1998 — 2021 |
Kirkwood, Alfredo |
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. |
Regulation of Synaptic Plasticity in Visual Cortex @ Johns Hopkins University
Visual experience during an early critical period is essential for the normal maturation of visual cortex, such that altered vision at this stage can have deleterious consequences, including amblyopia. Previous studies established that synaptic connections in the visual could be modified through a process that depends on both neural activity (Hebbian synaptic plasticity) and long-range neuromodulatory inputs that convey information on the behavioral state of the animals. The goal of this project is to elucidate the cellular mechanisms by which two prominent neuromodulators, norepinephrine and serotonin, control the induction Hebbian synaptic plasticity in the visual cortex. Specifically we will examine the hypothesis that norepinephrine and serotonin can act retroactively as reward-like signals to reinforce recently activated synapses. This proposal builds upon our recent finding that in cortical slices certain patterns of synaptic activity produce ?eligibility traces? for synaptic modification. These eligibility traces are transient and silent tags that can be converted into long-term potentiation if ?2-adrenergic receptors (?AR) are promptly activated, or into long-term depression if 5HT2C serotonergic receptors are activated. This retroactive action of the monoamines on Hebbian plasticity is a novel mechanism of neuromodulator that contrast and complement the more traditional view of neuromodulators as enabling factor that prime of promote subsequent plasticity. We plan to study the role of the induction/conversion of eligibility traces in visual cortical plasticity in vivo and to assess its impact in visual cortical responses. The findings resulting from the proposed can have translational consequences. In particular, the possibility of inducing rapid and targeted cortical modifications with the aid of neuromodulators can be relevant for restoring visual cortical functions in adults. Besides the obvious relevance of neural plasticity to the development of visual capabilities, it is likely that similar processes may form the basis for some forms of learning and memory in the adult brain.
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1 |
2007 — 2009 |
Kirkwood, Alfredo |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Senile Degeneration in the Brain of Octogon Degus @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and massive cell death in the cerebral cortex. A predominant view of the cause of AD is that the amyloid accumulation is the essential event leading to neurodegeneration. This hypothesis is supported by research on transgenic mice expressing familial mutations of the human amyloid precursor protein (APP) and presenilins. These animals reproduce key aspects of the disease, including amyloid plaques, deficits in cognitive tasks and abnormalities in the mechanisms of synaptic plasticity responsible for learning and memory. However, these mice rarely develop neurobibrillary tangles and exhibit little synaptic and neuronal loss, hallmarks of AD. In addition, these models of familial forms of AD might be less significant to study sporadic (non-familial) forms of AD, which represent about 95% of AD cases. We will examine the feasibility of using the rodent Octodon degus as a model to study sporadic forms of AD. Octodon degus, is a diurnal, visual and highly social rodent that naturally develop AD-like pathologies including amyloid plaques and neurobrillary tangles accumulation with age. Octodon degus also exhibit a marked age-related decline in the ability to discriminate novel from familiar objects, a working visual memory task. We hypothesize that the development of AD-like pathologies in O.degus alters synaptic plasticity and impairs visual memory. To test this hypothesis, we propose to determine in individual O. degus whether the degree of cognitive impairments correlates with deficits in synaptic plasticity and the Ab deposits. These investigations could establish an animal model for sporadic AD that will complement existing models of familial forms of the disease. [unreadable] [unreadable]
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1 |
2009 — 2012 |
Kirkwood, Alfredo |
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. |
Regulation of Synaptic Plastiticy in Visual Cortex @ Johns Hopkins University
DESCRIPTION (provided by applicant): It has long been appreciated that visual experience during an early critical period is essential for the normal maturation of visual cortex. Studies on animals reared in different environments have established that during this critical period, visual cortical connections can be modified in an activity dependent manner. Those studies have also shown that visual cortical plasticity depends on neuromodulary inputs that convey information on the behavioral state of the animals, and on the strength of intracortical inhibition. The long-term goal of this project is to elucidate the cellular mechanisms by which age, neuromodulators and synaptic inhibition control synaptic modification in visual cortex. This proposal builds upon two recent findings on the regulation of synaptic plasticity in cortex. First, we have found that neuromodulators control the polarity (increase or decrease) of synaptic changes induced by patterned neural activity in vitro, in slices of rat visual cortex. Therefore we will investigate the mechanisms of the neuromodulation of plasticity, and will examine whether these mechanism also operate in vivo and in primates. Second, prompted by the recent observation that exposure to complete darkness for a week reactivates juvenile-like plasticity in adults rats, the regulation of two forms of synaptic modification are believed to be involved in natural occurring plasticity: long-term potentiation (LTP) and long-term depression (LTD). The studies are aimed to test two hypotheses concerning how neuromodulators and synaptic inhibition might regulate the induction of these forms of plasticity. The first hypothesis states that neuromodulators control the polarity and magnitude of activity- dependent synaptic modification. The second hypothesis states that developmental increases in the strength of synaptic inhibition reduces or prevents the induction of LTP and LTD. The experiments will be performed in slices made from the visual cortex of rats and mice of different ages and raised in different environments. Changes in LTP and LTD will be compared with reported changes in naturally-occurring synaptic modifications. Understanding how LTP and LTD are regulated will yield insights into the mechanisms underlying the critical period and will provide a cellular understanding of the integrative aspects of cortical plasticity. Besides the obvious relevance of this neural plasticity to the development of visual capabilities, it seems likely that similar processes may form the basis for some forms of learning and memory in the adult brain. PUBLIC HEALTH RELEVANCE Abnormal or insufficient visual experience during early infancy can result in inappropriate wiring of the visual system, and in diminished visual capabilities. This proposal will investigate the mechanisms that control the wiring of the visual system. The conclusions will be relevant for preventing incorrect wiring, and for restoring normal vision.
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1 |
2009 — 2011 |
Kirkwood, Alfredo |
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. |
Synaptic Function &Plasticity in Ca3 Circuits in the Aging Hippocampus @ Johns Hopkins University
DESCRIPTION (provided by applicant): Aging has a profound impact on learning and encoding new memories. Advances in the field of aging suggest that changes at the cellular level rather than structural alterations are more relevant for understanding cognitive deficits associated with aging. In this regard, electrophysiological analysis of synaptic function in the CA1 region of the hippocampus has provided the important insights that age disrupts the mechanisms by which the synaptic connectivity is modified to encode new memories. These changes in synaptic plasticity provide a conceptual basis to understand learning deficits in aged individuals. Although focusing on alterations in CA1 associated with learning deficits has been fruitful, recently it has become clear the need to expand the research scope. First is the realization that other circuits in the hippocampus participate differently during memory encoding, and that aging affects them differently, and even more prominently, in the case of CA3. In addition, although on average cognitive abilities decline with age, a recognizable subpopulation of aged individuals maintains mental abilities. Thus, while an ultimate goal could be to preserve the integrity of the cellular processes normally affected by age, a complementary approach is to focus on adaptative changes occuring naturally in response to lost functions. We approach these issues ex vivo, by studying synaptic plasticity in hippocampal slices from aged rats characterized in a hippocampal- dependent learning task. The goals of this project are to 1) understand how aging affects the synaptic functions that support learning in CA3, 2) identify mechanisms that allow some aged individuals to maintain cognitive abilities and 3) understand how intervention treatments that improve learning in aged individuals affect synaptic plasticity. Our research suggests that some mechanisms of synaptic plasticity are irreversibly lost in aged rats. However, those aged individuals that maintained cognitive performance manage to compensate for the lost by boosting other mechanisms. These adaptatively enhanced plasticity mechanisms are an obvious target for therapeutical strategies aimed at restoring learning in aged individuals. PUBLIC HEALTH RELEVANCE: Aging can have a pronounced impact on mental abilities, particularly on learning and memory. Although such decline is widespread enough to be often considered a normal aspect of aging, some older individuals retain strong cognitive abilities. This proposal will investigate the type of neural adaptive changes that are required to maintain cognitive performance at old age.
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1 |
2012 — 2013 |
Kirkwood, Alfredo |
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. |
Synaptic Function & Plasticity in Ca3 Circuits in the Aging Hippocampus @ Johns Hopkins University
DESCRIPTION (provided by applicant): Aging has a profound impact on learning and encoding new memories. Advances in the field of aging suggest that changes at the cellular level rather than structural alterations are more relevant for understanding cognitive deficits associated with aging. In this regard, electrophysiological analysis of synaptic function in the CA1 region of the hippocampus has provided the important insights that age disrupts the mechanisms by which the synaptic connectivity is modified to encode new memories. These changes in synaptic plasticity provide a conceptual basis to understand learning deficits in aged individuals. Although focusing on alterations in CA1 associated with learning deficits has been fruitful, recently it has become clear the need to expand the research scope. First is the realization that other circuits in the hippocampus participate differently during memory encoding, and that aging affects them differently, and even more prominently, in the case of CA3. In addition, although on average cognitive abilities decline with age, a recognizable subpopulation of aged individuals maintains mental abilities. Thus, while an ultimate goal could be to preserve the integrity of the cellular processes normally affected by age, a complementary approach is to focus on adaptative changes occuring naturally in response to lost functions. We approach these issues ex vivo, by studying synaptic plasticity in hippocampal slices from aged rats characterized in a hippocampal- dependent learning task. The goals of this project are to 1) understand how aging affects the synaptic functions that support learning in CA3, 2) identify mechanisms that allow some aged individuals to maintain cognitive abilities and 3) understand how intervention treatments that improve learning in aged individuals affect synaptic plasticity. Our research suggests that some mechanisms of synaptic plasticity are irreversibly lost in aged rats. However, those aged individuals that maintained cognitive performance manage to compensate for the lost by boosting other mechanisms. These adaptatively enhanced plasticity mechanisms are an obvious target for therapeutical strategies aimed at restoring learning in aged individuals. PUBLIC HEALTH RELEVANCE: Aging can have a pronounced impact on mental abilities, particularly on learning and memory. Although such decline is widespread enough to be often considered a normal aspect of aging, some older individuals retain strong cognitive abilities. This proposal will investigate the type of neural adaptive changes that are required to maintain cognitive performance at old age.
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1 |
2015 — 2021 |
Kirkwood, Alfredo |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 3-Synaptic Function in Behaviorally-Characterized Aged Rats in Circuits of the Entorhinal Cortex and Dentate Gyrus @ Johns Hopkins University
Aging frequently impairs cognitive functions associated with the medial temporal lobe (MTL), particularly the formation of new memories, and it is also a major risk factor for Alzheimer?s disease (AD). Recent studies in rodent models and humans identified hyperactivity in specific circuits/subregions of the MTL, the lateral entorhinal cortex (LEC) and its downstream target the dentate/CA3 subfields of the hippocampus, as a distinctive feature that associates with impaired memory in aged individuals. A wealth of experimental and theoretical studies indicates that the deleterious consequences of hyperactivity are multiple. Hyperactivity not only compromises normal neural processing and the recruitment of plasticity mechanisms required for encoding new memories, but it can also accelerate activity dependent pathogenic processes, like A? production/deposition and spread of tau-hyperphosphorylation/toxicity along neural connections. In multiple brain areas, network activity is dynamically controlled primarily by GABAergic circuits subserved by parvalbumin-positive inhibitory interneurons (PV-INs). Importantly, mounting evidence indicates that dysfunction of these inhibitory circuits is a contributing factor in age-related hyperexcitability, particularly in the earliest phases of AD. In adults, the inhibitory output of the PV-INs is relatively stable, but the excitatory input onto PV-INs is comparatively dynamic and plastic. In this context, a particularly interesting research target for hyperxcitability during aging is Neuronal Pentraxin-2 (NPTX2), an extracellular protein released by excitatory neurons in an activity-dependent manner that is crucial for stabilizing AMPA receptors at synapses on PV-INs. Importantly, the genetic ablation of NPTX2 reduces these excitatory inputs by half in mouse cortex, and in elderly humans low levels of NPTX2 in the cerebral spinal fluid (CSF) correlates with reduced cognitive performance across the spectrum of aging/AD. In this proposal we will examine the novel hypothesis that a reduction in NPTX2- mediated stabilization of the excitatory connectivity onto PV-INs contributes to cognitive impairment during aging. We will directly evaluate the functional status of multiple excitatory inputs onto PV-INs within the MTL in a well-characterized rat model for individual cognitive differences in aging. We will also test whether manipulating NPTX2 affects these inputs as expected from the hypothesis. Testing the causal effect of NPTX2 in age-dependent cognitive impairment in a comprehensive manner in multiple pathways, might help identifying potential therapeutic targets to can alleviate age related cognitive decline.
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1 |
2015 — 2018 |
Kirkwood, Alfredo Lee, Hey-Kyoung (co-PI) [⬀] Quinlan, Elizabeth Mary [⬀] |
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. |
Reversible Activation On Critical Plasticity in Visual Cortex @ Univ of Maryland, College Park
? DESCRIPTION (provided by applicant): During a critical period of early postnatal development, an asymmetry in the quality of visual input to the two eyes shifts ocular preference away from the weaker eye and induces amblyopia, the most common cause of monocular visual deficits in humans. Amblyopia is highly resistant to reversal in adulthood, due in large part to th termination of the critical period of heightened plasticity. Understanding how the enhanced plasticity of the critical period is initiated and terminated over development is fundamental to th development of therapeutic strategies aimed to reactivate plasticity to treat amblyopia in adults, which can be translated to a clinical population and to other critical periods. A popular model for the regulation of the critical period proposes that inhibitory control of plasticity at excitatory synapses is mediated by the maturation of the output of fast-spiking interneurons (FS-INs) that mediate perisomatic inhibition. However, we have shown that ocular dominance plasticity can be induced several months after the maturation of perisomatic inhibition. We propose instead that ocular dominance plasticity is regulated by plasticity upstream of inhibitory output, likely affecting the recruitment of inhibition into functional circuits. In addition we propose that the functional connectivity of Pyr->FS synapses must be retained in a permissive range for ocular dominance plasticity to be expressed, as larger reductions in Pyr->FS connectivity induced by genetic manipulations inhibit the expression of ocular dominance plasticity. Our preliminary analysis of the regulation of excitation from pyramidal neurons onto FS-INs (Pyr->FS) reveals that monocular deprivation during the critical period may functionally disconnect FS-INs from the cortical network by significantly reducing the number of excitatory inputs onto these neurons. Therefore we hypothesize that a novel mechanism of plasticity, deprivation-induced loss of functional Pyr->FS connectivity 1) is an early and obligatory step in the shift in ocular dominance induced by MD, and 2) determines the timing of the critical period. We propose a multidisciplinary set of experiments to test these hypotheses that combine: the expertise of the Quinlan lab in the examination of physiological changes in visual cortex in vivo in response to monocular deprivation; the expertise of the Kirkwood lab in the direct assessment of contribution of changes in single synapses to activity-dependent plasticity in the visual cortex; and the expertise of the Lee lab in the use optogenetic methods to identify foci and mechanisms of activity-dependent changes in synaptic function. Our model for the regulation of the timing of the critical period refutes many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.
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0.901 |
2021 |
Kirkwood, Alfredo Quinlan, Elizabeth Mary [⬀] |
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. |
Reversible Activation of Critical Period Plasticity in Visual Cortex @ Univ of Maryland, College Park
Project Summary/Abstract Amblyopia is induced in model systems by monocular deprivation (MD), which changes the stimulus selectivity of neurons in the primary visual cortex. Prior research utilizing this model established that the changes in neural selectivity induced by MD result from the reorganization of excitatory glutamatergic cortical synapses onto excitatory cortical neurons, which is regulated by an inhibitory GABAergic network composed of parvalbumin positive inhibitory interneurons (PV INs). An emerging consensus is that a permissive level of inhibition from PV IN circuits in cortical layer 2/3 is required for plasticity at downstream excitatory synapses, and that inhibition above or below the permissive range constrains the response to MD. Accordingly, developmental strengthening of inhibition triggers the onset of the critical period; at later stages, the ?permissive? range of inhibition is achieved by reductions the recruitment of PV INs. Here we identify the plasticity of excitation onto layer 2/3 PV INs as a critical locus for the regulation of circuit reorganization in V1. Our preliminary data demonstrate that the initial response to MD is a rapid and transient elimination of excitatory connections made by local pyramidal neurons (Pyr) onto PV INs. Following 1 day of MD, we find that ~50% of local L2/3 Pyrà?PV-IN connections are eliminated. Importantly, synapses from distal L2/3 Pyrs and excitation from layer 4 Pyrs remains unchanged. This all-or-none elimination of specific connections coincides with the loss of synaptic structure, is transient, and returns to control values following 3 days of MD. Our preliminary results also demonstrate that the MD-induced elimination of proximal L2/3 Pyrà?PV INs inputs depends on mGluR5 activation and is inhibited by expression of activity-independent neuronal pentraxin 2 (NPTX2). We propose that the rapid mGluR5 and NPTX2-dependent elimination of local L2/3 Pyrà?PV INs connection is an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Accordingly, we show that accumulation of NPTX2 prevents L2/3 Pyrà?PV IN elimination and ocular dominance plasticity. Conversely, expression of dominant negative NPTX2 in adults reactivates the elimination of L2/3 Pyrà?PV INs and ocular dominance plasticity in response to MD We propose a series of multidisciplinary experiments to test the validity of this model that combine the expertise of the Quinlan lab in the assessment of physiological changes in vivo physiology and the Kirkwood lab in the assessment of changes in single synapses between identified neurons. We will test the hypothesis that the elimination of L2/3 Pyrà?PV INs excitatory synapses is 1) local, transient and confined to a postnatal critical period 2) dependent on mGluR and NPTX2 signaling and 3) an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Our model predicts that the end of the critical period reflects directly the loss of L2/3 Pyrà?PV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.
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0.901 |