Not available / text

No description available.

Optimal decision making requires one to determine the best action among available alternatives as well as the most appropriate level of engagement for performance. While current research and models of decision making have largely focused on the former problem, or action selection, less is known about the latter problem of the selection of motivational drive. Thus, I designed a self-paced decision-making paradigm that aimed to dissociate both facets of selection in rats. First, I showed that the expected net value of potential options influenced rats' general motivation to perform: rats globally exhibited shorter latency to initiate trials in states of high net return than in states of low net return. In contrast, the relative value of options biased choice direction. To study the neural substrates underlying either process, I examined the role of the striatum, which is closely connected with cortex and dopamine neurons, acting as a major hub for reward-related information. In chapter 1, I show that selective lesions of the dorsomedial (DMS) but not ventral striatum (VS) impaired net value-dependent motivational drive but largely spared choice biases. Specifically, DMS lesions rendered animals' latency to initiate trials dependent on the absolute value of immediately preceding trial outcomes rather than on the net value of options. Accordingly, tetrode recordings in Chapter 2 showed that the DMS rather than VS predominantly encodes net value. In fact, net value representation in the DMS was stronger than either absolute or relative value representations during early trial epochs. Thus, the DMS flexibly encodes net expected return, which can guide the selection of motivational drive.

No description available.

No description available.

Schizophrenia is among the most debilitating mental disorders, yet the pathophysiology remains unclear. The basal ganglia, a region of the brain involved in motor, cognitive, and sensory processes, may be involved in the pathophysiology of schizophrenia. Some, but not all, neuroimaging studies suggest abnormalities of the basal ganglia in schizophrenia. However, previous studies have examined whole basal ganglia nuclei as opposed to using a unified basal ganglia complex that incorporates anterior-posterior divisions, dorsal-ventral divisions, and gray-white matter segmentation. The hypothesis for the present study was that basal ganglia sub-regions forming functionally relevant subdivisions might be different in schizophrenia. Magnetic resonance imaging scans were acquired from 25 first-episode schizophrenia subjects and 24 healthy subjects. Using manual and automated neuroimaging techniques, total and segmented (gray-white matter) volumes were obtained for the caudate, putamen, and globus pallidus. For the striatum (caudate and putamen), total and segmented volumes were obtained for their respective sub-regions. These sub-regions were restructured into associative, limbic, and sensorimotor subdivisions. Schizophrenia subjects had 6% smaller gray matter volumes for the caudate and 8% smaller gray matter volumes for the associative striatum relative to healthy subjects. Basal ganglia function was studied by examining performance on a neuropsychological test that assesses frontostriatal functioning. For male subjects there was a significant negative correlation between volume of the associative striatum and performance on the neuropsychological test (r=-0.57, p=0.03). Smaller volumes of the associative striatum were associated with more errors on the neuropsychological test. This test was specific to the associative striatum, as another neuropsychological test did not reveal any correlation. In schizophrenia subjects, the relationship between basal ganglia volumes and motor symptoms severity was examined. For antipsychotic-naive subjects there was a significant negative correlation between volume of the motor striatum and severity of Parkinsonism (r=-0.65, p=0.03). The present study suggests that total basal ganglia nuclei volumes are not different in schizophrenia, but gray matter volumes of total basal ganglia nuclei and subdivisions forming functional units may be different in schizophrenia. Structural abnormalities involving the basal ganglia may lead to disrupted functional circuits in schizophrenia.

Individuals with Parkinson’s disease (PD) display deficits in voluntary saccade generation but improved automatic, visually-triggered saccade performance. This can be tested using prosaccades, saccades to visual stimuli, and antisaccades, saccades in the opposite direction from the visual stimuli. Voluntary saccade impairments resulting in antisaccade direction errors and longer saccadic reaction times (SRTs) are thought to be due to insufficient presetting of neural circuitry during saccade preparation in complex tasks involving suppression and selection. The basal ganglia, a major site of PD pathology, might be the cause of abnormalities in preparing for action selection in PD patients. Recently, microsaccade rates have been hypothesized to reflect the dual preparatory signals of saccade facilitation and suppression. In this thesis, we investigated the microsaccade behaviour of PD patients as they performed prosaccades and antisaccades. We hypothesized that deficits in voluntary movements in PD would result in impaired suppression of involuntary movements as reflected by increased microsaccade rates. Our findings demonstrate consistently elevated microsaccade rates in PD subjects compared to age-matched controls. Furthermore, positive correlations were found between antisaccade direction error rate and microsaccade rate as well as microsaccade rate and Hoehn-Yahr score, an indicator of disease severity in PD patients. We conclude that microsaccades reflect the impaired suppression of involuntary movements caused by voluntary movement deficits in PD pathology. Our findings indicate that microsaccades provide insight into action preparatory mechanisms and BG dysfunction. Therefore, measuring microsaccades in PD may provide a useful biomarker to follow disease progression and effectiveness of treatment therapies. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2014-01-09 23:31:21.78

Basal metabolic rate (BMR), the sum of maintenance energy costs, represents a major component of the energy budgets of ectothermic vertebrates and varies between individuals within a species. Individual ectotherms are generally assumed to have a constant BMR at any given temperature. A strategy of flexibility in BMR might have evolved to cope with differing environmental conditions. Within-individual variation in BMR was examined in two fishes, juvenile Atlantic salmon Salmo salar and juvenile northern pike Esox lucius, whilst the effects of exercise and ration on BMR, maximum metabolic rate (MMR), enzyme levels and body composition were studied in detail for pike. In the first part of the study, measurements of BMR were made for first-summer Atlantic salmon parr at rest by respirometry. In 1996, initial measurements of BMR were made for 25 fish held in a stock tank. Fish were then allocated in small groups to channels to represent a change in environment and BMR re-measured after a period of several weeks. The procedure was repeated for 30 fish in the summer of 1997, when fish were given a reduced food ration. Variation in BMR in each experiment was analysed for individual fish, and for all fish using a linear mixed model. There were statistically significant differences in BMR values between the two times, the within-individual, between-time variation representing approximately ± 21% of BMR in 1996 and ± 28% of BMR in 1997. Reduced-rafion fish (1997) displayed a significant decrease in the mean elevation of the allometric scaling relationship between body mass and BMR between time periods. To further explore possible mechanisms for flexibility in BMR and relationships with MMR, juvenile pike were used. Initial measurements of BMR and MMR (following exhaustive exercise) were made and factorial metabolic scope calculated (MMR/BMR). Fish were then split into a high ration no-exercise group (n = 10), low ration no-exercise group (n = 10) and sustained exercise group (n = 13). Initial measurements were termed time 1, with subsequent measurements made after approximately 3 weeks (time 2) and 11 weeks (time 3). Exercised fish had a significantly larger MMR and scope following 3 weeks of sustained swimming. For all fish there were significant correlations between BMR and MMR at times 1 and 3 but not at time 2.After the oxygen measurements made at time 3 all fish were humanely killed. Maximal enzyme assays were performed on six tissues for each remaining fish (n = 30). Levels of each of two enzymes (citrate synthase, CS, and lactate dehydrogenase, LDH, measured in the direction of lactate oxidation) were found to be similar between treatment groups for respective tissues. Total CS activity levels and LDH levels were highest in the heart and red muscle. In general there was little difference in the relative organ masses of fish exposed to different treatments. It is concluded that in these two fish species with very different life styles, between- and within- individual variation in BMR (salmon & pike) and MMR (pike only) is apparent and that differences in ration and exercise influence individual physiology.

Proper control of Hedgehog (Hh) signaling is critical for hair follicle morphogenesis and ectopic Hh pathway activity is a hallmark of basal cell carcinoma (BCC), the most common type of skin cancer. Mutations in Hh pathway components such as the Hh-binding receptor PATCHED1 (PTCH1) are frequently found in BCC. However, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formation remains poorly understood. Gli2, the major mediator of Hh signaling is essential for hair follicle development and its overexpression in the epidermis induces BCC formation. Despite the importance of Gli2 in the skin, how it is regulated during skin development and tumorigenesis is unclear. Using a genetic approach with loss-of-function mouse mutants and primary keratinocyte cultures, I have uncovered the distinct and overlapping functions of Sufu and Kif7, two evolutionarily conserved regulators of the Hh pathway, during skin development and tumorigenesis. Sufu and Kif7 play opposing roles in Hh signaling through the regulation of Gli2 subcellular distribution, and Kif7 performs distinct Sufu-dependent and –independent functions. In addition, deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate and compromised epidermal differentiation. In the adult skin, inactivation of Sufu does not drive BCC formation and requires additional genetic alterations such as the loss of Kif7. Using a Ptc1 mouse model for BCC, I have identified previously unrecognized molecular pathways and cellular events involved in BCC pathogenesis. This includes, aberrant cell cycle progression, loss of cell cycle checkpoint regulation, and suppression of the p53 response. Overall my work provides critical insight into the molecular control of Hh signaling and the downstream events driving BCC formation.

Proper control of Hedgehog (Hh) signaling is critical for hair follicle morphogenesis and ectopic Hh pathway activity is a hallmark of basal cell carcinoma (BCC), the most common type of skin cancer. Mutations in Hh pathway components such as the Hh-binding receptor PATCHED1 (PTCH1) are frequently found in BCC. However, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formation remains poorly understood. Gli2, the major mediator of Hh signaling is essential for hair follicle development and its overexpression in the epidermis induces BCC formation. Despite the importance of Gli2 in the skin, how it is regulated during skin development and tumorigenesis is unclear. Using a genetic approach with loss-of-function mouse mutants and primary keratinocyte cultures, I have uncovered the distinct and overlapping functions of Sufu and Kif7, two evolutionarily conserved regulators of the Hh pathway, during skin development and tumorigenesis. Sufu and Kif7 play opposing roles in Hh signaling through the regulation of Gli2 subcellular distribution, and Kif7 performs distinct Sufu-dependent and –independent functions. In addition, deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate and compromised epidermal differentiation. In the adult skin, inactivation of Sufu does not drive BCC formation and requires additional genetic alterations such as the loss of Kif7. Using a Ptc1 mouse model for BCC, I have identified previously unrecognized molecular pathways and cellular events involved in BCC pathogenesis. This includes, aberrant cell cycle progression, loss of cell cycle checkpoint regulation, and suppression of the p53 response. Overall my work provides critical insight into the molecular control of Hh signaling and the downstream events driving BCC formation.