Thesis Format
Monograph
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Schmid, Susanne
2nd Supervisor
Allman, Brian L.
Co-Supervisor
Abstract
Rats with a loss-of-function mutation in the contactin-associated protein-like 2 (Cntnap2) gene have increased acoustic startle responses, which parallels acoustic hyperreactivity in CNTNAP2-associated disorders (e.g., in autism spectrum disorder). Although the neural circuit for the acoustic startle response is well-characterized, the neural basis underlying hyperreactivity to sound in CNTNAP2-associated disorders is currently unknown. This thesis investigates various elements along the startle pathway that may contribute to increased acoustic startle in Cntnap2 knock-out rats, with a focus on the caudal pontine reticular nucleus (PnC). In vivo electrophysiological recordings showed that female Cntnap2 knock-out rats have increased multiunit firing rates in the PnC compared with female wildtypes, but male Cntnap2 knock-out rats showed either a modest increase or no difference compared with male wildtypes. This did not fully align with the behavioural findings of both female and male Cntnap2 knock-out rats having significantly increased acoustic startle magnitudes compared with their wildtype counterparts. Therefore, a factor other than PnC firing rates likely contributes to increased startle in male Cntnap2 knock-out rats. Next, immunohistochemical approaches were used to analyze PnC giant neurons, showing that there was increased activation of PnC giant neurons in Cntnap2 knock-out rats after exposure to startle sounds compared with wildtype rats. Additionally, male rats had increased activation of PnC giant neurons compared with female rats. Considering the increased firing rates and increased giant neuron recruitment in the PnC of Cntnap2 knock-out rats, the presynaptic cochlear root neurons (CRNs), the neural substrate upstream of the PnC in the startle circuit, were examined using immunohistochemical approaches. Cntnap2 knock-out rats showed increased activation of CRNs compared with wildtype rats, and CRN activation was correlated with PnC giant neuron activation. Overall, this work shows that loss of function of the Cntnap2 gene results in increased activity of the PnC and CRNs in rats, contributing to increased acoustic startle response magnitudes.
Summary for Lay Audience
The acoustic startle response is an involuntary reaction to loud, sudden sounds. Rats with a mutation in the contactin-associated protein-like 2 (Cntnap2) gene (Cntnap2 knock-out rats) have been shown to have increased acoustic startle responses, indicating that they are hyperreactive to sound. In humans, mutations in the CNTNAP2 gene are associated with various neurological disorders that are often comorbid with hyperreactivity to sound, such as in autism spectrum disorder. The changes in the brain that cause this acoustic hyperreactivity are currently unknown. The caudal pontine reticular nucleus (PnC) is a region in the brainstem that contains neurons that are important for mediating the acoustic startle response. In this thesis, various metrics of the PnC were examined in Cntnap2 knock-out rats. We found that PnC neurons had increased firing rates in response to startle sounds and that a greater percentage of startle-mediating neurons were activated by startle sounds in Cntnap2 knock-out rats compared with rats that did not have a mutation in the Cntnap2 gene. Thus, increased PnC activity contributes to increased acoustic startle response magnitudes in Cntnap2 knock-out rats. These findings prompted us to examine the neurons that precede PnC startle-mediating neurons in the acoustic startle neural pathway, which are the cochlear root neurons. We found that greater percentages of cochlear root neurons were also activated by startle sounds in Cntnap2 knock-out rats, which would contribute to the observed increase in PnC activity. Overall, this thesis provides insight as to why Cntnap2 knock-out rats have increased acoustic startle response magnitudes, which contributes to a better understanding of acoustic hyperreactivity in CNTNAP2-associated disorders in humans.
Recommended Citation
Zheng, Alice, "The Neural Basis of Altered Acoustic Processing in Cntnap2 Knock-out Rats" (2024). Electronic Thesis and Dissertation Repository. 10242.
https://ir.lib.uwo.ca/etd/10242
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