Thesis (M.A.)--York University, 2006. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 66-75). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR29554

Thesis (M.Sc.)--York University, 2008. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 69-81). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR51534

Memory formation and recall depend on a complex circuit that includes the hippocampus and associated cortical regions. The goal of this thesis was to understand how two of the cortical connections, the medial entorhinal cortex (MEC) and medial prefrontal cortex (mPFC), influence spatial and nonspatial activity in the hippocampus. Cells in the MEC exhibit prominent spatially selective activity and have been hypothesized to drive place representation in the hippocampus. In Experiment 1 the MEC was transiently inactivated using the inhibitory opsin ArchaerhodopsinT (ArchT), and simultaneous recordings from CA1 were made as rats ran on an elliptical track. In response to MEC disruption some cells in the hippocampus shifted the preferred location of activity, some changed firing rate and others were unaffected. The new representation that developed following MEC disruption remained stable despite the fact that inhibition was transient. If the MEC is the source of spatial activity in the hippocampus the activity would be either time-locked to periods of inhibition or unstable throughout the period of inconsistent input. These results show that the MEC guides spatial representation in the hippocampus but does not directly drive spatial firing. The mPFC is generally thought to guide behavior in response to contextual elements. Experiment 2 examined the interaction between the mPFC and the hippocampus as rats performed a contextual discrimination task. Recordings were made in CA1, and the mPFC was disrupted using ArchT during the odor sampling phase of the discrimination. As animals perform this task neurons in the hippocampus respond to a conjunction of odor and location which indicates an association of what and where information in the hippocampus. Optogenetic disruption of the mPFC led to a decrease in nonspatial representation. Individual cells showed lower levels of odor selectivity, but there was no change in the level of spatial representation. This indicates that the mPFC is important for determining how the hippocampus represents nonspatial information but does not alter the spatial representation. The results are discussed within a model of memory formation that includes binding spatial and nonspatial information in the hippocampus.

Parkinson’s disease (PD) and autism are prevalent diseases in two disparate age groups. The neuropathology underlying these diseases involves the major neurotransmitters, dopamine and GABA, and/ or their receptors. The current study investigated mRNA gene expressions of the GAD67 in autistic striatum and the DRD1 in the Parkinsonian dorsolateral prefrontal cortex. In situ hybridization histochemistry for GAD67 mRNA levels in postmortem striatal specimens from autistic individuals was compared to those of normal controls. Similarly, a nonradioactive in situ hybridization newly emerging method, RNAscope, was used to assess the D1 receptor mRNA gene expression in postmortem specimens of the dorsolateral prefrontal cortex of PD and control brains. The GAD67 mRNA labeling intensity that was measured on X-ray films and on emulsion radioautograph sections did not vary significantly between the autistic samples and the normal control samples. On the other hand, DRD1 mRNA levels showed a significant increase in the Parkinsonian dorsolateral prefrontal cortex specimens as compared to their normal counterparts. The GAD65 mRNA labeling results corresponded with the GAD67 mRNA levels. The similar GAD67 and GAD65 mRNA patterns in the autism group and the control group may suggest that the hyper-excitability hypothesis can be accounted for by an increase in the glutamatergic activity rather than a decrease in the GABAergic system. The increase in the DRD1 mRNA in the Parkinson’s disease dorsolateral prefrontal cortex may be interpreted in light of the expected upregulation of the D1 receptor in cases of dopamine depletion as the treatment-status was unknown. In conclusion, research investigating the neurotransmitters’ gene expression in Parkinson’s disease and in autism spectrum disorder needs more neurobiological studies in order to establish some knowledge regarding the temporality, and the genetic profile mapping of the diseases. Likewise, more research is encouraged to relate the symptoms and behaviors associated with disease to their anatomical origins.

The present thesis investigates the role of the prefrontal cortex and cholinergic modulation in attentional performance, and to a lesser extent, inhibitory response control, in rats. A greater understanding of these functions is important for the effective treatment of attentional and impulsive control deficits, present in a range of neuropsychiatric disorders. For this field to progress, the assessment of attentional performance in a similar manner across humans and animals is crucial. In the present thesis, attentional performance was assessed on the novel, touchscreen-based rodent continuous performance task (rCPT), which assesses sustained, focused attention in essentially an identical manner to CPTs commonly used in the clinic. Findings were compared to performance on the well-characterised 5-choice serial reaction time task (5-CSRTT), which assesses sustained, spatial divided attention and shares some, but not all characteristics of CPTs. The series of experiments described in this thesis contributes to the understanding of the role of the prefrontal cortex and cholinergic modulation in attentional performance; they also highlight differences between the two tasks in behaviour, brain functions and networks. Excitotoxic lesions of the medial prefrontal cortex (mPFC) and a range of cholinergic systemic pharmacology validated the role of the prefrontal cortex and cholinergic modulation in rCPT performance. A chemogenetic study also validated the role of the ascending cholinergic basal forebrain system in 5-CSRTT performance. These findings support 1. the idea of the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function; 2. a double dissociation of mPFC sub-regions on attentional performance, in which the prelimbic cortex (PL) appears to play a role in rCPT performance, compared with a role of the anterior cingulate cortex (ACC) in 5-CSRTT performance; and 3. a role of ascending cholinergic projections from the basal forebrain to the ACC in 5-CSRTT performance. These findings also establish the development of a successful flanker distractor probe in rodents on the rCPT. This thesis concludes with an important comparison of the attentional and impulsivity measures in the rCPT compared to the 5-CSRTT, to help provide guidelines as to which task is most appropriate to use for particular research questions.

Stroke is the third leading cause of death and the primary cause of adult long-term disability in Canada. Despite advances in rehabilitation research, stroke survivors experience an unusually high incidence of depressive symptoms which undermine recovery outcomes by reducing patient motivation levels. Human and animal studies have linked the incidence of post-stroke depression and the extent of prefrontal cortex (PFC) damage. The PFC and the lateral habenula (LHb) are limbic structures that are strongly connected to the serotonergic dorsal raphe nucleus (DRN), a key neuronal hub for mood regulation. We hypothesized that PFC stroke produces a depressive phenotype by triggering maladaptive reorganization in mood-related networks. We used viral and optogenetic strategies to functionally characterize PFC and LHb projections to DRN. Moreover, we found that PFC stroke causes a time-dependent remodeling of LHb inputs to DRN 5-HT neurons which results in altered postsynaptic glutamate receptor number and subunit composition. This remodeling likely reflects a homeostatic upregulation of LHb-DRN synapses in response to stroke-induced challenge to network activity. Since these synapses encode stress and aversion, potentiation of this pathway could contribute to depressive symptoms following stroke. However, more work will be needed to identify the behavioral and network-level consequences of altered LHb-DRN dynamics. Thus, a deeper understanding of circuit mechanisms implicated in post-stroke depression will provide insights into this disease and open new treatment avenues to improve recovery.

The feasibility of using real-time functional magnetic resonance imaging (fMRI) feedback regarding the level of activation in rostromedial prefrontal cortex (rMPFC) to learn improved regulation of this brain area was examined in a group of 5 young adults. Subjects received real-time feedback from the target brain region while engaging in a blocked-design task involving alternating blocks of attempted up-regulation and down-regulation of the target brain region. A transient negative emotional state was induced prior to each scanning session. Subjects completed 6 scanning sessions (a pre-training session, 4 feedback sessions and a post-training session - no feedback was provided for pre and post-training sessions). The guideline strategy provided to subjects of engaging in emotional awareness during up-regulation and bodily awareness during down-regulation was found to consistently regulate the region in the pre-training session prior to the fMRI feedback sessions. This finding is in line with the previously proposed role of the rMPFC in emotional awareness. In contrast to previous real-time fMRI findings, greater recruitment of the region was observed in the pre-training session compared to the post-training session, with a non-significant negative trend observed across feedback sessions. These results suggest that there may be limitations to which the feedback techniques successfully employed for other brain regions extend to yet unexplored brain regions. / Arts, Faculty of / Psychology, Department of / Graduate

This dissertation investigates the fronto-parietal representation of the structure of organised mental episodes by studying its effect on the representation of cognitive events occurring at various positions within it. The experiments in chapter 2 look at the completion of hierarchically organized mental (task/subtask) episodes. Multiple identical target-detection events were organized into a sequential task episode, and the individual events were connected in a means-to-end relationship. It is shown that events that are conceptualized as completing defined task episodes elicit greater activity compared to identical events lying within the episode; the magnitude of the end of episode activity depended on the hierarchical abstraction of the episode. In chapter 3, the effect of ordinal position of the cognitive events, making up the task episode, on their representation is investigated in the context of a biphasic task episode. The design further manipulated the cognitive load of the two phases independently. This allowed for a direct comparison of the effect of phase vis-à-vis the effect of cognitive load. The results showed that fronto-parietal regions that increased their activity in response to cognitive load, also increased their activity for the later phases of the task episode, even though the cognitive load associated with the later phase was, arguably, lower than the previous phase. Chapter 4 investigates if the characteristics of the higher-level representations, like organization of task descriptions, have a causal role in determining the structure of the ensuing mental episode. Results show this to be true. They also confirm the results of earlier chapters in a different framework. Chapter 5 shows that the effect of episode structure is not limited to the elicited activity, but also affects the information content of the representation of the events composing the episode. Specifically, the information content in many regions of later steps is higher than that of earlier steps. Together, the results show widespread representation of the structure of organised mental episodes.

Cognitive impairments and changes in the structure and function of related brain regions, namely the prefrontal cortex and striatum, have long been implicated in drug addiction. However, it is unknown whether these abnormalities predate substance abuse, potentially serving as risk factors for dependence, or if they are the consequence of protracted use. To address this question, endophenotype research using stimulant-dependent individuals’ biological siblings has been used to investigate traits implicated in the pathology of addiction. Impairments present in both groups suggest an underlying risk-state for dependence, while additional abnormalities present only in stimulant-dependent individuals reflect potential effects of the drugs themselves. Contrastingly, there are also individuals who use stimulant drugs in a controlled manner without developing dependence. These ‘recreational users’ may lack the underlying traits that comprise a greater risk for dependence, or they might maintain additional protective factors against the development of addiction. Experiments in the first half of this dissertation used functional magnetic resonance imaging to investigate neurocognitive similarities and differences between dependent stimulant users, their non-dependent siblings, recreational users of cocaine, and unrelated healthy control volunteers. In Chapter 2, performance on a colour-word Stroop task was impaired in both stimulant-dependent individuals and their siblings, suggesting an endophenotype of cognitive inefficiency. However, neural activity significantly differed between the groups, indicating additional changes specific to the use of stimulant drugs. In Chapter 3, dependent users showed significant attentional bias to salient stimuli on a cocaine-word Stroop task, with a concurrent increase in prefrontal activation. Conversely, recreational users showed resilience in the face of cocaine cues and a decrease in arousal. Finally, Chapter 4 explored differences in reward sensitivity to both generic and drug-specific reinforcers, comparing the effects of personal and family history of stimulant exposure on a monetary incentive delay task. It is also under debate whether the neurocognitive differences seen in stimulant-dependent individuals are unique to substance abuse, or if parallel changes in behaviour and neurobiology are present in similar addiction-spectrum disorders, such as binge eating leading to obesity. In Chapter 5, stimulant-dependent and obese individuals with binge-eating behaviours showed differences in their substance-specific and general reward responsivity on a novel reward-valuation task. However, in Chapter 6 a similar decline in orbitofrontal cortex grey matter volume in relation to both years of stimulant use and body mass index was identified, implicating an overlap in this area between both conditions. These findings are integrated in Chapter 7, discussing the neurocognitive risk and protective factors that underlie an individual’s vulnerability for addiction, not only to stimulant drugs, but also potentially for other addictive behaviours.

Cognitive impairments are a hallmark of many, if not all, psychiatric disorders. They include deficits in working memory, attention, and cognitive flexibility. The prefrontal cortex (PFC) is essential for these cognitive functions and has been implicated in psychiatric disorders, including schizophrenia. The PFC receives reciprocal inputs from the thalamus, and this thalamo-PFC circuitry supports cognition. In patients with schizophrenia, who have impaired cognitive functioning, thalamo-PFC connectivity is disrupted. This finding is also seen in adolescents at high risk for the disorder, even before diagnosis.While impaired cortical maturation has been postulated as a mechanism in the etiology of schizophrenia, the postnatal development of thalamo-PFC circuitry is still poorly understood. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. However, whether thalamic activity also shapes maturation of the PFC is unknown. Here, I will present evidence to support the hypothesis that adolescence represents a sensitive period, during which the PFC is susceptible to transient perturbations in thalamic input activity, resulting in persistent changes in circuitry. In Chapter 1, I present the existing literature on schizophrenia and our current understanding of its etiology. I then review the structure and connectivity of the PFC and its inputs, including the thalamus, in the context of schizophrenia and cognition. Next, I discuss the role of adolescence in the development of these structures and circuits. Finally, I introduce the concept of sensitive periods and outline the hypothesis that a similar process may occur in the context of the adolescent development of thalamo-PFC circuitry. To assess cognitive functioning in mouse models, I developed an operant-based working memory task. In Chapter 2, I describe this newly developed task and demonstrate that behavioral performance in the task is susceptible to PFC lesions. Thus, the task offers a new approach to studying PFC cognitive function. In Chapter 3, I discuss work done to address the hypothesis of adolescence as a sensitive period in the development of thalamo-PFC circuitry. I established an approach whereby I can transiently reduce activity in the thalamus during specific time windows. In this way, I compared the persistent effects of transient thalamic inhibition during adolescence and adulthood. I found that adolescent thalamic inhibition causes long-lasting deficits in cognitive behavioral performance, including the operant-based working memory task described in Chapter 2 and a cognitive flexibility task, decreased PFC cellular excitability, and reduced thalamo-PFC projection density. Meanwhile, adult thalamic inhibition has no persistent consequences on behavior or PFC excitability. Adolescent thalamic inhibition also results in disrupted PFC cellular cross-correlations and task outcome encoding during the cognitive flexibility task. Strikingly, exciting the thalamus in adulthood during the behavioral task rescues PFC cross-correlations, task outcome encoding, and the cognitive deficit. These data support the hypothesis that adolescence is a sensitive period in thalamo-PFC circuit maturation as adolescent thalamic inhibition has long-lasting consequences on PFC circuitry, while adult thalamic inhibition has no persistent effects. Moreover, these results highlight the role of the thalamus as a non-specific facilitator of PFC activity, expanding our understanding of this thalamic function to additional cognitive contexts. By supporting PFC network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders. Finally, in Chapter 4, I conclude with a general discussion. I highlight major take-aways from this work as well as next steps in our exploration of these crucial neural circuits. Together, the findings outlined here offer new promise for early diagnosis and treatment options for patients with cognitive impairments and psychiatric disorders.