1999 — 2001 |
Frazier, Charles J |
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. |
Inactivation of Delayed Rectifier Potassium Channels
Voltage gated "delayed rectifier" potassium channels in excitable cells are important for rapid repolarization of the membrane during an action potential. Delayed rectifiers slowly inactivate during maintained depolarization, however (in some cases) inactivation develops quite rapidly during a train of action potential-like pulses. The time- and voltage-dependence of inactivation profoundly affects the behavior of a neuron, and could potentially be related to a number of neurological disorders that involve abnormal neuronal excitability, such as epilepsy. There are three specific aims of this work: (1) to determine the nature and extent of several types of inactivation that may occur in a particular delayed rectifier, Kv2.1, (2) to determine how inactivation is coupled to gating in Kv2.1, and (3) to apply that information to the study of native delayed rectifiers in thalamic neurons. Those aims will be accomplished by conducting whole cell voltage clamp recordings in cultured HEK293 cells transfected with Kv2.1 (Aims 1 and 2), or in acutely dissociated ventrobasal thalamic neurons from rat (Aim 3). These experiments will contribute significantly to our long-term objectives of understanding both the mechanism of ion channel function and the contribution of that function to neuronal activity.
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0.936 |
2005 — 2009 |
Frazier, Charles J |
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. |
Endocannabinoids and Tonic Gaba in the Dentate Gyrus
DESCRIPTION (provided by applicant): This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of the neurophysiological mechanisms responsible for modulating the activity of synaptic inputs to hilar mossy cells. These unusual excitatory local circuit neurons receive strong glutamatergic, GABAergic, and likely cholinergic innervation from a variety of intrinsic and extrinsic sources. Normal function of mossy cells has been postulated to play a prominent role in information processing and memory formation in the hippocampus, while their loss and/or dysfunction has been implicated in the etiology of temporal lobe epilepsy. Preliminary data indicate that the activity of both inhibitory and excitatory inputs to mossy cells is modulated by depolarization-induced release of endogenous cannabinoids. Aim 1 of this proposal will provide a complete characterization of cannabinoid dependent signaling initiated by activation of mossy cells, and examine the role of postsynaptic cholinergic receptors in modulating the threshold for endocannabinoid release. Preliminary data has also indicated that presynaptic GABAergic receptors are expressed on some excitatory afferents to hilar mossy cells and further suggested that these receptors are likely subject to tonic inhibition by ambient GABA. Thus, Aim 2 will focus on ambient GABA as a potential modulator of these excitatory afferents and will ultimately determine if there is a useful relationship between endocannabinoid mediated retrograde signaling and inhibitory tone. Finally, Aim 3 will test the hypothesis that endocannabinoid mediated retrograde signaling in this system is impaired by chronic exposure to natural and/or synthetic cannabinoid agonists. These experiments may expose specific neurophysiological mechanisms that are fundamentally involved in regulation of excitability, information processing, and memory formation in the dentate gyrus, and further determine how they are altered over time in a chronic model of drug abuse.
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0.936 |
2006 — 2007 |
Frazier, Charles J |
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. |
Endocannabinoids and Tonic Gaba in the Dentate Gyrus.
DESCRIPTION (provided by applicant): This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of the neurophysiological mechanisms responsible for modulating the activity of synaptic inputs to hilar mossy cells. These unusual excitatory local circuit neurons receive strong glutamatergic, GABAergic, and likely cholinergic innervation from a variety of intrinsic and extrinsic sources. Normal function of mossy cells has been postulated to play a prominent role in information processing and memory formation in the hippocampus, while their loss and/or dysfunction has been implicated in the etiology of temporal lobe epilepsy. Preliminary data indicate that the activity of both inhibitory and excitatory inputs to mossy cells is modulated by depolarization-induced release of endogenous cannabinoids. Aim 1 of this proposal will provide a complete characterization of cannabinoid dependent signaling initiated by activation of mossy cells, and examine the role of postsynaptic cholinergic receptors in modulating the threshold for endocannabinoid release. Preliminary data has also indicated that presynaptic GABAergic receptors are expressed on some excitatory afferents to hilar mossy cells and further suggested that these receptors are likely subject to tonic inhibition by ambient GABA. Thus, Aim 2 will focus on ambient GABA as a potential modulator of these excitatory afferents and will ultimately determine if there is a useful relationship between endocannabinoid mediated retrograde signaling and inhibitory tone. Finally, Aim 3 will test the hypothesis that endocannabinoid mediated retrograde signaling in this system is impaired by chronic exposure to natural and/or synthetic cannabinoid agonists. These experiments may expose specific neurophysiological mechanisms that are fundamentally involved in regulation of excitability, information processing, and memory formation in the dentate gyrus, and further determine how they are altered over time in a chronic model of drug abuse.
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0.936 |
2011 — 2012 |
Frazier, Charles J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cb1r Independent Effects of Cannabinoids On Synaptic Physiology in the Cns.
DESCRIPTION (provided by applicant): This is a basic science proposal designed to use in vitro electrophysiological and optical techniques to further our understanding of an extremely unusual form of cannabinoid dependent signaling discovered in my lab. Specifically, we have observed that cannabinoid receptor agonists potentiate action potential independent release of GABA in the dentate gyrus through a cannabinoid type I (CB1) receptor independent mechanism. Although recent years have brought an enormous wealth of new information about the specific roles of endogenous cannabinoids in CNS physiology, the effect of cannabinoid receptor agonists that we have discovered appears to be unique in numerous respects. First, it does not depend on activation of CB1, CB2, or vanilloid type I receptors, and is still present in CB1-/- animals. Second, it clearly modulates action potential independent exocytotic events without altering action potential dependent events, and third, it ultimately results in the facilitation (rather than inhibition) of exocytosis. While our preliminary data represent significant progress towards characterizing a new role for cannabinoids in CNS physiology, many fundamental questions regarding this new phenomenon remain. Therefore this proposal requests funds to continue our investigation in this area through implementation of two Specific Aims. Aim 1 will test the hypothesis that cannabinoid mediated facilitation of action potential independent exocytosis depends on a specific ligand receptor interaction with an as yet unidentified GPCR. Specifically, we hypothesize that a G1s ->AC ->cAMP ->PKA signaling cascade is involved. Aim 2 will test the hypothesis that anandamide or one of its metabolites will be the most effective endogenously available ligand for facilitation of action potential independent release, and that the best agonists will work well within a physiologically relevant concentration range. Collectively, these Aims are designed to provide data that have the potential to clearly establish the significance of our findings for the cannabinoid field, and that will directly facilitate a longer term and larger scale investigation of the phenomenon. PUBLIC HEALTH RELEVANCE: Nearly all the known central effects of endogenous cannabinoids are thought to be mediated by activation of a single type of receptor, the CB1 cannabinoid receptor. We have recently discovered a highly novel form of cannabinoid mediated signaling that does not depend on CB1 receptor activation, and that has unique effects on CNS physiology. The current proposal is designed to address several fundamental questions about this new signaling system that we hope will ultimately establish the overall significance (and potential) of the finding.
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0.936 |
2015 — 2019 |
Frazier, Charles J |
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. |
Novel Aspects of Central Oxytocin Signaling Relevant to Mood/Anxiety Disorders
? DESCRIPTION (provided by applicant: Currently, centrally acting oxytocin receptor (OTR) agonists are generating considerable interest for their potential to be developed as novel therapeutics for a range of neuropsychiatric disorders including autism, schizophrenia, post-traumatic stress disorder, obsessive compulsive disorder, and more generalized mood and anxiety disorders. Indeed, an extensive literature implicates centrally acting oxytocin in pair bonding and social interactions, and further highlights well noted potential for oxytocin to produce antidepressive and anxiolytic effects. Because oxytocin in the periphery is a very poor penetrator of the blood brain barrier, it is likely that this wide array of powerful central effect depends on oxytocin released by magnocellular neurosecretory neurons located in the supraoptic and paraventricular nuclei of the hypothalamus; the only central nuclei to produce oxytocin in abundance. Oxytocinergic neurons in these areas are unlike many excitable cells in the CNS in that they have two distinctly different ways to release peptide: paracrine and synaptic (which depend on dendritic and axonal structures, respectively). To date, very little is known about the distinctly different mechanisms though which paracrine or synaptic release of oxytocin in the brain ultimately modulates central circuits underlying mood affect and social behavior. In a broad sense, this project seeks to address that gap by developing techniques to independently evaluate neurophysiological mechanisms engaged by these distinct types of endogenous oxytocinergic signaling. More specifically, current Aims will motivate sustained paracrine release of oxytocin in the PVN using a systemic osmotic stressor that has recently been demonstrated to blunt the physiological response to psychogenic stress, and to produce a clear anxiolytic behavioral phenotype in tests for social and generalized anxiety. Based on extensive preliminary data, Aim 1 will test the hypothesis that paracrine release of oxytocin in the hypothalamus contributes to an anxiolytic phenotype in large part by directly inhibiting parvocellular neurosecretory neurons that express corticotropin releasing factor (Aim 1). Aim 2 will then reveal a previously unexpected and likely disynaptic mechanism through which paracrine release of oxytocin can disinhibit parvocellular preautonomic neurons in the PVN. Finally, Aim 3 will examine the effect of autocrine receptor activation of both dendritic and presynaptic OTRs on PVN magnocellular neurons. This work is expected to reveal a powerful positive feedback loop that supports both sustained paracrine and enhanced synaptic oxytocin release. Overall, Aim 1 has high potential significance because it will indicate a clear mechanism through which centrally acting oxytocin can effectively modulate key aspects of the stress response that have long been implicated in the etiology of mood and anxiety disorders. Further, Aims 2-3 enhance the overall significance of the project by revealing several new functional aspects of the central paracrine oxytocin signal that are likely to help guide and infor rational development of new therapeutics that seek to transiently activate central OTRs.
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0.936 |
2018 |
Bizon, Jennifer Lynn [⬀] Frazier, Charles J (co-PI) [⬀] Setlow, Barry (co-PI) [⬀] |
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. |
Decision Making and Basolateral Amygdala Dysfunction in Aging
PROJECT SUMMARY. The ability to make effective decisions is critical for managing finances, health care, and other activities of daily living necessary to maintain personal independence. Decision making is altered in both normal aging and in Alzheimer's disease (AD), albeit in different ways. Specifically, healthy older adults tend to make less impulsive and risky choices compared to young adults, whereas AD is associated with greater impulsivity and maladaptive risk taking relative to age-matched healthy controls. While distinct, these decision biases associated with aging and AD can both be maladaptive and have significant implications for life quality. Optimizing decision making could broadly benefit functional outcomes and promote independent living among older adults; however, development of interventions is currently hindered by a poor understanding of the neural mechanisms underlying maladaptive decision making in aging and AD. To begin to address this gap in knowledge, our labs have shown that aged rats, which lack overt AD pathology, exhibit reductions in impulsive and risky choice in a manner similar to that observed in aged humans. Moreover, preliminary data suggest that these age differences in decision making are mediated by the basolateral amygdala (BLA). The BLA is implicated in affective processing and is highly interconnected within decision-making circuits. Using in vivo optogenetic approaches in both young and aged rats, we have identified multiple, temporally distinct contributions of BLA to both impulsive and risky choice and shown these contributions of BLA to decision making change with age. The long-term goal of this research program is to determine the mechanisms by which decision making is altered in aging and AD. The immediate objective is to determine the effects of aging and early tau pathology on BLA function and its role in decision making. Our overarching hypothesis is that aging and tau pathology disrupt adaptive decision making through alterations in BLA excitatory and inhibitory dynamics. Aim 1 will determine how optogenetic activation and inhibition of BLA at discrete stages of the decision process influence aged rats' decision making. Parallel biochemical assays will evaluate the influence of age on BLA synaptic and excitatory/inhibitory signaling proteins in conjunction with decision making behavior. Aim 2 will address similar questions in conjunction with a virally-mediated approach that induces medial temporal lobe tau pathology in a manner that is anatomically relevant to early stage AD. Aim 3 will use optogenetic approaches to determine how aging alters the contributions of distinct BLA efferent circuits to decision making, and will use cellular electrophysiology to evaluate effects of aging on anatomically defined subsets of BLA efferent neurons. Completion of these experiments will reveal at the biochemical, cellular, and systems level how the BLA is influenced by aging and tau pathology, as well as how such alterations contribute to maladaptive decision making. The information will be significant because it will provide foundational knowledge that is critical for development of novel interventions to maximize decision quality in both normal aging and AD.
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0.936 |