Neural Systems for Decision-Making and Startegy Implementation (360G-Wellcome-071291_Z_03_A)

The human frontal cortex controls attention, learning, memory, language, decision-making, judgment, and planning, in addition to other different cognitive functions. Damage to the frontal lobes is a frequent consequence of stroke and traumatic brain injury. Impairments in frontal lobe function are also common in Alzheimer disease, Parkinson's disease, and frontotemporal dementia, as well as neuropsychiatric disorders such as obsessive-compulsive disorder, mood disorders, and schizophrenia. Clinically, impairments in these functions make it impossible for people with these ailments to live independently. The available data, although very limited, suggests that these different functions may be regulated by different neurotransmitter systems within the frontal cortex. We need to know the neurobiological bases of cognitive functions controlled by the frontal lobe in order to understand the pathogenesis of cognitive impairment in these various conditions and to design therapies that could ameliorate these impairments. The experiments proposed in this programme of research will use sophisticated behavioural assessments of decision-making, planning, and strategy selection in animal models, to test the effects of selective depletion of particular neurotransmitters within the frontal cortex on these abilities. First we will identify the subregions within frontal cortex that are responsible for particular aspects of these complex cognitive functions, because there is evidence that different areas of the frontal cortex make different contributions to the regulation of behaviour. Then we will use immunotoxins to remove selectively input from a particular transmitter system (acetylcholine, dopamine, serotonin) to subregions of frontal cortex. The promise of this work is a fuller understanding of the neurochemical regulation of prefrontal cortex function, leading to the development of pharmacological agents that could be used to regulate selectively particular cognitive functions controlled by the frontal lobe.