2014 — 2018 |
Chin, Jeannie |
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. |
Accelerated Depletion of Hippocampal Neural Stem Cells in Neurological Disease @ Baylor College of Medicine
DESCRIPTION (provided by applicant): Adult-born neurons in the dentate gyrus (DG) play critical roles in learning, memory, depression, and anxiety. Both Alzheimer's disease (AD) and epilepsy are associated with marked alterations in neurogenesis, which may contribute to cognitive and psychiatric symptoms that are key features of both diseases. Recurrent seizures, which are characteristic of both AD and epilepsy, may critical in the (dys)-regulation of neurogenesis and downstream cognitive impairments. Acute seizure activity stimulates neurogenesis in rodents and humans, but chronic epilepsy is associated with decreased neurogenesis. Why acute and chronic seizures are associated with opposing effects on neurogenesis, and how this affects cognition, is unknown. Recent findings that neural stem cells in the mouse DG are disposable rather than self-renewing may provide an explanation. Upon exiting the quiescent state, these adult DG neural stem cells undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons, and then terminally differentiate into astrocytes. This disposable stem cell model accounts for the age-related disappearance of DG neural stem cells, appearance of new astrocytes, and age-related decline in neurogenesis. Such a model would predict that the robust increases in neurogenesis triggered by acute seizures accelerate division-coupled depletion of the neural stem cell pool, leading to reduced neurogenic potential in conditions with recurrent seizures such as AD and epilepsy. Our preliminary data support the hypothesis that loss of DG neural stem cells is accelerated in transgenic mice expressing human amyloid precursor protein (APP), a well-characterized model of AD with spontaneous seizures, and that accelerated loss affects specific cognitive functions that are regulated by adult- born DG neurons. We found similar results in the kainate model of epilepsy; moreover, treatment of APP mice with an anti-epileptic drug appeared to delay the rate of loss, supporting a role for seizures. Building on these preliminary studies, in Aim 1, we will establish that the DG neural stem cell pool undergoes accelerated division-coupled depletion that is commensurate with seizure activity and cognitive deficits in APP mice; in Aim 2 we will determine whether treatment with an anti-epileptic drug prevents depletion of the DG neural stem cell pool and ameliorates performance on a DG-dependent behavioral task; in Aim 3 we will assess whether pharmacologically-induced seizures in wild-type mice also induce division-coupled depletion of the DG neural stem cell pool and deficits in DG function. Determining if seizures accelerate division-coupled depletion of the DG neural stem cell pool will shed new light on understanding the processes that drive both normal use, and pathological depletion, of neural stem cells. The answer will have a major impact on determining the stages of neurogenesis that are most advantageous to focus on for therapeutic strategies. This is an essential step in achieving two major long-term goals: 1) prevent pathological effects of conditions that impact neurogenesis, 2) harness the power of neurogenesis as a treatment for devastating conditions like AD and epilepsy.
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2014 — 2017 |
Chin, Jeannie |
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. |
Role of Deltafosb in Epigenetic Regulation of Gene Expression and Cognition @ Baylor College of Medicine
DESCRIPTION (provided by applicant): Cognitive impairment is a devastating co-morbidity of epilepsy. However, the molecular mechanisms by which recurrent seizures induce cognitive impairments that persist even in seizure-free periods are not well understood. This gap in knowledge hampers the development of therapeutic interventions to reduce cognitive deficits associated with epilepsy. Our preliminary studies demonstrate that seizure-induced increase in hippocampal expression of the transcription factor ?FosB triggers a chain of events leading to epigenetic repression of a number of genes in the hippocampus, some of which are known to be critical for the induction of synaptic plasticity. Increasing seizure severity led to increasing expression of ?FosB that exerted long lasting epigenetic repression of gene expression, with detrimental consequences for hippocampal-dependent spatial memory. Such increases in ?FosB expression, epigenetic alterations, and associated spatial memory deficits were observed in a pharmacological kainate model of epilepsy as well as a transgenic mouse model of Alzheimer's disease (AD), both of which exhibit recurrent seizures. The goals of this proposal are to determine the precise mechanisms by which ?FosB induces epigenetic repression of key genes required for synaptic plasticity, and whether normalizing gene expression restores cognitive function in kainate and AD models with recurrent seizures. To achieve these goals, in Aim 1 we will characterize the dynamics of ?FosB expression, downstream gene repression, and cognitive deficits in kainate and AD mice. In Aim 2, we will determine the mechanisms by which ?FosB induces chromatin modifications that regulate gene expression in kainate and AD mice. In Aim 3, we will determine whether viral expression of a dominant negative antagonist of ?FosB blocks ?FosB's effects on gene expression in the hippocampus, and restores cognitive function in kainate and AD mice. Results from these studies will forge a new avenue of understanding how recurrent seizures impair cognitive function, and highlight a novel pathway for therapeutic targeting. In addition, they will provide novel insights into common mechanisms of cognitive impairment in any condition associated with recurrent seizures, such as AD. Given that epilepsy is a co-morbidity of a number of neurological conditions/diseases the results from our studies will have broad impact.
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2018 — 2021 |
Chin, Jeannie |
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. |
Role of Deltafosb in Hippocampal Gene Expression and Function in Neurological Disease @ Baylor College of Medicine
Project Summary Cognitive impairment is a devastating co-morbidity of conditions with recurrent seizures, such as Alzheimer's disease and epilepsy, which persists even in seizure-free periods. We recently published that one critical reason for this is that seizures induce dentate gyrus (DG) expression of ?FosB, a transcription factor that epigenetically suppresses key target genes that are crucial for plasticity and memory. ?FosB expression is associated with cognitive deficits in patients and mouse models of epilepsy as well as Alzheimer's disease, demonstrating common mechanisms of cognitive dysfunction in conditions with seizures. Our new studies indicate ?FosB acts on more than memory-related genes; it also represses genes that enhance intrinsic excitability, and thereby limits overall DG excitability. These findings indicate that seizure-induced ?FosB expression is a ?double-edged sword? that caps DG excitability, but at the cost of plasticity and cognitive function. Our goals are to build a comprehensive understanding of functional domains regulated by ?FosB in the hippocampus, and identify novel strategies to improve cognition but maintain regulation of neuronal excitability in conditions with seizures, such as Alzheimer's disease and epilepsy. We previously used hypothesis-driven approaches to identify ?FosB targets in hippocampus, but it was necessary to also obtain an unbiased, comprehensive view of ?FosB in seizure-related conditions. To do so, we performed ChIP- sequencing to identify all genes bound by ?FosB in the hippocampus of a well-characterized transgenic mouse model of Alzheimer's disease (AD mice) that exhibits recurrent seizures and high ?FosB levels. In AD mice, ?FosB bound to a novel network of genes involved in multiple aspects of neuronal excitability. Many of these genes were also bound by ?FosB in hippocampus of wild-type mice treated with pilocarpine, a pharmacological model of epilepsy. In wild-type mice, AAV-mediated overexpression of ?FosB decreased excitability whereas ?JunD, a dominant negative antagonist of ?FosB, increased excitability. Notably, long- term blockade of ?FosB signaling in DG of AD mice changed the phenotype of their seizures from primarily nonconvulsive to primarily convulsive, supporting the theory that the typically low excitability and sparse activation of DG cells acts as a filter or gate that restricts epileptogenesis. Our work indicates ?FosB plays critical roles in neuronal function in conditions with recurrent seizures. Understanding the mechanisms by which ?FosB coordinately regulates expression of genes that control synaptic plasticity or neuronal excitability may reveal novel therapeutic strategies to reduce epileptogenesis while improving cognition. To this end, we will examine both Alzheimer's mice and pilocarpine mice to: 1) Investigate the role of ?FosB in controlling intrinsic and network excitability of the DG, 2) identify and characterize the repertoire of hippocampal genes targeted by ?FosB to control excitability, and 3) test whether specific ?FosB target genes are key determinants of DG excitability and cognition.
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2020 — 2021 |
Beierlein, Michael (co-PI) [⬀] Chin, Jeannie |
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. |
Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease @ Baylor College of Medicine
PROJECT SUMMARY Sleep disturbances predict risk of Alzheimer?s disease (AD). Sleep-wake cycles critically regulate brain interstitial fluid (ISF) levels of A? and tau, two critical proteins that accumulate in AD. Both A? and tau are released by neuronal activity, which is higher during wakefulness than in sleep. Moreover, sleep is a critical phase during which factors in the ISF are cleared from the brain. Therefore, sleep disturbances affect daily function and also contribute to disease progression. However, little is known about which brain regions are affected in AD to give rise to sleep disturbances, making it difficult to identify the circuit level mechanisms that drive dysfunction, or to design targeted therapeutic strategies. This project tests the hypothesis that the thalamic reticular nucleus (TRN) is a critical brain region in AD, and that impairments in its activity drive sleep disturbances and exacerbate disease progression. The TRN is a major component of the thalamocortical- corticothalamic network that regulates sleep, attention, and memory, which are all affected in AD. However, little is known about the state of TRN in AD patients or in animal models. We found that in transgenic mice expressing mutant human amyloid precursor protein (APP mice), TRN activity is strikingly reduced, in the absence of cell loss. Such reductions in TRN activity led to sleep fragmentation and reductions in slow wave sleep (SWS), and predicted the magnitude of A? deposition in both hippocampus and cortex, which may relate to the fact that SWS is the phase of sleep during which activity-dependent production of A? is reduced, and A? is cleared from the brain. Moreover, deficits in SWS and sleep maintenance manifest early in disease in APP mice, prior to hippocampal deficits, suggesting that TRN impairment may both predict and contribute to disease progression. The goals of this proposal are to identify cellular mechanisms that impair TRN activity, and test if selectively manipulating neuronal activity in the TRN can normalize sleep, reduce A? accumulation, and improve memory. To achieve these goals, in Aim 1 we will use electrophysiology and pharmacology in thalamic slices to identify the intrinsic, synaptic, and network properties of TRN that result in its hypoactivity in APP mice. In Aim 2, we will use DREADDs to acutely activate TRN cells in APP mice to test if TRN activation affects dynamics of interstitial A?, and/or memory consolidation. In Aim 3, we will use DREADD-mediated activation of TRN in APP mice to test if chronic activation of TRN can normalize sleep parameters, reduce A? accumulation, and improve memory. Results from this project will have major impact because they: 1) highlight a vulnerable network early in disease that may predict and contribute to disease progression, and 2) identify a novel therapeutic strategy with potential to normalize sleep, improve memory, and delay disease progression in Alzheimer?s disease. Insights gained will also be used to derive general principles about the dynamics of AD-related proteins like A? and tau in the brain, which will impact our ability to treat this complex disease.
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