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Duke University
1.
West, AE.
Mechanisms of specificity in neuronal activity-regulated gene transcription.
Degree: 2011, Duke University
URL: http://hdl.handle.net/10161/5425 
► The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be…
(more)
▼ The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain.
Advisors/Committee Members: West, Anne (advisor).
Subjects/Keywords: Animals;
Brain-Derived Neurotrophic Factor;
Chromatin;
Gene Expression Profiling;
Gene Expression Regulation;
Histones;
Humans;
Neuronal Plasticity;
Neurons;
Promoter Regions, Genetic;
RNA Interference;
Receptors, N-Methyl-D-Aspartate;
Transcription Factors;
Transcription, Genetic
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APA (6th Edition):
West, A. (2011). Mechanisms of specificity in neuronal activity-regulated gene transcription.
(Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/5425
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
West, AE. “Mechanisms of specificity in neuronal activity-regulated gene transcription.
” 2011. Thesis, Duke University. Accessed February 22, 2019.
http://hdl.handle.net/10161/5425.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
West, AE. “Mechanisms of specificity in neuronal activity-regulated gene transcription.
” 2011. Web. 22 Feb 2019.
Vancouver:
West A. Mechanisms of specificity in neuronal activity-regulated gene transcription.
[Internet] [Thesis]. Duke University; 2011. [cited 2019 Feb 22].
Available from: http://hdl.handle.net/10161/5425.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
West A. Mechanisms of specificity in neuronal activity-regulated gene transcription.
[Thesis]. Duke University; 2011. Available from: http://hdl.handle.net/10161/5425
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Duke University
2.
WIJAYATUNGE, RANJULA.
The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
.
Degree: 2012, Duke University
URL: http://hdl.handle.net/10161/5577
► Changes in gene transcription driven by the activation of intracellular calcium signaling pathways play an important role in neural development and plasticity. A growing…
(more)
▼ Changes in gene transcription driven by the activation of intracellular calcium signaling pathways play an important role in neural development and plasticity. A growing body of evidence suggests that stimulus-driven modulation of histone modifications play an important role in the regulation of neuronal activity-regulated gene transcription. However, the histone modifying enzymes that are targets of activity-regulated signaling cascades in neurons remain to be identified. The histone demethylases (HDMs) are a large family of enzymes that have selective catalytic activity against specific sites of histone methylation. To identify HDMs that may be important for activity-regulated gene transcription in neurons, we induced seizures in mice and screened for HDMs whose expression is induced in the hippocampus. Among the few HDMs that changed expression, Kdm6b showed the highest induction. Kdm6B is a histone H3K27-specific HDM whose enzymatic activity leads to transcriptionally permissive chromatin environments. In situ hybridization analysis revealed that Kdm6b is highly induced in post-mitotic neurons of the dentate gyrus region of the hippocampus. We can recapitulate the activity-dependent induction of Kdm6b expression in cultured hippocampal neurons by application of Bicuculline, a GABAA receptor antagonist that leads to synaptic NMDA receptor activation and calcium influx. Kdm6b expression is also induced following application of BDNF, a neurotrophic factor that is upregulated in the seized hippocampus. To investigate possible functions of Kdm6b in neuronal development, we performed in situ hybridization analysis that allows for the identification of regions with high Kdm6b expression that could be sites of potential function in the developing mouse brain. We found high levels of Kdm6b expression in the inner layer of the external granule layer of the cerebellum, a region where pre-migratory immature neurons reside and a site of significant apoptosis. On the basis of this data and the fact that intracellular calcium signaling arising from synaptic firing supports neuronal survival, we explored the necessity for Kdm6b in the survival of cultured cerebellar granule cells. Knock down of Kdm6b by RNAi increases cell death, demonstrating that Kdm6b contributes to neuronal survival. Ongoing experiments are addressing the role of Kdm6b in neuronal differentiation. Overall these data raise the possibility that stimulus-dependent regulation of Kdm6b, and perhaps regulation of H3K27 methylation mediated by Kdm6b, may contribute to the regulation of gene expression in neurons and thus to their proper development and plasticity.
Advisors/Committee Members: WEST, ANNE E (advisor).
Subjects/Keywords: Neurosciences;
Differentiation;
Histone demethylases;
Kdm6b;
Survival
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APA ·
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APA (6th Edition):
WIJAYATUNGE, R. (2012). The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/5577
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
WIJAYATUNGE, RANJULA. “The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
.” 2012. Thesis, Duke University. Accessed February 22, 2019.
http://hdl.handle.net/10161/5577.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
WIJAYATUNGE, RANJULA. “The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
.” 2012. Web. 22 Feb 2019.
Vancouver:
WIJAYATUNGE R. The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
. [Internet] [Thesis]. Duke University; 2012. [cited 2019 Feb 22].
Available from: http://hdl.handle.net/10161/5577.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
WIJAYATUNGE R. The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation
. [Thesis]. Duke University; 2012. Available from: http://hdl.handle.net/10161/5577
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Duke University
3.
Bey, Alexandra Lyndon.
Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
.
Degree: 2017, Duke University
URL: http://hdl.handle.net/10161/14354
► Autism spectrum disorders (ASDs) are increasingly prevalent, and the costs associated with caring for affected patients across the lifespan are immense. However, the pathophysiology…
(more)
▼ Autism spectrum disorders (ASDs) are increasingly prevalent, and the costs associated with caring for affected patients across the lifespan are immense. However, the pathophysiology and brain regions involved in characteristic behavioral impairments remain poorly defined, which hinders progress towards targeted therapeutic development. Different brain regions have been suggested from human neuroimaging studies but the circuit mechanism is not known and cannot be easily defined in human studies. Genetic studies indicate that SHANK3, a gene encoding a scaffolding protein at the postsynaptic density, is a strong ASD causative gene. Studies of various isoform-specific knockout mice support these mice as valid models to dissect the pathophysiology of ASDs and implicate differential involvement of brain regions such as hippocampus and striatum. However, none of these mice recapitulate the most frequent SHANK-related mutation found in ASD patients: a deletion of the entire SHANK3 gene. For this reason, we have created conventional complete knockout mice by deleting almost the entire coding region of exons 4 to 22, Shank3 Δe4-22, and performed a thorough characterization of their behavioral phenotypes. Their abnormalities in complex social and communication behaviors in addition to their profound display of repetitive and restrictive behaviors in combination with comorbid anxiety, locomotor, and learning phenotypes support them as a mouse model for SHANK3-causing autism with good construct and face validity. Additional studies by collaborators identified a striatal-centered model of circuit and synaptic dysfunction. Manipulation of metabotropic glutamate receptor 5 (mGluR5) activity attenuated the excessive grooming and instrumental learning differentially in Δe4-22-/- mice. These findings show that deficiency of the autism-associated Shank3 gene can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities which underlie deficits in learning and ASD-like behaviors. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs. However, because these and other existing Shank3 mutant mice are not region specific, causality between different brain regions and ASD-like behaviors cannot be firmly established. In order to define anatomic regions implicated in behavioral manifestations of ASD, conditional knockout mice lacking Shank3 proteins in different brain regions including forebrain excitatory neurons (NEX-Cre) and striatal inhibitory neurons (Dlx5/6-Cre), as well as distinct cell populations including direct (D1-Cre) and indirect (D2-Cre) medium spiny neurons, were generated and subjected to behavioral phenotyping. Different autism-relevant behaviors as well as comorbid behaviors were recapitulated by targeting Shank3 deletion to different brain regions or cell types. Electrophysiological and biochemical studies further identified synaptic defects resulting from region- or cell-autonomous loss of Shank3, with different…
Advisors/Committee Members: Jiang, Yong-hui (advisor), West, Anne (advisor).
Subjects/Keywords: Neurosciences;
Genetics;
Mental health;
autism;
behavior;
genetics;
mouse models;
Shank3
Record Details
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Record Details
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Bey, A. L. (2017). Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/14354
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bey, Alexandra Lyndon. “Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
.” 2017. Thesis, Duke University. Accessed February 22, 2019.
http://hdl.handle.net/10161/14354.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bey, Alexandra Lyndon. “Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
.” 2017. Web. 22 Feb 2019.
Vancouver:
Bey AL. Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
. [Internet] [Thesis]. Duke University; 2017. [cited 2019 Feb 22].
Available from: http://hdl.handle.net/10161/14354.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bey AL. Using Shank3 Model Mice to Probe the Neuroanatomic Basis of Autism
. [Thesis]. Duke University; 2017. Available from: http://hdl.handle.net/10161/14354
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
4.
Hutchinson, Ashley Nicole.
Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
.
Degree: 2011, Duke University
URL: http://hdl.handle.net/10161/5033
► Activation of monoaminergic receptors is essential to the mechanism by which psychostimulants and antidepressants induce changes in behavior. Although these drugs rapidly increase monoaminergic…
(more)
▼ Activation of monoaminergic receptors is essential to the mechanism by which psychostimulants and antidepressants induce changes in behavior. Although these drugs rapidly increase monoaminergic transmission, they need to be administered for several weeks or months in order to produce long-lasting alterations in behavior. This observation suggests that it is likely that molecular mechanisms downstream of receptor activation contribute to the effects of psychostimulants and antidepressants on behavior. Recently, we and others have demonstrated that the methyl-CpG-binding protein 2 (MeCP2) contributes to both neural and behavioral adaptations induced by repeated psychostimulant exposure (Deng et al, 2010, Im et al, 2010). Psychostimulants induce rapid and robust phosphorylation of MeCP2 at Ser421 (pMeCP2), a site that is thought to modulate MeCP2-dependent chromatin regulation (Cohen et al, 2011), and this phosphorylation event is selectively induced in the GABAergic interneurons of the nucleus accumbens (NAc). In order to understand the signaling pathways that contribute to the pattern of pMeCP2 we observe, I characterized the monoaminergic signaling pathways that regulate pMeCP2. I found that activation of dopamine (DA) and serotonin (5-HT) transmission is sufficient to induce pMeCP2. The novel finding that drugs that activate serotonergic signaling induce pMeCP2 suggests that pMeCP2 may be involved in serotonergic mediated behaviors. To determine the requirement of pMeCP2 in serotonergic mediated behaviors, I utilized mice that bear a knockin (KI) mutation that converts serine to alanine at 421 (S421A) (Cohen et al, 2011). After characterizing the behavioral phenotype of these mice, I conducted tests to assess anxiety- and depression-like behavior. I found that the KI mice do not display heightened anxiety in several assays. However, the KI mice exhibit depression-like behavior in the forced swim and tail suspension but show no differences compared to wild-type (WT) littermates in the sucrose preference test, suggesting that pMeCP2 may be implicated in the behavioral response to stressful stimuli. Because we are interested in examining the role of pMeCP2 in the behavioral adaptations to chronic monoaminergic signaling, I then put the KI mice and their WT littermates through chronic social defeat stress, a behavioral paradigm in which repeated exposure to aggressive mice causes social avoidance that is reversed by chronic but not acute antidepressant treatment. Although the WT mice show an increase in social interaction following chronic imipramine treatment, the KI mice fail to show a behavioral response to chronic treatment. These data suggest that pMeCP2 may be implicated in the antidepressant action of chronic imipramine. Finally, investigation of the brain regions in which pMeCP2 may be contributing to the behavioral response to chronic imipramine treatment revealed that chronic but not acute imipramine treatment induces pMeCP2 in the lateral habenula (LHb), a brain region…
Advisors/Committee Members: West, Anne (advisor).
Subjects/Keywords: Pharmacology;
Neurosciences;
Behavioral sciences;
antidepressants;
depression;
dopamine;
MeCP2;
nucleus accumbens;
serotonin
Record Details
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hutchinson, A. N. (2011). Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/5033
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Hutchinson, Ashley Nicole. “Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
.” 2011. Thesis, Duke University. Accessed February 22, 2019.
http://hdl.handle.net/10161/5033.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hutchinson, Ashley Nicole. “Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
.” 2011. Web. 22 Feb 2019.
Vancouver:
Hutchinson AN. Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
. [Internet] [Thesis]. Duke University; 2011. [cited 2019 Feb 22].
Available from: http://hdl.handle.net/10161/5033.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hutchinson AN. Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease
. [Thesis]. Duke University; 2011. Available from: http://hdl.handle.net/10161/5033
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Duke University
5.
Lee, Ming-Chia.
Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
.
Degree: 2009, Duke University
URL: http://hdl.handle.net/10161/1148
► At excitatory synapses, NMDAR-mediated synaptic plasticity occurs in response to activity inputs by modifying synaptic strength. While comprehensive studies have been focused on the…
(more)
▼ At excitatory synapses, NMDAR-mediated synaptic plasticity occurs in response to activity inputs by modifying synaptic strength. While comprehensive studies have been focused on the induction and expression mechanisms underlying synaptic plasticity, it is less clear whether and how synaptic plasticity itself can be subjected to regulations. The presence of "plasticity of plasticity", or meta-plasticity, has been proposed as an essential mechanism to ensure a proper working range of plasticity, which may also offer an additional layer of information storage capacity. However, it remains elusive whether and how meta-plasticity occurs at single synapses and what molecular substrates are locally utilized. Here, I develop systems allowing for sustained alterations of individual synaptic inputs. By implementing a history of inactivity at single synapses, I demonstrate that individual synaptic inputs control synaptic molecular composition homosynaptically, while allowing heterosynaptic integration along dendrites. Furthermore, I report that subunit-specific regulation of NMDARs at single synapses mediates a novel form of input-specific metaplasticity. Prolonged suppression of synaptic releases at single synapses enhances synaptic NMDAR-mediated currents and increases the number of functional NMDARs containing NR2B. Interestingly, synaptic NMDAR composition is adjusted by spontaneous glutamate release rather than evoked activity. I also demonstrate that inactivated synapses with more NMDARs containing NR2B acquire a lower induction threshold for long-term synaptic potentiation. Together, these results suggest that at single synapses, spontaneous release primes the synapse by modifying its synaptic state with specific molecular compositions, which in turn determine the synaptic gain in an input-specific manner.
Advisors/Committee Members: Ehlers, Michael D (advisor), West, Anne E (advisor).
Subjects/Keywords: Biology, Neuroscience;
Input;
specific;
LTP;
Metaplasticity;
NMDA receptors;
Plasticity threshold
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lee, M. (2009). Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/1148
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lee, Ming-Chia. “Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
.” 2009. Thesis, Duke University. Accessed February 22, 2019.
http://hdl.handle.net/10161/1148.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lee, Ming-Chia. “Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
.” 2009. Web. 22 Feb 2019.
Vancouver:
Lee M. Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
. [Internet] [Thesis]. Duke University; 2009. [cited 2019 Feb 22].
Available from: http://hdl.handle.net/10161/1148.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lee M. Input-Specific Metaplasticity by a Local Switch in NMDA Receptors
. [Thesis]. Duke University; 2009. Available from: http://hdl.handle.net/10161/1148
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
. 
Open Access Theses and Dissertations
