The primary motor cortex (M1) is an important site for learning new motor skills. While rewardis known to both enhance and accelerate motor learning, the mechanism by which reward exertsthese effects remains unclear. Previous studies in primates have demonstrated reward-relatedactivity in M1, however, it is not known whether reward is represented among different neuronalcell types in M1, or if the representations change over the course of reward-based associativelearning. We begin by reviewing advances in optogenetic methods that have enabled thedissection of cortical circuits underlying sensorimotor behaviours with a special focus on thefunctional roles of cell-type specific connections in governing sensorimotor informationprocessing and learning and memory. We then used in vivo, two-photon calcium imaging tocharacterize reward and reward-related responses in pyramidal neurons (PNs), PV-INs, SST-INsand VIP-INs while mice simultaneously performed a head-fixed auditory classical conditioningtask. We found that different cell types had distinct responses to the conditioned stimulus (CS)and to reward, and these responses underwent differential changes over the course of associativelearning. Notably, VIP-INs preferentially represented reward and their reward responsesincreased with learning, while PV-INs preferentially represented the CS, and their CS responsesincreased with learning. Lastly, to identify which brain regions might provide reward-relatedinput to VIP-INs, we performed cell-type specific monosynaptic rabies tracing and generatedcomparative brain-wide maps of input to VIP-INs, PV-INs, SST-INs and PNs in M1. Weidentified preferential input from the orbital frontal cortex (ORB) to VIP-INs compared to theother IN subtypes. These results suggest that ORB may convey reward-related input to VIP-INsand thereby disinhibit local MOP circuitry during reward-based learning. Together, these studiesprovide a potential mechanism for how reward modulates motor learning.

Pavlov (1927) first reported that following appetitive conditioning of multiple stimuli, extinction of one CS attenuated responding to others which had not undergone direct extinction. Four experiments with rat subjects investigated potential mechanisms of this secondary extinction effect. Experiment 1 assessed whether secondary extinction would be more likely to occur with target CSs that have themselves undergone some prior extinction. Two CSs were initially paired with shock. One CS was subsequently extinguished before the second CS was tested. The target CS was partially extinguished for half the rats and not extinguished CS for the other half. A robust secondary extinction effect was obtained with the non-extinguished target CS. Experiment 2 investigated whether secondary extinction occurs if the target CS is tested outside the context where the first CS is extinguished. Despite the context switch secondary extinction was observed. Extinction of one CS was also found to thwart renewal of suppression to a second CS when it was tested in a neutral context. Experiment 3 examined whether secondary extinction can be attributed to mediated generalization caused by association of the CSs with a common US during conditioning. Rats received conditioning with three CSs and then extinction with one of them. Secondary extinction was observed with a shock-associated CS when the extinguished CS had been associated with either food pellets or shock, suggesting that secondary extinction is not US-specific and is thus not explained by this mediated generalization mechanism. Experiment 4 examined whether intermixing trials with the two stimuli during conditioning is necessary for secondary extinction to occur. Rats were either conditioned with intermixed trials as in Experiments 1-3, or with blocked trials of each CS presented in conditioning sessions separated by a day. Secondary extinction was observed only in the former condition. The results are consistent with the hypothesis that CSs must be associated with a common temporal context for secondary extinction to occur.

This thesis focuses on probabilistic associative learning. One of the classic effects in this field is the stimulus associability effect for which I derive a statistically optimal inference model and a corresponding approximation that addresses a number of problems with the original account of Mackintosh. My proposed account of associability - a variable learning rate depending on a relative informativeness of stimuli - also accounts of the classic blocking effect \cite{kamin1969predictability} without the need for Prediction Error [PE] computation. Given that blocking was the main impetus for placing PE at the centre of learning theories, I critically re-evaluate other evidence for PE in learning, particularly the recent neuroimaging evidence. I conclude that the brain data are not as clear cut as often presumed. The main shortcoming of the evidence implicating PE in learning is that probabilistic associative learning is mostly described as a transition from one state of belief to another, yet those beliefs are typically observed only after multiple learning episodes and in a very coarse manner. To address this problem, I develop an experimental paradigm and accompanying statistical methods that allow one to infer the beliefs at any given point in time. However, even with the rich data provided by this new paradigm, the blocking effect still cannot provide conclusive evidence for the role of PE in learning. I solve this problem by deriving a novel conceptualisation of learning as a flow in probability space. This allows me to derive two novel effects that can unambiguously distinguish learning that is driven by PE from learning not driven by PE. I call these effectsgeneralized blocking and false blocking, given their inspiration by the original paradigm of Kamin (1969). These two effects can be generalized to the entirety of probability space, rather than just the two specific points provided by the paradigms used by Mackintosh and Kamin, and therefore offer greater sensitivity to differences in learning mechanisms. In particular, I demonstrate that these effects are necessary consequences of PE-driven learning, but not learning based on the relative informativeness of stimuli. Lastly I develop an online experiment to acquire data on the new paradigm from a large number (approximately 2000) of participants recruited via social media. The results of model fitting, together with statistical tests of generalized blocking and false blocking, provide strong evidence against a PE-driven account of learning, instead favouring the relative informativeness account derived at the start of the thesis.

Imaging has revealed that brain activation of verbs with verifiable products (‘throw, kick’) activate language areas as well as the motor cortex responsible for the performance of the action described. An exploratory comparison of eye related verbs with no verifiable products (‘observe’) to mouth related verbs with verifiable products (‘shout’) has revealed a similar activation pattern. Thus in order to further study mental action verbs with no verifiable products, the present two-part study used words that were suitable across two modalities (e.g. you can ‘perceive’ both through vision and audition) and compare them to themselves under differing contexts of auditory and visual verbs so as to eliminate any word characteristics differences, as well as explored the two modalities directly. The primary purpose was to delineate whether associative learning or the mirror systems theory might better account for the acquisition of this unique subclass of verbs. Results suggest that Mirror systems theory more likely accounts for the observed cognitive processing differences between the two verbs. Keywords: Verbs, language, Event-related potentials, abstract, associative learning theory, mirror systems theory.

Behavioural phonotaxis (oriented movement in response to sound) is an effective means to quantify auditory perception in acoustically communicating insects. Previous phonotaxis studies on the acoustic parasitoid fly Ormia ochracea (Diptera: Tachinidae) have described stereotyped, reflex-like responses towards auditory stimuli modeled after their preferred cricket hosts, yet their ability to demonstrate plasticity of responses in the context of dynamically changing auditory cues has not previously been described. Using a behavioural sensitization protocol, I compared phonotaxis towards behaviourally irrelevant (non-attractive) test stimuli presented alone, and when preceded with the natural, response-evoking cricket song (attractive). Results demonstrate the cricket song as a sensitizing stimulus mediating phonotaxis towards otherwise non-attractive sounds, and differential walking patterns depending on temporal delay between song offset and test stimulus onset. My findings suggest an ecological purpose of sensitization, allowing flies to maintain orientation towards a cricket host amidst conditions of signal disruption in the environment.

Behavioural phonotaxis (oriented movement in response to sound) is an effective means to quantify auditory perception in acoustically communicating insects. Previous phonotaxis studies on the acoustic parasitoid fly Ormia ochracea (Diptera: Tachinidae) have described stereotyped, reflex-like responses towards auditory stimuli modeled after their preferred cricket hosts, yet their ability to demonstrate plasticity of responses in the context of dynamically changing auditory cues has not previously been described. Using a behavioural sensitization protocol, I compared phonotaxis towards behaviourally irrelevant (non-attractive) test stimuli presented alone, and when preceded with the natural, response-evoking cricket song (attractive). Results demonstrate the cricket song as a sensitizing stimulus mediating phonotaxis towards otherwise non-attractive sounds, and differential walking patterns depending on temporal delay between song offset and test stimulus onset. My findings suggest an ecological purpose of sensitization, allowing flies to maintain orientation towards a cricket host amidst conditions of signal disruption in the environment.

Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

No description available.

<p>One of the most central and current debates among those studying human contingency learning (HCL) concerns whether it is best understood as the result of associative learning, a product of higher-order cognitive processes, or some combination thereof. Though the field appears to be moving toward the latter accounts, much of the evidence being generated to evaluate and select among them comes from tasks that typically present only information about the few variables involved in the contingency(s), in the exact same manner on every trial. While effective for examining how the statistical properties of experience affect learning, these procedures do not capture some of the conditions of everyday cognition and are apt to be less effective for engaging non-associative and top-down influences on performance.</p> <p>The current work introduces a task that involves learning contingencies in others' behavior from descriptions that require the learner to determine the focus of learning, and to deal with both variability in manifestation of the objects of learning and extraneous information. Across several experiments, performance reflects phenomena, including ΔP, outcome density and blocking effects, which have been well established in HCL and are consistent with associative accounts. At the same time, the findings also suggest that (a) domain-specific theories affect the weighting of evidence in contingency perception and the discoverability of contingencies, and (b) outcome predictions, a typical measure in HCL, are influenced by specific instance memory in addition to abstract contingency knowledge. These findings are difficult to reconcile with the data-driven nature of associative views, and join a growing number of demonstrations suggesting that a viable account of HCL must involve higher-order cognitive processes or top-down influences on performance.</p> / Thesis / Doctor of Philosophy (PhD)