2010 |
Disney, Anita A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Cholinergic Mechanisms in Visual Spatial Attention @ Salk Institute For Biological Studies
DESCRIPTION (provided by applicant): Studies in rodents have suggested that the acetylcholine (ACh) is an essential component of the biological basis for directed attention. Questions arise, however, when one tries to model the cholinergic system as the basis for spatially and temporally precise attentional effects such as have been demonstrated in human and non-human primates. For example the smallest piece of cortical tissue which can be independently modulated by ACh may be too large to allow for the topographically precise enhancement of processing which appears to underlie attentional mechanisms. Studying cholinergic neuromodulation in a species where attention and arousal are more easily separable in behavioral tasks is essential, however such a move is hampered by a striking lack of circuit-level data regarding the structure and function of the cholinergic system in higher mammals. The proposed work will address this gap by 1) using anatomical techniques in the macaque to provide large-scale quantitative data on ACh receptor localization in cortical areas known to be involved in or modulated by attention (e.g. V4, MT and LIP), 2) using optogenetic techniques in rodents to examine the effect that naturalistic ACh release has on the processing of a visual stimulus at various stages of the visual pathway in vivo, and 3) using a high-resolution chemical sensing technique to determine the spatial and temporal profile of acetylcholine release in the visual cortex of the a) anesthetized rodent under optogenetic control and of the b) awake-behaving nonhuman primate during an attention task. PUBLIC HEALTH RELEVANCE: We will use cutting-edge technology to elucidate the function of acetylcholine in vision and visual attention. Abnormal cholinergic modulation is strongly implicated in age-related dementias including Alzheimer's disease (AD) and associated failures of vision and selective visual attention. Understanding how acetylcholine subserves normal cognitive and sensory processing will help elucidate which aspects of the deficits seen in AD are related to loss of cholinergic function and will also aid in understanding related deficits of attention, including attentional failures associated with Schizophrenia, neglect, extinction and Attention-Deficit- Hyperactivity-Disorder (ADHD).
|
0.891 |
2011 — 2016 |
Disney, Anita A |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Cholinergic Mechanisms in Spatial Attention @ Salk Institute For Biological Studies
DESCRIPTION (provided by applicant): Studying the normal functions and mechanisms of perception and attention is essential to identifying and understanding the failures in information processing and cognition that are aspects of many neuropathologies. Cognitive and attentional deficits are seen in a number of mental illnesses including schizophrenia, mood disorders and dementias of varying etiology. Studies in rodents suggest that acetylcholine (ACh) mediates attention, and cholinergic dysfunction is implicated in many cognitive neuropathologies. Questions arise, however, when one tries to model the cholinergic system as the basis for spatially precise attentional effects such as have been demonstrated in humans and non-human primates (NHPs). Specifically, the smallest piece of tissue which can be independently modulated by ACh may be too large to allow for the topographically precise enhancement of processing which appears to underlie attention in primates. Thus, while rodent studies have contributed much to our understanding of cholinergic processes, investigating cholinergic function in a species in which attention and arousal are more separable in behavioral tasks is essential. Also necessary, if we are to build the detailed mechanistic descriptions necessary to drive innovation in clinical practice, is a thorough understanding of cholinergic action in cortical circuits. Currently, our progress is hampered by a striking lack of circuit-level data regarding the structure and function of the cholinergic system and by a limited understanding of the behavioral drivers of ACh release. The work I propose to conduct during the mentored and independent phases of this award will address these gaps by 1) using anatomical techniques to provide quantitative data on ACh receptor localization in cortical areas modulated by attention (both phases), 2) using optogenetic techniques to examine the effect that naturalistic ACh release has on the processing of sensory input by a local cortical circuit in vivo (mentored phase), and 3) using high-resolution chemical sensing to determine the spatial profile of ACh release in the sensory cortex of a) the anesthetized rodent under optogenetic control (mentored phase) and b) the awake, behaving NHP during an attention task (both phases). To achieve these aims I need further training that will complement my existing skills in anatomy, physiology and pharmacology. Specifically, I need to learn how to train and record from NHPs that are engaged in tasks which probe attentional function. I also need a protected and innovative environment to work in while I develop protocols for chemical sensing in vivo in the behaving NHP. The Salk Institute is the ideal training environment for the achievement of these goals. Dr. John Reynolds, my mentor, is one of the world's foremost experts on the physiology of attention in NHPs and has a vibrant lab in which innovation is a normal part of the approach to research. The Salk Institute is also renowned for a collaborative atmosphere that fosters innovative approaches in the biological sciences. After a short period in this exciting environment, I expect to be ready to embark upon an independent research career and will seek a tenure-track position in Neuroscience. PUBLIC HEALTH RELEVANCE: We will use cutting-edge technology to understand the role of acetylcholine in the neocortical processes underlying perception and selective attention. Cholinergic dysfunction is strongly implicated the cognitive deficits seen in many neuropathologies;including schizophrenia, mood disorders, attention deficit-hyperactivity disorder, autism and dementias of various etiology. Understanding how acetylcholine subserves normal cognition and perception will help elucidate which aspects of the deficits seen in these disorders are related to the loss of cholinergic function and can thus help to suggest avenues for clinical intervention.
|
0.97 |
2019 — 2021 |
Disney, Anita A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bi-Directional, Task-Dependent Control of Thalamic Input Gain, in Layer 4c of the Primary Visual Cortex, by the Cholinergic and Serotonergic Neuromodulatory Systems.
PROJECT SUMMARY / ABSTRACT Controlling the input that arrives at the primary visual cortex (V1) from the eyes is a powerful means for altering the outcome of all subsequent processing of visual information. That the strength (or gain) of this visual input to cortex can be dynamically modified is not controversial, but debate continues regarding the means by which that gain control is achieved. Currently, there are well-described mechanisms for modifying the strength of visual input based on other visual input (such as contrast gain control and normalization). However, modification of cortical processing by behavioral and cognitive states (such as attention) almost certainly arises from circuits outside the visual pathway, and we know far less about how this extra-retinal control of vision is achieved. Anatomical studies in macaque monkeys indicate that modulation by the cholinergic and serotonergic systems is strongly directed toward the site of visual input to cortex ? the thalamic-recipient layer (4c) in V1. This localization positions the cholinergic and serotonergic systems to control the extent to which information from the eyes gets processed, and therefore whether and how it is perceived. We hypothesize that acetylcholine and serotonin bi-directionally control the ?gate? to cortex, such that acetylcholine increases (and serotonin decreases) the strength of the input from the eyes. We will causally manipulate this modulatory control of layer 4c during active vision, and determine the resulting effects on both neural responses and behavior. At the neural level, we will determine the extent to which gain changes induced in layer 4c propagate to other layers, including the conditions under which propagation occurs, and the form the propagated signal takes. We will also determine the impact of these gain effects on behavior. Understanding how neuromodulators allow state variables (such as arousal and motivation) to dynamically rebalance cortical processing is critically important: Eight of the ten most-prescribed psychiatric drugs target neuromodulatory systems, as does the only approved drug treatment for dementia. Thus, it is through controlling neuromodulators that we (and the brain) modify perception, cognition, and behavior. It is generally assumed that these drugs act by altering late-stage cortical processing, but the anatomy points us towards a concurrent early modification of cortical input. We will elucidate the mechanism(s) behind, and determine the consequences of, that early control upon which all later processing depends.
|
1 |
2020 |
Disney, Anita A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bi-Directional, Task-Dependent Control of Thalamic Input Gain, in Layer 4c of the Primary Visual Cortex, by the Cholinergic and Serotonergic Neuromodulatory Systems
PROJECT SUMMARY / ABSTRACT Controlling the input that arrives at the primary visual cortex (V1) from the eyes is a powerful means for altering the outcome of all subsequent processing of visual information. That the strength (or gain) of this visual input to cortex can be dynamically modified is not controversial, but debate continues regarding the means by which that gain control is achieved. Currently, there are well-described mechanisms for modifying the strength of visual input based on other visual input (such as contrast gain control and normalization). However, modification of cortical processing by behavioral and cognitive states (such as attention) almost certainly arises from circuits outside the visual pathway, and we know far less about how this extra-retinal control of vision is achieved. Anatomical studies in macaque monkeys indicate that modulation by the cholinergic and serotonergic systems is strongly directed toward the site of visual input to cortex ? the thalamic-recipient layer (4c) in V1. This localization positions the cholinergic and serotonergic systems to control the extent to which information from the eyes gets processed, and therefore whether and how it is perceived. We hypothesize that acetylcholine and serotonin bi-directionally control the ?gate? to cortex, such that acetylcholine increases (and serotonin decreases) the strength of the input from the eyes. We will causally manipulate this modulatory control of layer 4c during active vision, and determine the resulting effects on both neural responses and behavior. At the neural level, we will determine the extent to which gain changes induced in layer 4c propagate to other layers, including the conditions under which propagation occurs, and the form the propagated signal takes. We will also determine the impact of these gain effects on behavior. Understanding how neuromodulators allow state variables (such as arousal and motivation) to dynamically rebalance cortical processing is critically important: Eight of the ten most-prescribed psychiatric drugs target neuromodulatory systems, as does the only approved drug treatment for dementia. Thus, it is through controlling neuromodulators that we (and the brain) modify perception, cognition, and behavior. It is generally assumed that these drugs act by altering late-stage cortical processing, but the anatomy points us towards a concurrent early modification of cortical input. We will elucidate the mechanism(s) behind, and determine the consequences of, that early control upon which all later processing depends.
|
1 |