Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Susanne Schmid

Abstract

At every moment, our brain is bombarded with sensory information. How we filter and process sensory information is critical for daily functioning and cognition. Examples of sensory filtering include habituation (a progressive decrease in responding) and prepulse inhibition (PPI, gating of responding). Our aim is to understand the differential role acetylcholine (ACh) plays in these processes.

To study this we used both reflexive (acoustic startle response: ASR) and non-reflexive (locomotor) behaviours. PPI is hypothesized to occur via inhibitory cholinergic projections from the Pedunculopontine Tegmental Nucleus (PPT) to the startle pathway. The role of ACh in habituation of reflexive and non-reflexive behaviours is controversial. We found that, contrary to the predictions of the field, ACh modulated, not mediated, PPI. There was no impairment of PPI in cholinergic deficient mice. When we inhibited PPT cholinergic neurons using DREADDs we did not detect an impairment of PPI. Likewise, we were unable to induce PPI by optogenetic activation of these neurons.

Instead we found that cholinergic function is critical for long-term habituation (decrement occurring across days) as cholinergic deficient mice showed an impairment which was rescued by galantamine. Furthermore, inhibition of PPT cholinergic cells decreased startle magnitude, whereas optogenetic activation of cholinergic PPT neurons increased startle. This demonstrates that these neurons are critical for regulating startle reactivity. Despite modulating reflexive behaviours, PPT cholinergic inhibition did not impact habituation of locomotion, re-affirming differential regulation of habituation of reflexive and non-reflexive behaviours.

To uncover which cholinergic receptor type mediates effects on PPI and habituation we used an α7-nicotinic acetylcholine receptor (nAChR) knock-out mouse. These mice displayed a mild impairment of PPI, and no enhancement of startle magnitude or PPI via nicotine. This suggests ACh modulates PPI through this receptor, and confirms that cholinergic function enhances startle. Of interest, optogenetic enhancement of startle was blocked by nAChR antagonism.

In conclusion, we demonstrate that ACh modulates PPI through α7-nAChRs and that ACh is critical for regulating startle reactivity, indicating a potential role in long-term habituation or sensitization of startle. In contrast to the common view, cholinergic PPT function does not inhibit startle, ruling out a mechanistic role in PPI.

Available for download on Saturday, October 27, 2018

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