Browsing by Subject "hippocampus"

Now showing 1 - 7 of 7
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    Hippocampal Girk-Dependent Signaling In Cognitive Function And Alzheimer’S Disease
    (2024-07) Luo, Shirley (Haichang)
    Many neurological disorders derive from, or can be attributed to the disruptions in neuronal plasticity. The GABAB receptor (GABABR) mediates slow inhibitory neurotransmission in the central nervous system and plays a crucial role in neuronal plasticity underlying learning and memory. The signaling via the receptor and the regulation of receptor signaling is one fundamental process contributing to the balance between excitatory and inhibitory signaling that mediates neuronal plasticity. GABABR can signal through a G protein-gated inwardly rectifying K+ (GIRK) channel in most neurons to directly and promptly regulate cell excitability. My thesis work focuses on how neuronal GIRK-dependent signaling (Chapter I) in the hippocampus (HPC) – a crucial region in learning and memory – is regulated by GABABR and other inhibitory G protein-coupled receptors (GPCRs) as well as their regulators (Chapter II), is involved in HPC-related cognitive deficits (Chapter III), and is maladapted in Alzheimer’s Disease (AD), a cognitive disorder and neurodegenerative disease showing severe atrophy in the HPC (Chapter IV). I use mice as my primary experimental model. My work concentrates on the excitatory HPC neurons in vitro and dorsal CA1 pyramidal neurons in vivo. Sex is considered as a biological variant in Chapter III-V. The discussion in Chapter V provides more insights into the sex differences observed in previous chapters.
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    The Impact of Iron Deficiency During Development on Mammalian Target of Rapamycin Signaling, Neuronal Structure, and Learning and Memory Behavior
    (2010-11) Fretham, Stephanie
    Iron deficiency (ID) is the most common micronutrient deficiency, affecting an estimated 2 billion people world wide including 20-30% of pregnant women and their offspring. Many human studies have demonstrated negative effects of early life ID on learning and memory which persist beyond the period of ID despite of prompt iron treatment, observations which are supported by rodent models of early iron deficiency anemia (IDA). In spite of a large, observational literature the mechanisms through which early ID causes acute and persistent brain dysfunction are largely unknown. Mammalian target of rapamycin (mTOR) signaling is an attractive candidate for mediating the effects of early ID because it integrates cellular metabolic status to regulate fundamental aspects of cellular growth and differentiation. The overall goal of the current studies is to understand the role of iron in regulating mTOR signaling during a critical period of development in the hippocampus by using unique genetic mouse models of hippocampal ID to: 1) Determine when iron is required for hippocampal development 2) Determine the role of iron in mTOR signaling 3) Manipulate iron and mTOR to determine effects on hippocampal structure and behavior. The findings from these experiments demonstrate that mTOR signaling is upregulated by neuronal ID during the same period that rapid hippocampal development requires large amounts of iron. Additionally, rescue of behavioral outcomes in adult animals following restoration of mTOR signaling (through either timely iron repletion or pharmacological suppression) provides functional evidence for a connection between mTOR and the persistent effects of early ID.
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    Long-range inhibition in the healthy and epileptic hippocampus
    (2019-08) Christenson Wick, Zoé
    There are many sources of inhibition and excitation that are carefully, and crucially, balanced within the brain. When this balance is off, pathological neuronal activity can emerge and lead to diseases such as epilepsy. My research identifies unique sources of inhibition in the hippocampus that are particularly interesting in the context of healthy hippocampal functioning as well as for temporal lobe epilepsy. Specifically, my dissertation has focused on two inhibitory neuron populations: one which has previously been shown to suppress seizures in a rodent model of chronic temporal lobe epilepsy, the other a previously uncharacterized and novel source of inhibition to the hippocampus that has several unique and surprising characteristics.
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    Model-Free and Model-Based Influence on Choice in Rodents and Interactions between Hippocampus and Dorsomedial Prefrontal Cortex during Deliberation
    (2020-01) Hasz, Brendan
    Decision making is driven by multiple, somewhat independent systems within the brain. One of these systems makes slow, deliberative decisions, and is thought to be driven by a model-based neural algorithm, in that it learns an internal model of the world which it uses to make decisions. Another system makes fast, habitual choices, and is hypothesized to depend on a model-free neural algorithm, in that it does not learn a model of the world, but simply stores state-action-reward associations. While the habitual system is relatively well-studied, the neural underpinnings of the deliberative system are less clear. Specifically, it is not known how areas comprising the deliberative system, such as prefrontal cortex and the hippocampus, share information on fast timescales. Also, representations of contingency information in prefrontal areas have previously been impossible to disambiguate from the encoding of other time-varying information. In this thesis, we adapted for rats a task which enabled the dissociation of model-based from model-free influence on choice, and we found evidence for both model-based and model-free control. We also developed a simpler task which caused rats to repeatedly transition between deliberative and habitual modes. On this second task, we found that both dmPFC and CA1 encoded information about task contingencies, while simultaneously representing unrelated time-varying information. Lastly, we examined interactions between dmPFC and CA1 on fast timescales, and found that both areas represented prospective information simultaneously, but that the content of this prospective information was not always identical between the two areas. Activity in dmPFC predicted whether HPC would represent prospective information on broad timescales, and prospective representation in HPC changed reward encoding in dmPFC on faster, sub-second timescales. Our work begins to bridge the neural underpinnings of decision making in rodents and the algorithms by which they select actions, confirms that the deliberative system represents contingency information, and uncovers asymmetries in the transfer of information between dmPFC and HPC.
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    Modulation of Adult Neurogenesis in Opioid Addiction
    (2016-05) ZHANG, YUE
    One of the major problems in treatment of opioid addiction is the repeated reuse and long-term memory of the drug-experience even after prolonged periods of abstinence. During the past decades, there has been enormous expansion in our understanding of how opioid drugs act on the nervous system. A complex brain network including the mesolimbic dopamine system, ventral striatum, extended amygdala, prefrontal cortex and hippocampus is suggested to be associated with the addiction cycle, in particular, the adult neurogenesis taken place in the dentate gyrus (DG) of the hippocampus has a functional implication in opioid addiction. It is intriguing to study the convergence between the modulation of adult neurogenesis and opioid addiction, since the adult-born granule cells were shown to play a role in neuroplasticity of hippocampus function and in the development and retention of drug-contextual memory. In the first part of my study, I attempted to define the temporal window of morphine’s inhibitory effect on adult neurogenesis with a transgenic mouse model. Four days of conditioned place preference (CPP) training with morphine significantly reduced the number of late stage progenitors and immature neurons in the sub-granular zone (SGZ) of mouse hippocampus but did not affect the number of early progenitor cells. The results from colocalization of cell-type selective markers suggested that under the condition of CPP training, morphine affects the transition of neural progenitor/stem cells differentiate into immature neurons. When the transcription factor neural differentiation1 (NeuroD1) was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. Next, a synthetic small molecule KHS101 which was reported to increase NeuroD1 mRNA in cultured neural progenitors and induce neuronal differentiation in the DG of hippocampus, was utilized to mimic the effect of lentivirus-mediated NeuroD1 overexpression on morphine-primed CPP. The results indicated that subcutaneous injection of KHS101 before conditional training could enhance the retention of drug-related memory and prolong CPP extinction; while the same treatment after conditional training disrupted the drug-contextual associations and shortened CPP extinction. Such KHS101’s effect paralleled that observed when the over-expression of NeuroD1 was temporally controlled with an inducible tetracycline system. Furthermore, the KHS101’s effect could be abolished by the stereotaxic injected NeuroD1 shRNA lentivirus. These studies suggest that morphine decrease the total numbers of newborn neurons in the SGZ by interfering with neural progenitors’ differentiation via a mechanism involving NeuroD1. Since adult neurogenesis serves as an important form of neural plasticity, we assume that certain immature neurons contribute to the formation and consolidation of drug-contextual association memory, and NeuroD1 plays a key role during this process. Such assumption is supported by the observation that compounds such as KHS101 that could regulate NeuroD1 expression in the hippocampus possess the ability to manipulate the extinction of drug contextual memory. In conclusion, the regulation of NeuroD1 activity leads to modulation of adult neurogenesis, thus affecting the drug-association memory.
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    Molecular mechanisms and therapeutic potential of inhibitory G protein signaling in anxiety disorders
    (2020-08) Vo, Baovi
    Anxiety disorders are common and debilitating. Current medications for treating anxiety disorders carry addictive potential and have adverse side effects, highlighting the need for improved therapeutics. Several commonly prescribed drugs used to treat anxiety disorders enhance inhibitory G protein signaling in neurons, leading to the modulation of multiple enzymes and ion channels. The relative contributions of these individual G protein-regulated effectors to anxiety-related behavior are unclear. My thesis research focuses on one such effector – the G protein-gated inwardly rectifying K+ (GIRK) channel. GIRK channels mediate the postsynaptic inhibitory effect of GABA and other inhibitory neurotransmitters in the central nervous system. There are 4 GIRK subunits (GIRK1-4). Neuronal GIRK channels typically contain GIRK1 and GIRK2. Previous work from our lab found that the GIRK channel activator (ML297), which shows a slight preference for GIRK1/2 channels, reduces anxiety-related behavior in mice without exhibiting addictive potential. My central hypothesis is that activators of the GIRK1/2 channel subtype could treat anxiety-related disorders. My thesis explored three interrelated questions: Which brain regions and neuronal populations underlie the influence of GIRK channels on anxiety-related behavior? While ML297 reduces anxiety-related behavior in mice, the relevant brain regions and neuron populations underlying this effect were unclear. I utilized pharmacologic and viral genetic approaches to manipulate GIRK-dependent signaling in distinct neuron populations in the ventral hippocampus (vHPC) and the basolateral amygdala (BLA), and evaluated the impact of these manipulations on anxiety-like behavior using the elevated plus maze (EPM) test. Intra-vHPC ML297 reduced anxiety-related behavior, akin to the effect observed with systemic ML297. In contrast, ML297 infusion into the BLA increased anxiety-related behavior in the EPM. Chemogenetic neuron-specific manipulations revealed neuronal subtypes within vHPC and BLA mediate these effects. These findings could inform targeted treatments for anxiety-related disorders. Do GIRK channel activators have anxiolytic therapeutic potential? Despite the promise of ML297 in studies of anxiety-related behavior, its modest selectivity for neuronal channels, its poor in vivo stability, and its limited ability to penetrate the blood-brain barrier preclude its clinical utility. I characterized a new GIRK channel activator, VU0810464, which showed improved brain penetration and enhanced selectivity for GIRK1/2 channels. I also demonstrated its in vivo efficacy in the stress-induced hyperthermia test. VU0810464 is a new, important tool for investigating the relevance of GIRK1/2 channels in physiology and behavior. What factors influence GIRK-dependent signaling? The GIRK2 subunit is necessary for neuronal GIRK channel function and has three distinct splice variants that have not been extensively characterized. I demonstrated the influence of these splice variants on three different GIRK-dependent signaling pathways in cultured hippocampal neurons using an electrophysiological approach. We found that these GIRK2 splice variants differed in their subcellular distribution, and this difference impacted their contribution to the processing of inhibitory input and to fear learning behavior. This knowledge provides insight into a key element influencing GIRK channel function, and importantly, opens more opportunities for future studies targeting GIRK-dependent signaling for therapeutics. In brief, I present a body of work in this thesis that contributes to the field’s knowledge of GIRK-dependent signaling and offers the potential for novel treatment for anxiety-related disorders.
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    Site-Specific Hippocampal Modulation In Disease And Health: Temporal Lobe Epilepsy And Cerebello-Hippocampal Influence
    (2020-08) Zeidler, Zachary
    Like other areas of the brain, the hippocampus is finely tuned to receive information, transform it, and output the result. Unlike other areas of the brain, the hippocampus is a critical player for many cognitive processes, including spatial memory. When aberrant modulation of the hippocampus occurs, it can be manifested neurally, in the activity of the hippocampus itself, as well as behaviorally, through impaired hippocampal-dependent behaviors. My research examines two distinct forms of hippocampal modulation. The first: chronic temporal lobe epilepsy induced via a targeted, focal intrahippocampal insult in either the dorsal or ventral hippocampus. The second: indirect modulation of the hippocampus from stimulation of the medial or lateral cerebellar cortex. Both forms of modulation create broad yet specific changes to hippocampal activity and hippocampal dependent behavior. Interestingly, site-specificity with regard to both hippocampal and cerebellar targeting reveal overlapping yet distinct effects in their respective forms of hippocampal modulation. Together, my research advances the epilepsy field's ability to model particular temporal lobe epilepsy phenotypes, as well as our understanding of how cerebellar modulation affects hippocampal function.