Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Ossenkopp, Klaus-Peter

Affiliation

Western University

2nd Supervisor

Kavaliers, Martin

Affiliation

Western University, University of Guelph

Co-Supervisor

Abstract

Anticipatory nausea is a classically conditioned response to cues previously associated with a nauseating stimulus. In rodents, this can be modelled by pairing the novel cue of a context with the toxic effects of lithium chloride (LiCl). This leads to conditioned disgust responses (indicative of anticipatory nausea, e.g. gaping) when exposed to the context alone. Selective immune activation using the endotoxin lipopolysaccharide (LPS) has emerged as a reliable way to attenuate anticipatory nausea prior to acquisition. However, there are gaps in our understanding of the effects of LPS during other memory stages known to be critical within the LiCl-induced anticipatory nausea paradigm. While expanding the rodent model of LiCl-induced anticipatory nausea, the current thesis aimed to investigate the role of LPS in attenuating these responses across consolidation and extinction. Upon reproducing the ability of LPS to attenuate LiCl-induced anticipatory nausea prior to acquisition, LPS was found to attenuate the consolidation of these behaviours when administered immediately after conditioning, and 24 h later, but not 72 h later within Chapters 2 and 3. These results suggest that specific memory stages are necessary to target for immune activation to attenuate anticipatory nausea. Although prior exposure to LPS did not significantly affect extinction, Chapters 2 and 3 established the extinction of LiCl-induced anticipatory nausea. Further, Chapter 3 demonstrated that LiCl-induced anticipatory nausea can be learned after long inter-trial intervals. These findings align with toxin-induced anticipatory nausea in humans and add to the validity of the current rodent model. In Chapter 4, second-order conditioning was established between an aversive context and a taste cue using the anticipatory nausea paradigm. Avoidance of the taste cue was examined in the two-bottle preference task. LPS attenuated conditioned disgust within the anticipatory nausea context but did not alter avoidance behaviours in the two-bottle task. The experiments presented in the thesis strengthen the rodent model of anticipatory nausea. Moreover, this thesis begins to provide an understanding of the mechanisms underlying LPS-induced anticipatory nausea attenuation by establishing the boundaries of the effects of LPS on these responses.

Summary for Lay Audience

Forgetting, such as walking into a room and not remembering why, is typically frustrating. However, forgetting serves a vital function when it can reduce an unpleasant emotion.

An example of such an unpleasant emotion is disgust. Disgust can be understood in terms of chemotherapy-induced conditioned disgust, or anticipatory nausea. Chemotherapy-induced anticipatory nausea occurs when an environment (such as a hospital or clinic), in which someone undergoes chemotherapy, becomes associated with the nauseating side effects of chemotherapy. Due to this learned association, individuals re-entering the hospital or clinic often feel nauseous as soon as they step foot into this environment. With current antinausea drugs doing little to treat it, anticipatory nausea is recognized as one of the most distressing side effects of chemotherapy and is one of the primary reasons why treatable patients choose to drop out of this lifesaving intervention.

Animal models are helping us make strides in understanding anticipatory nausea. However, many gaps remain to be bridged between the experience of this sensation in humans and current models. This includes demonstrating the development of anticipatory nausea after long periods of time and its fading over time. I was able to fill these gaps and create a more well-rounded and reliable model of anticipatory nausea, which can be used to further our understanding and potentially uncover new ways in which it can be reduced.

Activating the immune system through viral (e.g. COVID-19) or bacterial (e.g. E. coli) infections leads to memory impairments. This led me to the examination of whether or not immune activation can alter anticipatory nausea. Although immune activation reduced this type of nausea, I found that specific stages of memory are necessary to target for this effect. I then wanted to understand how immune activation may aid in the “forgetting” of anticipatory nausea. By modifying the animal model, I found that LPS may be targeting brain regions which can hinder the ability to retrieve anticipatory nausea-related memories within the environment it was learned.

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Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

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