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Investigation of the spatiotemporal dynamics of cAMP and PKA signaling and the role of HCN4 subunits in anxiety-related behavior and memory- [electronic resource]
Investigation of the spatiotemporal dynamics of cAMP and PKA signaling and the role of HCN4 subunits in anxiety-related behavior and memory- [electronic resource]
상세정보
- 자료유형
- 학위논문(국외)
- 자관 청구기호
- 기본표목-개인명
- 표제와 책임표시사항
- Investigation of the spatiotemporal dynamics of cAMP and PKA signaling and the role of HCN4 subunits in anxiety-related behavior and memory - [electronic resource] / Luczak, Vincent Gerard.
- 발행, 배포, 간사 사항
- 형태사항
- 1 online resource(119 p)
- 일반주기
- Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
- 일반주기
- Adviser: Ted Abel.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2016.
- 요약 등 주기
- 요약In the hippocampus, long-term memory and synaptic plasticity occur through a series of coordinated intracellular signaling cascades that strengthen and stabilize subsets of synaptic connections while leaving thousands of others unaltered. Therefore, understanding how molecular signals are accurately transmitted is critical to understanding how hippocampal neurons store information. Molecules like cAMP and protein kinase A are critical components of memory and plasticity, but it is unclear how these diffusible signals are dynamically regulated to achieve the spatial and temporal specificity that underlies pathway-specific plasticity. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are ion channels that are modulated by cAMP and are known to regulate the spatial and temporal dynamics of excitatory postsynaptic potentials. HCN1 and HCN2 subunits have been implicated in memory, plasticity and anxiety-related behaviors, but the role for HCN4 subunits remains untested. In Chapter 1, I review the role of cAMP signaling in hippocampal synaptic plasticity and memory consolidation with emphasis on the molecular mechanisms regulating cAMP, PKA and HCN channels. In Chapter 2, I combine live two-photon imaging of genetically-encoded fluorescent FRET sensors and computational modeling to investigate the molecular mechanisms regulating the spatiotemporal dynamics of cAMP and PKA activity in hippocampal neurons during stimulation of beta-adrenergic receptors. Results suggest that the ratio between adenylyl cyclase and phosphodiesterase-4 scales with neuronal compartment size to maintain basal cAMP levels and produce rapid-onset, high-amplitude cAMP transients in small compartments. Conversely, imaging experiments show that PKA activity is greater in large neuronal compartments and modeling suggests that compartmental differences in PKA activity depend on the concentration of protein phosphatase and not on the concentration of PKA substrates or PKA holoenzyme. In Chapter 3, I use recombinant adeno-associated viruses and shRNA-mediated silencing of HCN4 subunits to examine their role in anxiety, memory, and contextual fear extinction. Results from a battery of behavioral assays suggest that reduction of HCN4 subunits increases anxiety-related behavior, but does not affect object-location memory or contextual fear conditioning. Together, my thesis work provides novel insight into the molecular mechanism regulating the spatiotemporal dynamics of cAMP/PKA signaling and provides suggests a role for HCN4 subunits in anxiety-related behavior.
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 주제명부출표목-일반주제명
- 부출표목-단체명
- 기본자료저록
- Dissertation Abstracts International. 78-06B(E).
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 원문정보보기
- 소장사항
-
20170404 2017
MARC
008170601s2016 us esm 001c eng■001MOKWON01253140
■00520170418120607
■007cr
■020 ▼a9781369511567
■035 ▼a(MiAaPQ)AAI10246569
■040 ▼aMiAaPQ▼cMiAaPQ
■090 ▼a전자도서(박사논문)
■1001 ▼aLuczak, Vincent Gerard.
■24510▼aInvestigation of the spatiotemporal dynamics of cAMP and PKA signaling and the role of HCN4 subunits in anxiety-related behavior and memory▼h[electronic resource]▼cLuczak, Vincent Gerard.
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2016
■300 ▼a1 online resource(119 p)
■500 ▼aSource: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
■500 ▼aAdviser: Ted Abel.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2016.
■520 ▼aIn the hippocampus, long-term memory and synaptic plasticity occur through a series of coordinated intracellular signaling cascades that strengthen and stabilize subsets of synaptic connections while leaving thousands of others unaltered. Therefore, understanding how molecular signals are accurately transmitted is critical to understanding how hippocampal neurons store information. Molecules like cAMP and protein kinase A are critical components of memory and plasticity, but it is unclear how these diffusible signals are dynamically regulated to achieve the spatial and temporal specificity that underlies pathway-specific plasticity. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are ion channels that are modulated by cAMP and are known to regulate the spatial and temporal dynamics of excitatory postsynaptic potentials. HCN1 and HCN2 subunits have been implicated in memory, plasticity and anxiety-related behaviors, but the role for HCN4 subunits remains untested. In Chapter 1, I review the role of cAMP signaling in hippocampal synaptic plasticity and memory consolidation with emphasis on the molecular mechanisms regulating cAMP, PKA and HCN channels. In Chapter 2, I combine live two-photon imaging of genetically-encoded fluorescent FRET sensors and computational modeling to investigate the molecular mechanisms regulating the spatiotemporal dynamics of cAMP and PKA activity in hippocampal neurons during stimulation of beta-adrenergic receptors. Results suggest that the ratio between adenylyl cyclase and phosphodiesterase-4 scales with neuronal compartment size to maintain basal cAMP levels and produce rapid-onset, high-amplitude cAMP transients in small compartments. Conversely, imaging experiments show that PKA activity is greater in large neuronal compartments and modeling suggests that compartmental differences in PKA activity depend on the concentration of protein phosphatase and not on the concentration of PKA substrates or PKA holoenzyme. In Chapter 3, I use recombinant adeno-associated viruses and shRNA-mediated silencing of HCN4 subunits to examine their role in anxiety, memory, and contextual fear extinction. Results from a battery of behavioral assays suggest that reduction of HCN4 subunits increases anxiety-related behavior, but does not affect object-location memory or contextual fear conditioning. Together, my thesis work provides novel insight into the molecular mechanism regulating the spatiotemporal dynamics of cAMP/PKA signaling and provides suggests a role for HCN4 subunits in anxiety-related behavior.
■590 ▼aSchool code: 0175.
■650 4▼aBiology
■650 4▼aNeurosciences
■650 4▼aCellular biology
■690 ▼a0306
■690 ▼a0317
■690 ▼a0379
■71020▼aUniversity of Pennsylvania▼bBiology.
■7730 ▼tDissertation Abstracts International▼g78-06B(E).
■773 ▼tDissertation Abstract International
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2016
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T14490371▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a20170404▼f2017
