Browsing by Subject "Hippocampus"
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Item 3 Tesla Magnetic Resonance Imaging of Hippocampal Asymmetry: Results from the Dallas Heart Study(2013-06-01) Lucarelli, Richard T.; Peshock, Ronald M.BACKGROUND: Asymmetry of the hippocampus is regarded as an important clinical finding but limited data on hippocampal asymmetry is available for the general population. Here we present hippocampal asymmetry data from the Dallas Heart Study determined by automated methods and its relationship to age, sex, and ethnicity. METHODS: 3D-MPRAGE MRI were obtained in 2082 DHS-2 participants. The MR images were analyzed using two standard automated brain segmentation programs, FSL-FIRST and Freesurfer. Individuals with imaging error, self-reported stroke, or major structural abnormalities were excluded. Statistical analyses were performed to determine significance of the findings across age, sex, and ethnicity. RESULTS: At the 90th percentile FSL-FIRST demonstrated hippocampal asymmetry of 9.8% (95% CI 9.3 to 10.5%). The 90th percentile of hippocampal asymmetry measured by the difference between hippocampii over the larger hippocampus was 17.9% (95% CI 17.0 to 19.1%). Hippocampal asymmetry increases with age (P=0.0216) and men have greater asymmetry than women as shown by FSL-FIRST (P=0.0036), but ethnicity is not significantly correlated with asymmetry. To confirm these findings Freesurfer was used. Freesurfer showed asymmetry of 4.4% (95% CI 4.3 to 4.7%) normalized to total volume, and 8.5% (95% CI 8.3 to 9.0%) when normalized by difference/larger hippocampus. Freesurfer also showed that hippocampal asymmetry increases with age (P=0.0024), and that men had greater asymmetry than women (P=0.03). CONCLUSION: There is a significant degree of hippocampal asymmetry in the population. The data provided will aid in the research, diagnosis, and treatment of temporal lobe epilepsy and other neurological disease.Item Astrocytic Contribution to the Glutamatergic Transmission in Schizophrenia(2011-02-01) Stan, Ana Despina; Tamminga, CarolSchizophrenia is a chronic mental disorder encompassing an array of cognitive and behavioral manifestations. Although the disease molecular pathophysiology remains essentially unknown, evidence exists for abnormalities within all the main neurotransmitter systems and various cortical and subcortical brain structures, albeit with no unifying/overarching hypothesis connecting the existent knowledge. Moreover, no current animal model or biological construct reproduces the complexity of the disease with acceptable validity. In my work I have taken a multidisciplinary approach to study the live and postmortem human brains of people with schizophrenia, focusing specifically on the glutamatergic abnormalities in the hippocampus, one brain region repeatedly found to bear structural, molecular, and blood flow abnormalities in the disease. I have started with the in vivo measurement of glutamate and glutamine using magnetic resonance spectroscopy, thus getting a “high-level” sense of the glutamatergic transmission changes in the hippocampi of subjects with schizophrenia. Concretely, I have found that untreated people with schizophrenia have reduced levels of glutamate compared to their healthy counterparts, but this reduction can be partially reversed by antipsychotic medication. To allow for a more “small-scale” characterization of the glutamatergic transmission impairments, I have used postmortem brain tissue to zoom in on the glutamatergic synapse, viewed as a “tripartite synapse”. Apart from the pre- and postsynaptic neurons, the third component is represented by the astrocyte, the brain glial cell that is responsible for most of the glutamate recycling and that attunes the glutamatergic synapse to the overall energetic metabolism of the brain. I have found that glutamate recycling is impaired in schizophrenia, selectively in the dentate gyrus, one of vii the hippocampal subregions, and the specific abnormalities reside in the glutamate transporters, responsible clearing up synaptic glutamate.Item Exploring the Role and Sensitivity of the Hippocampal Dentate Gyrus: From Addiction-Relevant Memories to the Influence of Space Radiation on Hippocampal Neurogenesis(2015-04-09) Rivera, Phillip Daniel; German, Dwight; Eisch, Amelia J.; Chen, Benjamin P.; Powell, Craig M.; Zhang, Chun-LiThe hippocampus and its subregion the dentate gyrus (DG) are involved in learning and memory. Adult hippocampal neurogenesis, which takes place in the DG, is also thought to contribute to learning and memory. Understanding the neural basis of learning and memory could help in a wide range of situations, from helping addicts break the cycle of substance abuse to ensuring appropriate astronaut action during spaceflight missions. This doctoral dissertation spans this wide range by using animal models relevant to addiction and spaceflight to improve understanding of the DG and adult neurogenesis, and obliquely, of learning and memory. After an introductory chapter, I show morphine-context reward memories are established via drug/context associations (D/CA, Chapter 2), and require adult neurogenesis for extinction of young reward memories (Chapter 3). Using conditioned place preference, a behavioral test classically used to assess drug strength, and the immediate early gene cFos as an indirect marker of neuronal activity, I found that morphine-paired mice sequestered to a morphine-paired context had more DG cFos+ cells than those sequestered to a saline-paired context or other controls. Thus, the retrieval of D/CA memory is accompanied by activation of hippocampal DG neurons. Surprisingly, image-guided cranial irradiation (IG-IR) prevented extinction of young, but not old, morphine D/CA memories without affecting retrieval. These data suggest that deficits in adult neurogenesis may contribute to stronger D/CA reward memory. The second section of my dissertation (Chapter 4) examines the influence of space radiation on adult neurogenesis. I find acute and fractionated space radiation similarly diminish adult neurogenesis, but neither decrease neural stem cell number, the putative source of new neurons. Thus, while spaceflight mission success may be hampered by space radiation due to diminished neurogenesis, my data raise the possibility that neurogenesis may recover overtime. Taken together, my data show an impaired DG (and perhaps neurogenesis) diminishes extinction of morphine-context reward memories, and that adult neurogenesis is decreased (perhaps reversibly) by space radiation. In my final chapter (Chapter 5), I discuss implications of these data for the fields of learning/memory and neuroscience in general, and suggest future directions that may help addicts recover and allow astronauts to perform optimally during spaceflight missions.Item Hippocampal Subfield Transcriptome Analysis in Schizophrenia Psychosis(2018-11-29) Perez, Jessica Marie; Eisch, Amelia J.; Tamminga, Carol; Kim, Tae-Kyung; Zinn, Andrew R.Schizophrenia is one of the thirty most incapacitating conditions in the world and affects tens of millions of people worldwide. Devastatingly, suicide occurs in 10% of those diagnosed with schizophrenia. Symptoms are persistent and often severe and available treatments are not curative. In fact, 20-33% of people with schizophrenia are entirely resistant to treatment. The complex symptom manifestations of schizophrenia lack a molecular pathology. Consequently, advances in novel treatment directions are limited. Schizophrenia is recognized as a polygenic disorder influenced by environmental factors. This dissertation aims to examine this polygenic nature of this disorder. Genome wide association studies have identified hundreds of common genetic variants, which individually confer a small risk for schizophrenia. However, all identified genetic variants combined only account for a modest amount of the total heritability of schizophrenia. In this dissertation, I capitalize on the unique ability of next-generation sequencing to identify in a global and unbiased manner molecular changes, which have not been previously hypothesized, but may contribute to the origin of the missing heritability of schizophrenia and play a role in schizophrenia symptomatology. The Tamminga lab has particular interest in schizophrenia psychosis, conceptualizing it as a disorder of learning and memory, critically involving dentate gyrus (DG), CA3, and CA1 of the hippocampus. Therefore, this doctoral dissertation examines the transcriptome of all three subfields, DG, CA3, and CA1 in human postmortem tissue of controls and individuals diagnosed with schizophrenia, using RNA-seq to identify additional psychosis-mediating molecular candidates and produce plausible targets for therapeutic treatment. After Chapters 1, 2, and 3 introduce the significance and contribution of this dissertation to the field of neuroscience in psychiatry, I show (Chapter 4) that each hippocampal subfield in schizophrenia has a unique molecular identity based on its transcriptome profile. As well, I show only slight effects of antipsychotic medication on schizophrenia-dependent gene changes in DG, CA3, and CA1. Taken together, my data identify molecular candidates and specific cell populations that we previously did not hypothesize as potential contributors to schizophrenia pathology. Finally, in Chapter 5, I outline future directions based on the contributions of my doctoral dissertation to the field.Item Hippocampal Volume Changes in Patients with Asthma(2015-01-26) Carlson, Scott; Jeon-Slaughter, Haekyung; Kim, Julie; Khan, David A.; King, Kevin; Lucarelli, Richard T.; McColl, Roderick; Peshock, Ronald M.; Brown, E. SherwoodBACKGROUND: Prior research suggests a possible association between asthma and decreased hippocampal volumes. OBJECTIVE: This study examines the association between asthma and hippocampal volume. METHODS: We conducted an analysis of participants in the Dallas Heart Study (DHS). The DHS collected an epidemiological sample of Dallas County residents to explore risk factors for heart disease. Included were 1,287 adults with complete data on study variables and without history of stroke, emphysema, or more than 5 drinks per day. Study variables included gender, age, race, and education as demographic characteristics, cognitive ability measured by the Montreal Cognitive Assessment (MoCA), and brain segment volumes measured by FreeSurfer. Study outcome variables were total, right, and left hippocampal volumes measured using FreeSurfer. General Linear Models (GLM) were conducted to examine the association of asthma diagnosis with hippocampal volumes after controlling for demographic characteristics, total MoCA score, and brain segment volume. Analysis of Variance (ANOVA) was used to examine the effect of gender on hippocampal volumes. RESULTS: The prevalence of lifetime asthma diagnosis among our study samples was 10.8% with 9.6% in males and 11.7% in females. Our study participants with a self-reported asthma diagnosis had significantly smaller estimated total, right, and left hippocampal volumes (95% CI 0.13%-2.9%; p = 0.03) than those without an asthma diagnosis. Asthma was significantly associated with total, right, and left hippocampal volumes in males, while not significantly associated in females after controlling for demographic characteristics, total MoCA score, and brain segment volume. Total, right, and left hippocampal volumes of males with asthma diagnoses, respectively, were 3.0% smaller (95% CI 0.77%-5.2%; p = 0.008), 2.9% smaller (95% CI 0.58%-5.2%; p = 0.014), and 3.1% smaller (95% CI 0.70%-5.6%; p =0.012) than males without asthma. CONCLUSION: Hippocampal volume in a large and diverse sample of adults was significantly smaller in people with asthma as compared to those without asthma. This difference in volume was limited to males. These findings suggest that asthma may be associated with structural brain differences as well as respiratory effects. Because the hippocampus is a brain region involved in memory formation these findings may have implications for treatment adherence.Item The Impact of Opioids and Opiates on Adult Hippocampal Neurogenesis(2007-12-17) Harburg, Gwyndolen Colleen; Eisch, Amelia J.Opiate addiction is a growing problem in today's society. Thus, it is of crucial importance that we understand the physiological basis for opiate addiction and the long-term consequences of opiate use in order to develop more effective means of treatment. Chronic morphine and heroin have previously been shown to decrease proliferation and survival of progenitor cells in the adult rat and mouse hippocampus. Here, I show that endogenous opioids may act through the mu opioid receptor (MOR) to similarly decrease survival of new hippocampal neurons. An exon 1 MOR knockout mouse showed increased survival of new neurons independent of effects on cell proliferation or cell death. In concordance with the increased numbers of granule cells maturing into neurons, knockout mice also had larger hippocampal granule cells layers and increased numbers of granule cells. Exploration of the impact of chronic morphine on different stages of neurogenesis showed that chronic morphine decreased numbers of Type 1 stem cells and proliferating progenitor cells. Progenitor cells exposed to chronic morphine during early maturation were not significantly decreased in number, but appeared to have retarded cell maturation since fewer had reached the immature neuron stage in chronic morphine mice. Chronic morphine also appeared to result in anterior hippocampus specific decreases in stem cells as well as maturation retardation. These findings show that morphine has distinct effects on different stages of neurogenesis, and that the anterior hippocampus may be more sensitive to some effects. Cell proliferation levels in the brains of human heroin abusers and normal controls were assessed using the endogenous proliferation marker Ki67. Heroin abusers had decreased numbers, but larger clusters of proliferating cells in the dentate gyrus hilus as compared with controls. There was also a trend towards a decrease in number of proliferating cells in the granule cell layer of heroin abusers. Although these findings are preliminary, they suggest that chronic heroin use in humans, as in rodents, may negatively impact neurogenesis. Together, these findings support a negative role for opioids and opiates in regulating adult hippocampal neurogenesis.Item Inhibitory Control of Contextual Fear Memory and Memory Specificity(August 2021) Guo, Jun; Pfeiffer, Brad E.; Roberts, Todd; Takahashi, Joseph; Xu, WeiThe brain functions are supported by close interactions between excitation and inhibition. Inhibition contributes to neural computation by gating information flow, tuning the gain of the network, and modulating the output strength of the system. The inhibition in the brain is mainly achieved by GABAergic inhibitory neurons which exert their effect by acting on multiple types of GABA receptors. In this dissertation, I examined the roles of specific types of GABAergic neurons and GABA receptors in learning and memory. The study consists of three major components. In the first component (Chapter 2), I developed a novel technique to selectively target and control GABAergic interneurons (NDNF cells) distributed at the SLM of the hippocampus. With this technique, I found that the activities of NDNF cells increased during memory encoding and decreased during retrieval. Enhancing their activity improved memory encoding but impaired memory retrieval. I further discovered that NDNF cells coordinate memory encoding and retrieval by differentially regulating the two major excitatory inputs to the CA1 region of the hippocampus. In the second component (Chapter 3), I identified a single nucleotide deletion in the gene of a subunit of GABA receptors - Gabra2 that reduces contextual fear memory in C57BL/6J by using quantitative trait locus analysis. In the third component (Chapter 4), I found a change in GABAB receptor-mediated feedforward inhibition led to distinct hippocampal responses to environmental stimuli. This difference further led to distinct hippocampal representation and generalization of contextual fear memory. These studies were carried out at genetic, molecular, circuit, and behavioral levels, and involved a combination of techniques including genetic mapping, in vivo recording, circuit manipulation, and behavior analysis. They exemplify how inhibition shapes neuronal activity and animal behavior. They also provide valuable tools and ideas for future research on the function of inhibition in the brain. The knowledge gained through these studies on how the brain inhibitory network interacts with excitatory neurons to regulate memory facilitates our understanding of the cognitive processes in the brain.Item Optimization of the Fair Technique for Specific Brain Region Perfusion Studies(2009-01-14) Li, Xiufeng; Briggs, Richard W.Most of the technical development and applications of ASL (arterial spin labeling) imaging have mainly focused on the superior cortical regions of the brain. However, optimal ASL measurements to quantify cerebral blood flow (CBF) in specific brain regions may require optimized parameters, improved techniques, or new imaging schemes based upon physiological or anatomic characteristics of those brain regions. In this thesis, the advantages of this region-targeted approach are demonstrated by performing quantitative perfusion studies of two representative brain regions, the cerebellum in the inferior part of the brain and the hippocampus in the mid-brain. To minimize or eliminate the venous artifacts found in cerebellum perfusion studies using traditional FAIR (flow-sensitive alternating inversion recovery) technique, FAIR ASST (FAIR with active suppression of superior tagging technique), as well as MDS FAIR, (modulated dual saturation pulse trains for FAIR) was developed and compared to PICORE (proximal inversion with a control for off-resonance effects) for quantifying cerebellum perfusion. The data indicate that FAIR ASST yields more robust CBF (cerebral blood flow) measurements. OPTIMAL FAIR (orthogonally-positioned tagging imaging method for arterial labeling of FAIR) was developed and shown to reduce the heterogeneity of within-slice transit time and to minimize partial volume effects, improving quantitative CBF maps for cerebellum and hippocampus. These techniques were optimized and applied to the study of perfusion abnormalities in brain regions important to the study of Gulf War Syndrome. Together with regionally optimized parameters, these ASL methods provide more reliable, efficient, accurate, and artifact-free CBF measurements than methods previously available.Item Regulation of Adult Hippocampal Neurogenesis: Insights from Mouse Models of Dementia and Depression(2009-05-13) Donovan, Michael Harry; Eisch, Amelia J.While neurogenesis is largely complete by birth, the subgranular zone (SGZ) in the adult hippocampus continues to produce functional young neurons. The last decade has produced a multitude of research demonstrating that the process of SGZ neurogenesis is dynamically regulated. Stimuli that negatively impact SGZ neurogenesis include stress, depression models, aging and models of neurodegenerative disease. Positive regulators of SGZ neurogenesis include antidepressants and hippocampal-dependent learning. These results have sparked tremendous speculation, both scientific and popular, that adult hippocampal neurogenesis might be critical for mood regulation and/or memory, and might be a promising target for the treatment of depression and dementia. However, we still know little about underlying mechanisms of how increases and decreases in SGZ neurogenesis occur. Here, I examine several manipulations of adult hippocampal neurogenesis, focusing on potential neuromechanisms underlying alterations in SGZ neurogenesis. First, in a mouse model of dementia, I find that in addition to agedependant decline in SGZ proliferation, these mice have retarded migration and maturation of new SGZ neurons and ectopic proliferation in a normally non-neurogenic region. Second, I explore how the antidepressant fluoxetine increases SGZ neurogenesis. I show that the increase occurs only after chronic administration and is not preceded by changes in cell death, cell-cycle or proliferating cell lineage. I next address the capacity of proliferating SGZ cells to respond to brain-derived neurotrophic factor (BDNF), a neurochemical implicated in antidepressant action and neurogenesis regulation. I find that most proliferating cells do not contain the necessary TrkB receptors in vivo, and thus BDNF action is likely indirect or through type-1 stem cells, which contain TrkB. Finally, I look at changes in neurogenesis in a social-defeat depression model. I find that, like other models of repeated stress, social-defeat stress appears to produce a stress-induced decrease in S-phase cells. However, closer analysis reveals that this decrease does not indicate decreased proliferation, and mice that are behaviorally sensitive to the stress actually show an increase in neurogenesis overall. Taken together, these results emphasize the complexity of the processes that comprise adult hippocampal neurogenesis, highlighting the importance of further investigation into the neuromechanisms of changes in neurogenesis.Item Regulation of Synaptic Vesicle Trafficking at Central Synapses(2009-09-04) Chung, Chihye; Kavalali, Ege T.Synapses are where electrical information is converted to chemical signaling, allowing for careful regulation of inter-neuronal communication in the brain. At presynaptic terminals, synaptic vesicles fuse with plasma membrane in response to electrical stimulation, followed by rapid retrieval to the terminal and re-organization for reuse. Thus, synaptic vesicle trafficking is of interest as to where presynaptic regulations of synaptic transmission begins to occur. The first two chapters explored a novel secretagogue, lanthanum (La³⁺), and its potential usage as a probe to study vesicle recycling at central synapses. Chapter two describes the characteristics of La³⁺-evoked transmission at hippocampal synapses. La³⁺ has two separate actions on transmission, with a different time course and underlying mechanism of action. This newly characterized rapid action of La³⁺ is intracellular Ca²⁺-independent, in contrast to its delayed action, yet requires functional SNARE complex formation. Therefore, chapter three took advantage of La³⁺-evoked transmission as a tool to investigate the coupling between exo- and endocytosis in SNARE-dependent fusion. Using multifaceted approaches, I propose that La³⁺ induces transmitter release via narrow fusion pore opening and closure, or a ‘kiss-and-run’ mode of exo- and endocytosis. Chapter four investigates the molecular requirement for the synaptic vesicle recycling pathway. I analyzed the impact of one of main players in endocytosis, dynamin in different forms of release. Acute inhibition of dynamin in central synapses impairs activity-dependent synaptic vesicle recycling while leaves spontaneous recycling intact, suggesting the operation of two parallel recycling pathways in central synapses as well as proposing the molecular signature between spontaneously and activity-dependently recycling pathways. In chapter five, I further investigated the origins of spontaneously recycling synaptic vesicles by simultaneous monitoring of spectrally separable FM dyes, as chapter suggested four that they are originated from an isolated pool. This chapter includes comprehensive analysis of the endocytic pathway operating at rest and its molecular participants –specifically dynamin, which was implicated to play a role in the endocytic pathway from observations I made in chapter four. Chapter six expands the investigation as to how presynaptic signaling regulates synaptic vesicle trafficking in glutamatergic synapses. I focused on the impact of ambient glutamate concentration on vesicle recycling as a feedback signal to rapid synaptic reuse to impact short-term synaptic plasticity. Taken together, these results suggest that synaptic vesicle trafficking is an actively regulated process, impacting various aspects of information cascades between neurons.Item Resting State Functional Magnetic Resonance Imaging Alterations In Psychosis Spectrum Disorders(2015-03-20) Samudra, Niyatee; Tamminga, CarolBACKGROUND: Many psychiatric disorders, especially those on the psychosis spectrum, are as yet without good diagnostic and treatment options. Neuroimaging research, most recently research into brain functional connectivity via resting-state fMRI, may provide a window into this problem, creating possibilities for discovering disease state-specific biomarkers important for diagnosis or to follow treatment efficacy. Hippocampal hyperactivity is known to be a feature of schizophrenia. The anterior hippocampus in particular, because of its structural connectivity relationships to frontal and limbic areas, may have specific connectivity alterations in psychosis spectrum disorders. In addition, it is important to understand whether putative changes in hippocampal functional connectivity are unique to a particular conventional (Diagnostic and Statistical Manual) psychosis disorder or whether they are present in multiple psychosis spectrum disorders, as this helps establish a biological foundation for psychosis. This work examines hippocampal functional connectivity changes in psychosis spectrum disorders in light of a possible imaging signature for psychosis. It is best understood in light of the work done by the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, a multi-site study group to establish imaging and molecular biomarkers across the psychosis dimension. OBJECTIVES: 1) To understand abnormal hippocampal connectivity and its targets in the rest of the brain in psychosis spectrum disorders. 2) To assess whether hippocampal connectivity changes are specific to one DSM diagnostic group or common across the psychosis spectrum. 3) To correlate hippocampal connectivity alterations with specific cognitive and clinical outcomes. METHODS: We tested resting state connectivity in 88 participants with psychosis disorders (21 schizophrenia; 40 schizoaffective disorder; 27 psychotic bipolar I disorder) and 65 healthy controls. Image processing and seed-based, voxel-wise connectivity analyses were carried out in the Analysis of Functional Neuroimaging (AFNI) software package to understand differential connectivity in psychosis spectrum vs. healthy controls using whole, anterior, and posterior hippocampal seeds. Connectivity measures for psychosis participants, as assessed by z-scores, were correlated with multiple clinical and cognitive measures. RESULTS: We found no significant differences in hippocampal functional connectivity across the three DSM diagnoses tested, thus justifying combining the groups for an analysis versus healthy controls. For the whole psychosis group, there were strong reductions in anterior hippocampal connectivity to anterior neocortical regions, including medial frontal and anterior cingulate cortices, as well as to superior temporal gyrus, precuneus, thalamus and cerebellum. Posterior hippocampal seeds also demonstrated decreased connectivity in psychosis subjects, with fewer regions of altered connectivity and a predominantly posterior/cerebellar distribution. Whole hippocampal outcomes were consistent with anterior/posterior hippocampal connectivity changes. These changes did not correspond to measures of cognition, medication effect, or clinical symptoms. CONCLUSION: This research underlines the possibility of a neuroimaging signature for psychosis spectrum disorders consisting of decreased predominantly anterior hippocampal connectivity with frontal and temporal regions, among others. The changes observed do not seem to correspond to medication effect or demographic variables in our analysis, thereby suggesting a primary disease effect. Further research is necessary to establish a hippocampal network in psychosis which may serve as a biomarker, with implications for more definitive diagnosis and treatment response prediction.Item A Reverse Translation Mouse Model for Schizophrenic Psychosis: Contribution of Hippocampal Subfield Pathology(2016-11-30) Southcott, Sarah Ann; Hsieh, Jenny; Huber, Kimberly M.; Rothenfluh, Adrian; Tamminga, CarolSchizophrenia is a serious and lifelong psychotic illness that affects all aspects of cognitive and affective function and whose etiology and brain mechanisms remain elusive. Schizophrenia affects not only those who express the condition, but also their family members, friends, and society as a whole. There is a worldwide prevalence of 1%, and the illness in 2012 alone, cost the USA an estimated $62.7 billion in medical care cost and lost wages. Schizophrenia is an extremely complex disease with a heterogeneous mixture of symptoms, including cognitive dysfunction, mood dysfunction, negative symptoms, and the defining symptom set, positive psychotic symptoms. The antipsychotic effects of dopamine receptor antagonists led people to hypothesize that schizophrenia is a disorder of dopamine hyperfunction, but considerable research has generated no strong evidence to support such a simple mechanistic hypothesis. Most recently, the glutamate system has become an etiologic focus in schizophrenia research and its research is proving more promising. We have studied the molecular basis of psychosis in human post mortem hippocampus in schizophrenia, and its related proteins important for learning and memory, especially the n-methyl-d-aspartate (NMDA) glutamate receptor system. Based on our findings we have developed a testable hypothesis of psychosis, formulated as a learning and memory disorder. In order to fully test this hypothesis we first needed to create a dynamic animal model based on our tissue findings that could be manipulated and probed. We found that knocking out the obligate subunit (GluN1) of the NMDA receptor selectively in the dentate gyrus paradoxically led to an increase in neuronal activity in the CA3 and several behavioral changes parallel to those we observe in schizophrenia. Furthermore we combined a pharmacological risk factor (phencyclidine) and a genetic risk factor (DISC1) with the knockout mouse that we believed would have the highest probability of interacting in a manner reminiscent of schizophrenia. These particular combinations did not exacerbate the symptoms of the dentate gyrus-specific GluN1 knockout mouse. Now we plan to use this dynamic mouse preparation to study the mechanisms whereby the reduction in GluN1 protein in dentate gyrus sensitizes and stimulates neuronal activity downstream within the hippocampus to better understand psychosis processes.Item The Role of Adult Hippocampal Neurogenesis in Morphine Addiction(2015-04-09) Bulin, Sarah Elizabeth; Hsieh, Jenny; Self, David W.; Powell, Craig M.; Eisch, Amelia J.The hippocampus plays a large role in modulating the reward pathway, being especially important in craving and context-dependent relapse. One form a neuroplasticity within the hippocampus is adult neurogenesis, which occurs in the subgranular zone of the dentate gyrus. While a growing amount of literature has explored the effects of drugs of abuse on adult DG neurogenesis, the relationship between self-administered opiates and adult DG neurogenesis remains unexplored. This dissertation investigates both the role of adult DG neurogenesis in morphine-related behaviors and the effects of self-administered opiates (morphine and heroin) on adult DG neurogenesis. I first explore the background literature important in the work completed within this dissertation (Chapter 1). Next, using a self-administration paradigm, I proceed to show that ablation of adult neurogenesis via cranial irradiation results in increased in morphine intake, decreased extinction, and decreased cognitive flexibility. Additionally, rats lacking adult DG neurogenesis exhibited increased morphine locomotor sensitization with increased DG activation in the infrablade after a low dose morphine challenge (Chapter 2). I will then go on to investigate the consequences of long-term self-administered opiates (morphine and heroin) on the different stages of maturation of adult-generated neurons. I demonstrate that morphine self-administration has no effect on proliferation, survival, or maturation immediately after exposure or after 28 days of withdrawal (Chapter 3). Additionally, I demonstrate that heroin self-administration does not alter DCX+ cell density or granule cell layer volume (Chapter 4). Taken together, my data suggests the adult DG neurogenesis is robust and normally unaffected by self-administered opiates. However, preexisting deficits in DG neurogenesis may lead to an increased vulnerability to addiction-related behaviors. In the final chapter (Chapter 5), I discuss potential implications of this work and future directions in which it may be taken.Item The Role of Adult Neurogenesis in Cocaine Addiction(2009-01-14) Noonan, Michele Ann; Eisch, Amelia J.New neurons are born in the adult hippocampus in a region known as the subgranular zone (SGZ). This process is dynamically regulated and new neurons are thought to be important for certain types of spatial learning and memory. Proliferation of SGZ neural progenitors is decreased by drugs of abuse, yet it is not clear how the type and amount of drug as well as the pattern of administration changes long-term effects on neurogenesis. In addition, it is unclear what role if any SGZ neurogenesis plays in initiating drug-taking or relapse behaviors, or whether changes in neurogenesis are merely side effects of drug-taking. I first examined effects of chronic cocaine self-administration and withdrawal on the different stages of neurogenesis. I found an early deficit in proliferation of neural progenitors, as well as a 4 week delayed increase in doublecortin-positive (DCX+) immature neurons which were common to both rats in withdrawal or those continuing to self-administer cocaine. I next asked the question of the functional consequence of changes in adult hippocampal neurogenesis to the acquisition and maintenance of drug-taking, as well as relapse to drug-taking. I found that reduced adult neurogenesis via cranial irradiation prior to cocaine-taking was associated with increased acquisition of drug-taking and increased motivation for cocaine, but not sucrose, while reduced adult neurogenesis after rats have acquired cocaine self-administration was associated with increased resistance to extinction of drug-seeking behavior. Finally, I asked if formation of drug-context associations would be altered in rodents with reduced neurogenesis in a passive drug exposure paradigm. I found that a transgenic mouse with reduced adult neurogenesis has impaired long-term drug-context memory in the cocaine conditioned place preference paradigm (CPP). Together these findings suggest that reduced adult hippocampal neurogenesis is a risk factor for drug addiction, that decreased proliferation after chronic drug intake likely contributes to drug-taking and drug-seeking behaviors, and that the delayed increase in immature neurons after drug-taking is likely protective against relapse. In sum, increases in adult hippocampal neurogenesis are beneficial both to the naïve and addicted brain, and therapeutics specifically increasing adult neurogenesis could aid in preventing initial addiction as well preventing future relapse.Item The Role of Chromatin Remodeling in Hippocampus in Depression and Antidepressant Action(2008-05-13) Tsankova, Nadejda Mincheva; Nestler, Eric J.This thesis presents a novel level by which neuroplastic changes in the brain may be disrupted with depression and reversed by treatment with antidepressants: regulation at the level of chromatin remodeling. The technique of brain chromatin immunoprecipitation was pioneered to directly measure the in vivo modifications of histones, a form of chromatin remodeling, at gene promoter regions in the hippocampus after chronic defeat stress, a model of depression, and chronic treatment with the antidepressants imipramine and electroconvulsive seizure (ECS). Chromatin modifications and transcriptional changes were assayed in one gene in particular, the brain-derived neurotrophic factor (BDNF). BDNF is alternatively spliced to generate several mRNA transcripts, driven by unique promoters. I measured the expression levels of each BDNF transcript (I-IV) in rat after ECS, as well as each BDNF transcript (I-V) in mice after chronic stress and imipramine treatments, and found that these chronic treatments induce lasting changes in the expression of specific BDNF splice variants. These changes correlated with sustained modifications in histones at the exact promoter regions, driving the differential changes in BDNF expression. Chronic defeat stress induced robust enrichment of H3-K27 methylation at BDNF P3 and P4 promoters (modifications expected to repress promoter activity), while chronic imipramine in defeated animals lead to lasting upregulation in the levels of H3 acetylation and H3-K4 methylation at P3 and P4 (modifications expected to stimulate promoter activity). Finally, I discovered a novel role for the histone deacetylase HDAC5 in the therapeutic efficacy of chronic imipramine after defeat stress. I found that chronic imipramine downregulates HDAC5 after stress, that HDAC5 overexpression in the hippocampus blocks the behavioral effects of imipramine in defeated mice, that HDAC5 inhibition exerts a subtle antidepressant-like effect, and that HDAC5 deficiency reduces the pathological response to stress. This unexpected role for HDAC5 provides an important mechanistic link between the adaptive chromatin remodeling changes at genes and the ability of chronic antidepressants to exert therapeutic efficacy after chronic stress. These experiments provide one of the first endeavors to understand the role of chromatin remodeling in modulating long-term adaptive changes in brain associated with complex psychiatric conditions, such as depression.Item The Role of NeuroD1 in Physiological and Pathological Neurogenesis(2016-12-05) Brulet, Rebecca R.; Schneider, Jay W.; Hsieh, Jenny; Eisch, Amelia J.; Ge, Woo-PingNeurogenesis in the adult brain is a complex and highly regulated process. Under normal physiological conditions neurogenesis in the hippocampal subgranular zone (SGZ) is important for learning, memory, and mood regulation. What is not well understood, however, is whether in certain disease contexts, like epilepsy, aberrant neurogenesis can contribute to the progression of spontaneous reoccurring seizures (SRS) and associated memory decline. In this work, I present evidence that aberrant hippocampal neurogenesis is causative in the perpetuation of SRS. In an effort to target a select stage of adult neurogenesis I identified the bHLH transcription factor NeuroD1, known to be important in adult neurogenesis, as being strongly upregulated after status epilepticus (SE). Additionally, I show expression of NeuroD1 in aberrant ectopically localized granule cells suggesting a potential role for this transcription factor in the progression of epilepsy. NeuroD1 conditional knockout (cKO) in progenitor cells of the hippocampus may be sufficient to reduce the number of immature and mature neurons amongst the labeled population, however the total number of immature and mature neurons was not significantly changed aside from the immature neurons ectopically localized to the hilus. Consistent with this, the total SRS was unchanged in the NeuroD1 cKO. Transdifferentiation, or the direct inter-lineage conversion of adult somatic cells is a powerful tool with the potential to be used in neuronal replacement strategies in certain neurological disorders or CNS injuries. Transdifferentiation of reactive astrocytes into glutamatergic neurons via retroviral targeting in the cortex can be accomplished by overexpression of the transcription factor NeuroD1. However, what is not well understood is whether the state of reactive gliosis is necessary to "prime" these cells for the transdifferentiation process. In this work I present evidence to suggest that overexpression of NeuroD1 in the absence of reactive gliosis is capable of astrocyte to neuron transdifferentiation, however the total number of converted cells is vastly lower than what was previously published, suggesting that reactive gliosis does indeed enhance and facilitate the conversion process.Item The Role of Notch1 in Adult Hippocampal Neurogenesis and Function(2009-09-04) Ables, Jessica Lynn; Eisch, Amelia J.Neurogenesis occurs throughout life in the hippocampal subgranular zone (SGZ) and is potently stimulated by exercise, but the underlying mechanisms are still poorly defined. Notch1 is a master regulator of developmental neurogenesis, yet its role in adult hippocampal neurogenesis is unclear. To test the hypothesis that cell-intrinsic Notch1 is critical to both basal and exercise-induced SGZ neurogenesis, we generated Nestin-creERT2/R26R-YFP/Notch1loxP/loxP (Notch1 iKO) mice to inducibly ablate Notch1 in Nestin-expressing stem and progenitor SGZ cells. The total number of YFP+ SGZ cells increased over time in wild type littermates, but not in Notch1 iKO mice. Morphological and phenotypic analyses revealed that fewer YFP+ DG neurons were generated over time in Notch1 iKO mice due to smaller pools of YFP+ stem-like and progenitor cells. Likewise, neural progenitors isolated from Notch1 iKO mice were incapable of forming new neurospheres with extended passaging. While non-running Notch1 iKO mice had fewer YFP+ SGZ cells relative to wild type littermates, Notch1 iKO mice given 30 days access to a running wheel had equal number of YFP+ SGZ cells relative to controls, suggesting that running rescued total YFP+ SGZ cell number independent of Notch1. However, running did not rescue YFP+ stem-like cell number in Notch1 iKO mice, suggesting that the putative stem-like SGZ cells make little contribution to adult hippocampal neurogenesis in these conditions. From these data, we conclude that Notch1 in Nestin+ stem and progenitor cells is critical to maintain basal adult hippocampal neurogenesis, but is not critical for exercise-induced neurogenesis. Neurogenesis has also been implicating in depression and behavioral response to antidepressants. To determine if reduced neurogenesis contributed to depression- or anxiety-related behavior, we assessed several measures of depression and anxiety in Notch1 iKO mice. We found that Notch1 iKO mice did not differ from WT mice in their behavior, suggesting that reduced neurogenesis is not associated with mood disturbances.Item Study of the Mechanisms Underlying Hippocampal Neuron Synaptogenesis: The Roles of Neurotrophin Signaling and MicroRNAs(2010-11-02) Zhang, Wei; Parada, Luis F.Synapse formation requires contacts between dendrites and axons. Although this process is often viewed as axon mediated, dendritic filopodia may be actively involved in mediating synaptogenic contacts. Brain-derived neurotrophic factor (BDNF) increases the density of dendritic filopodia and the conditional deletion of tyrosine receptor kinase B (TrkB) reduces synapse density in vivo (Luikart et al., 2005). Here, we report that TrkB associates with dendritic growth cones and filopodia, mediates filopodial motility, and does so via the phosphoinositide 3 kinase (PI3K) pathway. We used genetic and pharmacological manipulations of mouse hippocampal neurons to assess signaling downstream of TrkB. Conditional knock-out of two downstream negative regulators of TrkB signaling, Pten (phosphatase with tensin homolog) and Nf1 (neurofibromatosis type 1), enhanced filopodial motility. This effect was PI3K-dependent and correlated with synapse density. Phosphatidylinositol 3,4,5- trisphosphate (PIP3) was preferentially localized in filopodia and this distribution was enhanced by BDNF application. Thus, intracellular control of filopodial dynamics converged on PI3K activation and PIP3 accumulation, a cellular paradigm conserved for chemotaxis in other cell types. Our results suggest that filopodial movement is not random, but responsive to synaptic guidance cues. In order to further elucidate the mechanisms of BDNF-TrkB-PI3K pathway downstream signaling involved in regulating dendritic filopodial motility, we used a pharmacological approach as well as a gene expression approach to show that Rac1 and RhoA may play a role in this pathway. Rac1 positively regulated dendritic filopodial motility while RhoA had a negative effect. Our data suggest that BDNF-TrkB signaling might function to regulate the balance between Rac1 and RhoA, thus controlling dendritic filopodial motility. The developing nervous system is shaped by highly orchestrated programs of gene expression. This tight regulation is regulated by various transcriptional and post-transcriptional events that control individual gene expression. The recent discovery of small, non-coding RNAs has greatly expanded our understanding of the mechanisms that regulate gene expression at the post-transcriptional level. Here, I characterized the expression pattern of one neuronal microRNA, miR-381, and used in vitro cultured hippocampal neurons to show that miR-381 regulates neurite growth, as overexpression of miR-381 promotes neuronal dendritic branching. The effect of miR-381 on neuronal dendritic branching might be through a net regulation of multiple target genes.Item Using Multimodal MRI Techniques to Understand the Role of Hippocampus in Schizophrenia(2013-07-29) Fang, Yan; Lenkinski, Robert; Tamminga, Carol; Choi, Changho; Lu, Hanzhang; Maher, ElizabethAccording to our hippocampal metaplasticity model for schizophrenia (SZ), reduced glutamate signaling in dentate gyrus could lower the LTP threshold in its target region CA3, thus generates increased associative function in CA3, resulting in memories with psychotic content. The loss of mnemonic functions in dentate gyrus could decrease its pattern separation function. Multimodal MRI techniques including proton magnetic resonance spectroscopy (1H-MRS), cerebral blood volume (CBV), cerebral blood flow (CBF) and functional MRI at 3T were used to examine the metaplasticity model and probe the role of hippocampus in schizophrenia both with (SZ-on) and without (SZ-off) antipsychotic drug treatment. Single-voxel localized scalar (J) difference editing sequence was used in 1H MRS to measure glutamate (Glu), GABA and N-acetylaspartate (NAA) concentrations in the left hippocampus in normal control (NC), SZ-on and SZ-off groups. Significant decreases in Glu and NAA concentrations relative to creatine (Cr) were found in SZ group, which confirms our hypothesis of decreased dentate gyrus glutamatergic output in SZ. High resolution vascular-space occupancy (VASO) technique using Gd-DTPA as contrast agent acquired CBV maps with resolution of 0.78mm x 0.78 mm x 4 mm, and found increased CA3+CA1+Sub relative CBV value normalized by thalamus CBV in SZ group compared to NC group, which suggests a basal hypermetabolic state in these hippocampal subregions in SZ. Pseudo-continuous arterial spin labeling (pCASL) was used to measure whole brain CBF at standard resolution, and we found hippocampal CBF had positive correlation with PANSS total scores. In the acquired equivalence (AE) fMRI study, reduced midbrain and hippocampal activity was found in both trained and transfer tasks in SZ-on group compared to NC group. The behavior data also support this finding although lacking statistical significance, which may indicate a hyperactivity-induced inefficiency in memory processing in hippocampus. Some of our results support while some modify our original hypotheses. The reduced glutamate concentration in left hippocampus can be interpreted as deriving from the putative NMDA receptor lesion in dentate gyrus in SZ. And that the hypoglutamatergic lesion in dentate gyrus would be sufficient to generate reduced hippocampal glutamate detected by MRS is demonstrated in our NR1-KO mouse study. The increased basal neuronal activity in CA3 and CA1 is supposed to decrease the efficiency of the pattern completion function within CA3, resulting in hyperassociative memory. The positive correlation between hippocampal CBF and PANSS total reveals that the increased CBF in hippocampus is related to psychosis. The AE fMRI result also gives a support to our hypothesis. We could not distinguish the SZ-on and SZ-off groups in our 1H MRS and VASO studies. This might be due to the limited sample sizes of these studies. In the AE fMRI study, the SZ-off group had better performance than the SZ-on group and the brain activity of the SZ-off group was more similar to the NC group compared to the SZ-on group, which contradicts our prediction. The age range and the match between groups shall be considered more strictly in our future studies.Item [UT Southwestern Medical Center News](2011-03-30) Donihoo, Rachel