuli
such as an elevation of corticosterone, a stress hormone, in rodents. These findings fuel our central hypothesis
that SI impairs the cerebellar output activity by specifically affecting the intrinsic excitability of PCs; and restoring
PC excitability rectifies SI-caused behavioral deficits via the cerebello-cortical networks. To test the hypothesis,
we propose a multidisciplinary approach with three specific aims: (1) Determine the molecular basis of reduced
PC intrinsic excitability by SI. We will employ two genome-wide RNA sequencing techniques to obtain an
unbiased view of transcriptional signatures and epigenetic modifications of SI as well as to identify SI-responsive
ion channels in PCs, e.g., Kv1.5. PC-specific knockout of GR will uncover the GR-dependent genomic
reprogramming by SI. (2) Define the significance of PC activity in systemic response to SI. Using viral gene
transfer, we will gain precise spatiotemporal control of PC excitability to test the necessity and sufficiency of
cerebellar activity in mediating the system-wide response to SI. (3) Specify the cerebellum-cortex gateways
underlying maladaptive behaviors of SI. Our efforts will be focused on dissecting the neural circuits that connect
the cerebellum to the downstream sub/cortical areas and their contributions to the behavioral phenotypes of SI.
Completion of this work will advance our understanding of the molecular, cellular and circuitry mechanisms
underpinning the non-conventional role of the cerebellum in the stress response, and the results will ultimately
help develop novel therapeutic strategies to improve mental health.