Princeton University Library Catalog
- Metzger, Julia Winslow [Browse]
- Senior thesis
- Wang, Samuel S. [Browse]
- Princeton University. Department of Molecular Biology [Browse]
- Class year:
- 93 pages
- Summary note:
- Specific cerebellar lobules form reciprocal loops with neocortical regions associated with
executive functions, yet the functional significance of these connections has not yet been
explored. Perinatal cerebellar disruption is associated with later cognitive deficit and autism
spectrum disorder, suggesting that during postnatal life, the cerebellum may influence social
and cognitive development. Interruption of this process has been termed “developmental
diaschisis.” Here I report that pharmacogenetic disruption of cerebellar activity
can lead to cognitive and social impairments that depend on the age and location of inactivation.
Inactivation was accomplished using Designer Receptors Exclusively Activated
by Designer Drugs (DREADDs) via lobule-specific injections of construct AAV8-hSynh-M4D(
Gi)-mCherry. DREADD agonist clozapine-N-oxide (CNO) was either administered
orally from P30 through P56 and then withdrawn for testing (the developmental condition)
or administered via intraperitoneal injection at the time of testing (the acute adult condition).
In both cases, adult mice were tested in learning ability, perseveration, sociability,
exploratory behavior, and anxiety tasks. To analyze the data, we used Principal Component
Analysis to define behavioral modes that combined multiple parameters of learning
and behavior. Developmental inactivation of Crus II reduced exploratory and social behavior,
and developmental inactivation of Crus I caused reduced social interaction, impaired
learning ability, and repetitive behavior. These effects were specific to the developmental
condition, and were not found when Crus I and II were perturbed acutely in adult mice.
Developmental and adult disruption of Lobules VI and VII had complex, age-dependent
effects on learning and reversal in the Ymaze assay and anxiety in the Elevated Plus Maze,
suggesting that these lobules continue to moderate cognitive behaviors in adulthood. This
study provides direct evidence for the developmental diaschisis hypothesis of cerebellar
contribution to cognitive and social function.