Neurobiological mechanisms of conflict resolution and goal-directed behaviour

This thesis investigated theories regarding the neurobiological substrates of conflict resolution in rodents. An operant biconditional discrimination task was used that modelled elements of response conflict similar to that observed in the human Stroop task. Correct performance required the use of incidental (context) cues to guide performance during compound cues that signalled conflicting responses. This task was used to test hypotheses related to the role of dopamine, the frontal cortex and hippocampus in conflict resolution. In addition, a transgenic mouse model of frontotemporal dementia (tau V337M) was used to assess the effects of this mutation on frontal cortex-dependent conflict resolution. The first set of experiments examined the effects of dopaminergic agonists (d- amphetamine and phencyclidine) on conflict resolution in rats. It was found that the modulation of dopamine tone generally disrupted conditional responding as opposed to selectively disrupting conflict resolution. In order to understand how genetic models of human frontal cortex disorders influence conflict resolution, the conflict task was successfully adapted for use with mice. Lesions of the prefrontal cortex in mice selectively disrupted the use of context cues to resolve response conflict. Hippocampal lesions, however, did not disrupt contextual control of response conflict. In contrast to predictions, mice with the tau V337M mutation linked to frontotemporal dementia were not impaired at conflict resolution. However, these mice were impaired in acquisition of a spatial navigation task, indicative of abnormal hippocampal function. In summary, this thesis provides evidence that rats and mice are able to use incidental contextual cues to influence responding during situations in which punctate cues signal conflicting responses. Modulation of dopamine did not influence response conflict in this paradigm. Nevertheless, conflict resolution was reliant upon an intact frontal cortex (but not hippocampus) in rodents. Surprisingly, a mouse genetic model of frontotemporal dementia did not impair conflict resolution but did impair elements of the associative structures supporting performance

Impact of Diet on Learning, Memory and Cognition

Changes in food composition and availability have contributed to the dramatic increase in obesity over the past 30-40 years in developed and, increasingly, in developing countries. The modern diet now contains many foods that are rich in saturated fat and refined sugar. People who eat excessive amounts of this diet are not only likely to become overweight, even obese, develop metabolic and cardiovascular diseases, some forms of cancer, but also undergo a more rapid rate of normal age-related cognitive decline and more rapid progression of neurological diseases such as dementia. A central problem is why people persist in consuming this diet in spite of its adverse health effects and when alternative food choices are available. As high fat / high sugar foods are inherently rewarding, eating for pleasure, like taking psychoactive drugs, can modulate reward neurocircuitry, causing changes in responsiveness to reward-predicting stimuli and incentive motivation. Indeed, the excessive ingestion in modern societies and the resulting obesity epidemic may be viewed as a form of food addiction. Thus, a diet high in palatable foods is proposed to impact upon reward systems in the brain, modulating appetitive learning and altering reward thresholds. Impairments in other forms of cognition have been associated with obesity, and these have a rapid onset. The hippocampus appears to be particularly vulnerable to the detrimental effects of high fat and high sugar diets. Recent research has shown that as little as one week of exposure to a high fat, high sugar diet leads to impairments in place but not object recognition memory in the rat. Excess sugar alone had similar effects, and the detrimental effects of diet consumption was linked to increased inflammatory markers in the hippocampus, a critical region involved in memory. Furthermore, obesity-related inflammatory changes have also been described in the human brain that may lead to memory impairments. These memory deficits may contribute to pathological eating behaviour through changes in the amount consumed and timing of eating. The aim of this eBook is to present up-to-date information about the impact of diet and diet-induced obesity on reward driven learning, memory and cognition, encompassing both animal and human literature, and also potential therapeutic targets to attenuate such deficits

Age-dependent and region-specific alteration of parvalbumin neurons, perineuronal nets and microglia in the mouse prefrontal cortex and hippocampus following obesogenic diet consumption

Emergent evidence demonstrates that excessive consumption of high fat and high sugar (HFHS) diets has negative consequences on hippocampal and prefrontal cortex (PFC) function. Moreover, the delayed maturation of the PFC including the late development of parvalbumin-expressing (PV) interneurons and perineuronal nets (PNNs) may promote vulnerability to HFHS diet-induced nutritional stress. However, the young brain may have some resistance to diet-induced neuroinflammation. Thus, we examined the impact of a HFHS diet commencing either in adolescence or adulthood in male mice. PV interneurons, PNNs and microglia were assessed using immunohistochemistry. We observed greater numbers of PV neurons and PNNs in the hippocampus and the prelimbic and infralimbic PFC in adult mice in comparison to our younger cohort. Mice that consumed HFHS diet as adults had reduced numbers of hippocampal PV neurons and PNNs, which correlated with adiposity. However, we saw no effects of diet on PV and PNNs in the PFC. HFHS diet increased microgliosis in the adult cohort, and morphological changes to microglia were observed in the PFC and hippocampus of the adolescent cohort, with a shift to activated microglia phenotypes. Taken together, these findings demonstrate different regional and age-specific effects of obesogenic diets on PV neurons, PNNs and microglia

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes