Christos Constantinidis - US grants

PROJECT SUMMARY The study will investigate how visual information is represented in the prefrontal cortex, the brain area involved with higher cognitive functions, before and after learning to perform a cognitive task. Monkeys will be trained in cognitive tasks that require them to observe and remember visual stimuli. Neurophysiological recordings with an array of microelectrodes at various training stages will allow us to determine the patterns of neuronal activation and the functional interactions between neurons. The experiments will uncover the nature of changes that take place in the prefrontal cortex by learning to perform a cognitive task.

DESCRIPTION (provided by applicant): A decline in core cognitive functions of attention, memory, and learning ability is commonly observed in neurodegenerative conditions such as Alzheimer's disease. These deficits can be partially reversed by cholinergic agents, for example acetylcholine agonists or acetylcholinesterase inhibitors. Cholinergic agents have also shown promise in enhancing recovery of cognitive functions after brain insult or disease, as in the case of Traumatic Brain Injury. Despite the known effectiveness of cholinergic agents, the neuronal mechanisms mediating cognitive performance that are targeted by ACh are poorly understood. The prefrontal cortex is known to be essential for higher cognitive functions, yet it is unknown how prefrontal neuronal activity mediating cognitive performance is affected by ACh levels. Taking advantage of recent technical innovations and experimental findings, we propose to use a non-human primate model to perform neurophysiological recordings from a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents. The project relies on monitoring neuronal discharges from multiple cortical sites each day, in the same animals, before and after pharmacological intervention. This research will identify the aspects of neuronal activity that co-vary with behavioral performance during execution of cognitive tasks and will determine which of these are degraded by ACh antagonists and improved by ACh enhancers. Successful completion of the project will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation after neurodegenerative conditions and brain trauma. PUBLIC HEALTH RELEVANCE: Regulation of acetylcholine levels in the brain has been linked to the cognitive impairments associated with ageing, dementia, and schizophrenia. The proposed research will rely on a primate model to determine the effects of acetylcholine levels in a brain area critical for higher cognitive functions, the lateral prefrontal cortex. Successful completion of the project will provide a novel, primate model for the evaluation of different types of drugs as they relate to cognitive performance and rehabilitation.

Description (provided by applicant): Elucidating the biological basis of perception and cognition has been an enduring goal of neuroscience research because it is essential for treating brain disorders that can devastate the ability to think and act. Higher mental processes have traditionally been attributed to the prefrontal cortex, the part of the brain most developed in higher primates and humans. In recent years, however, it has become clear that many neural correlates of mental functions are not exclusive traits of the prefrontal cortex but are already evident in the cortical pathways that project to it, for example, the association areas of the temporal and parietal lobes. Uncovering the unique and cooperative roles of these cortical regions is therefore necessary for understanding the biological basis of higher mental functions. Even less is known about how the circuit organization and nature of neural processing differs between high-order cortical areas, so as to account for their distinct functional roles. We propose to use an integrative methodological framework to elucidate the unique and cooperative roles of areas involved with the processing of visual-spatial information. We will comparatively investigate the physiological responses and neural-circuit organization of the dorsal prefrontal and posterior parietal cortex. Our experiments will make use of neurophysiological recordings with arrays of closely-spaced electrodes in monkeys trained to perform visual-spatial tasks. We will examine the patterns of neural responses during the presentation of multiple visual stimuli, concurrently or in sequence, and analyze the functional interactions between neurons. Experiments will specifically test whether prefrontal cortex is characterized by more robust, more widely distributed or dynamically modulated neuronal connectivity, or functionally specialized cell types. These experiments will help unveil the functional specialization of cortical areas involved in higher cognitive functions and offer insights on normal perceptual processing as well as the consequences of brain injury and mental illness. PUBLIC HEALTH RELEVANCE Understanding the organization and function of cortical areas mediating higher cognitive processes is key to ameliorating the disorders that can devastate one's ability to think and act. The proposed research will rely on a primate model to determine the role and functional specialization of two areas of the cerebral cortex involved in the processing of visual spatial information, the posterior parietal and dorsal prefrontal cortex.

DESCRIPTION (provided by applicant): The size of the prefrontal cortex has increased dramatically in primates compared to other vertebrates and its evolutionary expansion mirrors the development of attention, memory, and executive function in these species. Developmentally, the prefrontal cortex undergoes a long maturation process that extends through puberty and into early adulthood. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Impulse control also improves in adulthood, and failure to develop adequately is associated with delinquency, drug abuse, and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes during puberty and early adulthood so as to mediate increased cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology and functional connectivity that occur after puberty. We propose to use a non-human primate model which will allow us to conduct neurophysiological recordings in the prefrontal cortex of juvenile and adult animals. Our studies will also sample the posterior parietal cortex, an area interconnected with the prefrontal cortex. This will serve as a control area allowing us to determine what is unique about the maturation of the prefrontal cortex, and it will also allow us to study changes of functional connectivity between the prefrontal cortex and posterior parietal cortex. Our study will make use of monkeys trained to perform behavioral tasks that require attention, working memory, and executive control. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses which will be essential for understanding and treating mental illnesses associated with problems of prefrontal cortical maturation. PUBLIC HEALTH RELEVANCE: The proposed research will determine how the functions of prefrontal cortex neurons change between adolescence and adulthood. Knowledge drawn from these experiments will elucidate the development of higher cognitive processes such as attention and memory, which is necessary for understanding the biological basis of conditions such as Attention Deficit Disorder and mental illnesses such as schizophrenia.

DESCRIPTION (provided by applicant): A decline in cognitive functions such as attention, memory, and decision making is observed in a series of neurodegenerative conditions and mental illnesses. Cholinergic drugs (acetylcholine agonists and acetylcholinesterase inhibitors) can reverse these symptoms. Despite the known effectiveness of cholinergic drugs in improving cognitive function, the neuronal mechanisms of action in cortical areas involved in these processes, such as the prefrontal cortex are poorly understood. This project will investigate the effects of cholinergic drugs on prefrontal cortical activity during the execution of cognitive task and the effects of stimulation of the Nucleus Basalis, the main source of endogenous cortical acetylcholine. Neurophysiological recordings will be performed by a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents and deep brain stimulation in a non- human primate model. The experiments will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. They will also evaluate the relative effectiveness of drug administration compared to deep brain stimulation. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation following injury or illness.

PROJECT SUMMARY We will investigate the neural substrates of the maturation of response inhibition between the time of adolescence and adulthood. Response inhibition is thought to be mediated by the prefrontal cortex, a cortical area greatly expanded in primates compared to other vertebrates, which undergoes a long maturation process that mirrors the development of higher cognitive functions after adolescence. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Executive function also improves in adulthood, and inadequate development of this capacity is associated with delinquency and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes in adolescence so as to mediate improved cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology and anatomical connectivity that occur after puberty. We propose to use a non-human primate model that will allow us to conduct behavioral assessments, neurophysiological recordings, and MR imaging in the prefrontal cortex of developing animals and controls. Our study will make use behavioral tasks that test response inhibition. We will rely primarily on the anti-saccade task which requires subjects to make an eye movement in the opposite direction of a visual stimulus, thus resisting the pre-potent stimulus. Experiments will record neuronal activity related to task performance to understand what neural variables maturate after the onset of puberty. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses, findings that will be essential for understanding and treating mental illnesses thought to be associated with a failure of prefrontal cortical maturation.

PROJECT SUMMARY The goal of this project is to investigate the neural substrates of the maturation process that takes place around puberty and which is associated with the development of a key cognitive ability, working memory. The prefrontal cortex, a part of the brain greatly expanded in primates compared to other vertebrates, undergoes a long maturation process that extends through puberty and into early adulthood. This process mirrors the development of higher cognitive functions. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Executive function also improves in adulthood, and inadequate development of this capacity is associated with delinquency and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes in adolescence so as to mediate increased cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology that occur after puberty. We propose to use a non-human primate model that will allow us to conduct neurophysiological recordings in the prefrontal cortex of peri-pubertal and adult animals. Our study will make use of monkeys trained to perform behavioral tasks that test working memory ability. Experiments will record neuronal activity related to task performance to understand what neural variables maturate after the onset of puberty. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses, findings that will be essential for understanding and treating mental illnesses thought to be associated with a failure of prefrontal cortical maturation.

PROJECT SUMMARY This project will investigate the potential of deep brain stimulation to improve cognitive abilities in aging, and counteract the effects of Alzheimer's and other types of dementias. We will perform experiments in nonhuman primates, because they experience a similar age-related cognitive decline as humans. Stimulation will be applied in the Nucleus Basalis of Meynert, the sole source of acetylcholine to neocortex. Drawing from recent experiments showing success of this method, intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute in old monkeys. The study design will test the efficacy of stimulation, and the duration of benefits after the intervention. Use of complementary pharmacological agents will determine if short-term effects of stimulation on cognition may be augmented by other agents, and what pharmacological systems they interact with. Partial nicotinic acetylcholine receptor agonists, positive allosteric modulators, serotonergic and noradrenergic agents will be tested, as will other agents that interact with cholinesterase inhibitors. In addition, the project will determine whether deep brain stimulation can ameliorate pathological changes associated with Alzheimer's dementias, as noted by biochemical, metabolic, and brain structural measures.