2010 — 2014 |
Bender, Kevin J |
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. |
Function and Regulation of Action Potential Bursts in the Auditory System. @ Oregon Health &Science University
DESCRIPTION (provided by applicant): Circuits in the auditory brainstem dorsal cochlear nucleus (DCN) are believed to aid in sound localization in the vertical plane using monaural cues. Moreover, DCN circuitry integrates auditory and non-auditory inputs to aid in orientation toward sounds or to suppress self-generated noise, thereby increasing the salience of external sounds. Our long-term goal is to understand the synaptic mechanisms that contribute to these functions. Multisensory integration is controlled, in part, by high-frequency action potential bursts from inhibitory cartwheel cells;yet the way in which bursts are generated, and the effects of burst inhibition on postsynaptic integration, remain unclear. The objective of this proposal is to define mechanisms governing burst generation, focusing on the role of newly-discovered low-threshold activated calcium channels localized to the site of action potential initiation in the axon initial segment. First, we will use a combination of electrophysiology and 2-photon imaging to identify signaling pathways that control neuronal output by regulating initial segment calcium channel activity. Second, we will take advantage of novel voltage imaging techniques to determine how calcium channels contribute to the generation of bursts in the initial segment. Finally, we will determine how inhibitory synaptic input affects integration in the efferent neurons of the DCN, fusiform cells, contrasting the effects of single action potentials and bursts. PUBLIC HEALTH RELEVANCE: Dysfunctions in low-voltage activated calcium channel activity contributes to hyperexcitability in many brain regions, and may be etiological to tinnitus and epilepsy. This proposal examines the function and regulation of low-voltage activated calcium channels localized to the site of action potential initiation. Understanding how these channels affect neuronal output may uncover new avenues for treatment of hyperexcitability conditions.
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1 |
2013 — 2017 |
Bender, Kevin 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. |
Cellular Mechanisms For Dopaminergic Control of Learning in Prefrontal Cortex @ University of California, San Francisco
DESCRIPTION (provided by applicant): Prefrontal cortex is critical for many high-order executive functions, including decision making, attention, and working memory. Dysfunctions in prefrontal executive control and decision making have been implicated in all aspects of addiction, including addiction establishment, expression, and relapse. To make decisions, prefrontal cortex requires information about current sensory and motor states, conveyed via long-range intracortical inputs, and information about reward states, conveyed via dopaminergic inputs. Indeed, dopamine is hypothesized to be a major regulator of intracortical connectivity, and is critical for models of associative learning in prefrontal circuits. Yet how this regulation occurs at the cellular level is unclear. The objective of this proposal is to identify cellular mechanisms by which dopamine regulates intracortical processing in prefrontal circuits, with particular focus on how dopamine can modulate learning rules at intracortical synaptic inputs. We will use a combination of electrophysiology, 2-photon imaging, and optogenetics to examine dopaminergic regulatory mechanisms, their recruitment by endogenous dopamine signaling, their time course, and dysfunction with drug use. Results of this study will provide insight into how PFC networks function normally and when challenged by drug use.
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1 |
2016 — 2017 |
Bender, Kevin 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.) |
Development and Physiology of Axo-Axonic Synapses @ University of California, San Francisco
During adolescence, many high-order cognitive functions develop and mature, including impulse control, long-term planning, and risk evaluation. Neurological disorders that impair executive function, such as schizophrenia, are often diagnosed during adolescence. One major site of adolescent maturation in prefrontal cortex are GABAergic inhibitory circuits, including parvalbumin positive chandelier cells. Chandelier cells synapse directly onto the axon potential initiating sites of neighboring glutamatergic pyramidal cells. They are therefore uniquely poised to regulate pyramidal cell spiking. Here, our goal is to understand how chandelier cells regulate the activity of pyramidal cells as prefrontal cortical networks undergo adolescent development. We will use a combination of electrophysiology, including perforated patch recording, 2-photon imaging and genetic techniques to understand how these unique interneurons regulate the integrative properties of the axon initial segment. Results of this study will provide insight into how inhibitory circuit maturation contributes to the normal maturation of prefrontal circuits and may elucidate potential therapeutic targets in neurological disorders such as schizophrenia.
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1 |
2017 — 2021 |
Bender, Kevin J Whistler, Jennifer L (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. |
Molecular and Circuit Mechanisms of Antipsychotics @ University of California, San Francisco
Project Abstract/Summary Dysregulation of prefrontal cortex (PFC) dopaminergic signaling is associated with multiple neuropsychiatric diseases, including depression, bipolar disorder, and schizophrenia. Current antipsychotics have high affinity for Gi/o-coupled D2 and D3 receptors (D2R, D3R). While there has been considerable focus on the role of prefrontal D2Rs in neuropsychiatric disease, there is emerging evidence that the D3R is also critically important. However, we know very little about the cellular distribution and function of D3Rs in prefrontal circuits, or how antipsychotics regulate their function. The goal of this proposal is to determine the neuronal distribution and function of D3R in prefrontal cortex, the cellular mechanisms by which D3R regulates neuronal excitability, and the mechanisms by which antipsychotics regulate their function. We will use a combination of electrophysiology, 2-photon imaging, and molecular biology in native and heterologous systems to examine D3R signaling mechanisms, with particular focus on the potential role of arrestin-mediated signaling. Results of this study will provide insight into how PFC networks function normally and abnormally in psychiatric disease.
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1 |
2019 — 2020 |
Bender, Kevin J Ron, Dorit (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. |
Adolescent Alcohol Drinking and Gaba Signaling @ University of California, San Francisco
PROJECT SUMMARY Adolescence marks a period of increased risk taking and exploration. As part of this exploratory behavior, many individuals initiate alcohol use during adolescence, which can lead to increased risk for alcohol use disorders later in life. One major site of adolescent maturation in prefrontal cortex are GABAergic inhibitory neurons, including parvalbumin positive chandelier cells. Chandelier cells synapse directly onto the axon potential initiating sites of neighboring glutamatergic pyramidal cells. They are therefore uniquely poised to regulate pyramidal cell spiking. Here, our goal is to understand how the function of these two inhibitory cell classes are affected by adolescent alcohol consumption, and to determine if manipulations to chloride transporter function alters drinking behavior. We will use a combination of electrophysiology and 2-photon imaging to understand how interneuron function is regulated at the cellular level, and viral manipulation of chloride transporter function paired with behavior to understand how prefrontal inhibitory function regulates drinking. Results of this study will provide insight into how inhibitory circuits contribute to drinking behavior and may elucidate potential therapeutic targets to treat alcohol abuse disorders.
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1 |
2021 |
Bender, Kevin J Jenkins, Paul Michael [⬀] |
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. |
Convergent Mechanisms For Neurodevelopmental Disorder Genes @ University of Michigan At Ann Arbor
Thanks to the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). What is currently missing is a mechanism linking these genes into a convergent pathway that gives insight into disease etiology. In this proposal, we will test the hypothesis that ANK2 and SCN2A, two of the top genes implicated in ASD, are linked at the molecular level to control dendritic excitability. NaV1.2, product of the SCN2A gene, is a voltage-gated sodium channel found primarily in pyramidal neurons where it localizes to the axon initial segment (AIS) early in development. Later in development, NaV1.2 relocalizes to dendrites where it plays critical roles in synaptic plasticity and stability. The timing of the subcellular relocalization of NaV1.2 away from the AIS (~ 1 year in humans) also correlates with the onset of symptoms in ASD patients, suggesting that understanding the new role for NaV1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD. While our group and others have shown that the intracellular scaffolding protein, ankyrin-G (ANK3), is necessary for NaV1.2 localization to the AIS, very little is known about the mechanisms underlying the dendritic localization of NaV1.2. Ankyrin-B, product of the ANK2 gene, is a member of the ankyrin gene family that shares significant homology with ankyrin-G, yet it is localized at high levels to dendrites where it may play a key role in NaV1.2 dendritic localization. Testing the hypothesis that ANK2 and SCN2A are linked at the molecular level to control dendritic excitability will have a positive impact by increasing our understanding of the mechanisms underlying synaptic alterations in ASD, which may provide novel targets for therapeutic intervention.
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0.945 |