Establishment of an Animal Model of Depression: The Serotonin Transporter Knockout Rat

<p>Major depressive disorder (MDD) is a serious and debilitating psychiatric illness found of increasing prevalence. Despite this, our current first line treatments have been shown to lack efficacy and possess a high non-response rate. Most new pharmacological developments have not shown efficacy in humans, likely due to our current models being outdated. This thesis attempts to use a range of novel approaches, integrating behavioural, physiological, and biological methods to provide support for the use of the serotonin transporter knockout (SERT-KO) rat to model components of MDD in humans. Social anhedonia is assessed through conditioned place preference and play behaviour analysis, demonstrating significantly reduced reward sensitivity in SERT-/- animals. Comorbid anxiety is assessed using a modified successive alleys test, whereby SERT-/- animals demonstrate increased anxiety behaviour, which persist over the course of the experiment. The assessment of heart rate variability, a physiological correlate of MDD was impacted by time constraints, however suggests a likely reduction to be present in the SERT-/- animals. Finally, neurogenesis was found to be significantly increased in SERT-/- animals during early development (PND7), demonstrating neurodevelopmental alterations associated with reduced SERT expression. These data demonstrate that the SERT knockout rat possesses many deficits associated with MDD, thus being a likely candidate for novel pharmacological development. A final pilot experiment was conducted using MALDI-TOF to provide a method of examining potentially thousands of compounds in brain and cardiac tissue with high spatial definition. Applications and implication of this research are discussed in detail with suggestions for future studies being presented.</p>

Establishment of an Animal Model of Depression: The Serotonin Transporter Knockout Rat

<p>Major depressive disorder (MDD) is a serious and debilitating psychiatric illness found of increasing prevalence. Despite this, our current first line treatments have been shown to lack efficacy and possess a high non-response rate. Most new pharmacological developments have not shown efficacy in humans, likely due to our current models being outdated. This thesis attempts to use a range of novel approaches, integrating behavioural, physiological, and biological methods to provide support for the use of the serotonin transporter knockout (SERT-KO) rat to model components of MDD in humans. Social anhedonia is assessed through conditioned place preference and play behaviour analysis, demonstrating significantly reduced reward sensitivity in SERT-/- animals. Comorbid anxiety is assessed using a modified successive alleys test, whereby SERT-/- animals demonstrate increased anxiety behaviour, which persist over the course of the experiment. The assessment of heart rate variability, a physiological correlate of MDD was impacted by time constraints, however suggests a likely reduction to be present in the SERT-/- animals. Finally, neurogenesis was found to be significantly increased in SERT-/- animals during early development (PND7), demonstrating neurodevelopmental alterations associated with reduced SERT expression. These data demonstrate that the SERT knockout rat possesses many deficits associated with MDD, thus being a likely candidate for novel pharmacological development. A final pilot experiment was conducted using MALDI-TOF to provide a method of examining potentially thousands of compounds in brain and cardiac tissue with high spatial definition. Applications and implication of this research are discussed in detail with suggestions for future studies being presented.</p>

An implicit representation of stimulus ambiguity in pupil size

To guide behavior, perceptual systems must operate on intrinsically ambiguous sensory input. Observers are usually able to acknowledge the uncertainty of their perception, but in some cases, they critically fail to do so. Here, we show that a physiological correlate of ambiguity can be found in pupil dilation even when the observer is not aware of such ambiguity. We used a well-known auditory ambiguous stimulus, known as the tritone paradox, which can induce the perception of an upward or downward pitch shift within the same individual. In two experiments, behavioral responses showed that listeners could not explicitly access the ambiguity in this stimulus, even though their responses varied from trial to trial. However, pupil dilation was larger for the more ambiguous cases. The ambiguity of the stimulus for each listener was indexed by the entropy of behavioral responses, and this entropy was also a significant predictor of pupil size. In particular, entropy explained additional variation in pupil size independent of the explicit judgment of confidence in the specific situation that we investigated, in which the two measures were decoupled. Our data thus suggest that stimulus ambiguity is implicitly represented in the brain even without explicit awareness of this ambiguity.

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Auditory Brainstem Responses to Successive Sounds: Effects of Gap Duration and Depth

Temporal acuity is the ability to differentiate between sounds based on fluctuations in the waveform envelope. The proximity of successive sounds and background noise diminishes the ability to track rapid changes between consecutive sounds. We determined whether a physiological correlate of temporal acuity is also affected by these factors. We recorded the auditory brainstem response (ABR) from human listeners using a harmonic complex (S1) followed by a brief tone burst (S2) with the latter serving as the evoking signal. The duration and depth of the silent gap between S1 and S2 were manipulated, and the peak latency and amplitude of wave V were measured. The latency of the responses decreased significantly as the duration or depth of the gap increased. The amplitude of the responses was not affected by the duration or depth of the gap. These findings suggest that changing the physical parameters of the gap affects the auditory system’s ability to encode successive sounds.

Galvanic Skin Response As a Measure of Engagement During Play in Virtual Reality

Competition is a common design strategy used to enhance user engagement and participation. However, it remains unclear how winning or losing might influence player’s engagement. In a recent study, we used behavioral metrics to quantify player engagement during competitive gameplay in virtual reality. To control for players’ status of winning or losing, we programmed a virtual opponent to either under-perform, over-perform, or tie with them. We conducted a series of experiments and found that players’ engagement was higher when they were losing, compared to when they played alone. Nevertheless, players’ engagement did not change during competition with an under-performing or equally-performing opponent. By applying the information-theoretic notion of transfer entropy, we unveiled a causal relationships between relative performance and engagement, whereby players monitored the scores and adapted their behavior accordingly. However, behavioral metrics are not detached from volition and may be influenced by confounding factors. This limitation is addressed by the use of physiological metrics, which offer largely unbiased measurements of cognitive and emotional processes. In the present study, we sought to strengthen our prior findings by measuring engagement with a physiological correlate. We conducted experiments in the same experimental setting and we measured players’ galvanic skin response during competition. We discovered that players’ skin conductance was higher when they were outperformed by their opponent, indicating that they were experiencing less flow. The results inform the design of technology-mediated applications toward sustaining user engagement and participation.

Coordination effort in joint action is reflected in pupil size

Humans often perform visual tasks together, and when doing so, they tend to devise division of labor strategies to share the load. Implementing such strategies, however, is effortful as co-actors need to coordinate their actions. We tested if pupil size – a physiological correlate of mental effort – can detect such a coordination effort in a multiple object tracking task (MOT). Participants performed the MOT task jointly with a computer partner and either devised a division of labor strategy (main experiment) or the labor division was already pre-determined (control experiment). We observed that pupil sizes increase relative to performing the MOT task alone in the main experiment while this is not the case in the control experiment. These findings suggest that pupil size can detect a rise in coordination effort, extending the view that pupil size indexes mental effort across a wide range of cognitively demanding tasks.

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.