Medicine and Health Sciences Commons^™

Full-Gestational Exposure To Nicotine And Ethanol Results In Long-Term Dysregulation In The Ventral Tegmental Area, Emily Elizabeth Roguski

Theses and Dissertations (ETD)

Nicotine is considered a gateway drug for other drugs of abuse. The majority of smokers that begin smoking in adolescence, continue into adulthood. Multiple factors have been linked with smoking initiation, including maternal smoking. Drug exposure during pregnancy has long been suspected to exert deleterious effects on the fetal brain. Concurrent use of smoking and drinking alcohol throughout pregnancy is an all too frequent occurrence in the human population especially in disadvantaged and younger women.

The present study investigated the potential contributing factors for the enhanced nicotine selfadministration as seen in offspring with gestational exposure to nicotine and ethanol (Nic+EtOH).* …

Metabotropic Glutamate Receptor 5 In The Medial Prefrontal Cortex: Role In Cocaine Sensitization And Addiction, Kristin Marie Timmer

Theses and Dissertations (ETD)

Cocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drugseeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 …

Neocortical Layer 4 To Layer 2/3 Sensory Information Processing Investigated With Digital-Light-Projection Neuronal Photostimulation, Jason Paul Jerome

Theses and Dissertations (ETD)

The mammalian brain forms neuronal networks and microcircuits with cell-type- and anatomical-specific synaptic connections. Despite great advances in elucidating the cellular physiology of the nervous system, little is known about the computational processes occurring at the level of neuronal microcircuits. Much success has been reported in describing the synaptic input patterns of many brain regions and cell types using photostimulation systems; however, these systems are severely limited in their ability to study the integration of synaptic input from multiple synchronous or temporally correlated presynaptic locations. Here we describe a system that allows the generation of arbitrary 2-D stimulus patterns with …

Phenotypic And Electrophysiologic Characterization Of A Mouse Model Of Fragile X Syndrome, Snigdha Roy

Theses and Dissertations (ETD)

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is caused by a mutation in the fragile X mental retardation (FMR1) gene on the X chromosome. Many children with FXS exhibit autistic behaviors and deficits in motor coordination including speech articulation deficits. The development of the FMR1 knockout (Fmr1 KO) mouse, in which the Fmr1 gene is inactivated, has provided an animal model that can be used to investigate underlying neuro-physiological mechanisms associated with FXS as well as to evaluate potential therapeutic treatments. In this study, quantitative behavioral assays were used, such as long term …

The Effects Of Pten Deletion On Cell Size And Plasticity In The Hippocampus, Margaret Sperow

Theses and Dissertations (ETD)

The tumor suppressor phosphatase and tensin homolog (PTEN) is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) -signaling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size and synaptic transmission and plasticity. Neurologic abnormalities such as autism, seizures, and ataxia are associated with inherited PTEN mutations. Yet, how PTEN loss contributes to neurologic dysfunction remains unknown. PTEN loss during early development is associated with extensive deficits in neuronal migration and substantial hypotrophy of neurons and synaptic densities. However, whether its effect on synaptic transmission and plasticity is direct …

A Behavioral And Anatomical Analysis Of Conditioned Taste Aversion In C57bl/6j And Dba/2j Mice, April Rebecca Glatt

Theses and Dissertations (ETD)

Conditioned taste aversion (CTA) has been commonly used as a model of learning and memory. Traditionally, CTA approaches have used a paradigm that follows the model of classical conditioning. This involves presentation of a novel tastant, such as sucrose (conditioned stimulus, CS), followed by an intraperitoneal injection of lithium chloride that induces gastric malaise (unconditioned stimulus, US), which results in the aversion of sucrose (conditioned response, CR). However, a more natural classical conditioning paradigm involves the consumption, rather than injection, of the US by using a self‑administration paradigm that allows for time‑dependent analysis of formation, generalization, and extinction of CTA …

The Mglur2/3 Agonist Ly397268 Improves Morphometric And Behavioral Outcomes In R6/2 Huntington's Disease Mice, Dennis Craig Lafferty

Theses and Dissertations (ETD)

A prominent theory for the pathology of Huntington's Disease (HD) is the excitotoxic injury to the striatum. Continual exposure of ionotropic NMDA receptors to glutamate from the cortex can be excitotoxic in HD and leave striatal neurons vulnerable to damage. Activation of presynaptic mGluR2/3 by an agonist dampens glutamate release from corticostriatal terminals. Treatments that target excitoxicity and oxidative stress thus may improve some of the symptoms in HD patients and it is therefore logical to pursue therapies aimed in this direction. LY379268 is an inviting mGluR2/3 agonist that has been shown to be neuroprotective in hypoxic and ischemic injuries …

Tetrahydroisoquinoline Neurotoxins In Parkinson Disease, Michael G. Decuypere

Theses and Dissertations (ETD)

The goal of this dissertation work was to (1) determine the distribution of several tetrahydroisoquinoline (TIQ) derivatives in rodent, normal human and Parkinson disease (PD) brain, (2) quantify the levels of these TIQ derivatives in common food sources in an effort to link specific food intake patterns with the development of PD and (3) examine the neurotoxicity of select TIQ derivatives in human dopaminergic cell culture. The TIQs are a family of monoamine alkaloids that share structural homology with 1-methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP), can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell …

H5n1 Influenza Virus Induces A Parkinsonian Pathology, Haeman Jang

Theses and Dissertations (ETD)

The greatest threat for an influenza pandemic at this time is posed by the highly pathogenic H5N1 avian influenza virus. To date, 63% of the 436 known human cases of H5N1 infection have proven fatal. Animals infected by H5N1 viruses have demonstrated acute neurological signs ranging from mild encephalitis to motor disturbances and coma. However, no studies have examined the longer-term neurologic consequences of H5N1 infection. We show that this virus travels from the peripheral nervous system into the central nervous system (CNS) to higher levels of the neuroaxis, using C57BL/6J mice that are infected by the A/VN/1203/04 H5N1 virus …

Distinct Dna Damage Signaling In The Brain Distinguishes Atld, Nbs, And Atr-Seckel Syndrome, Erin Renee Phillips Shull

Theses and Dissertations (ETD)

DNA double strand breaks create a situation of extreme stress under which a cell must either be capable of repairing the lesions in order to continue replication or succumb to death. Not surprisingly, deficiencies in DNA repair genes often lead to human diseases frequently associated with genomic instability, cancer proneness, and neuropathology. Neurological consequences of aberrant DNA repair mechanisms vary depending upon the affected gene and the pathway in which it operates. Ataxia-telangiectasia (A-T) is the prototypical disease associated with DNA double strand break (DSB) repair deficiency and is characterized by severe neural pathology. A-T results from homozygous mutations that …

Multiscale Genomic Analysis Of The Corticolimbic System: Uncovering The Molecular And Anatomic Substrates Of Anxiety-Related Behavior, Khyobeni Mozhui

Theses and Dissertations (ETD)

Genetic diversity generates variation at multiple phenotypic levels, ranging from the most basic molecular to higher-order cognitive and behavioral traits. The far-reaching impact that genes have on higher traits is apparent in several neuropsychiatric conditions such as stress and anxiety disorders. Like most, if not all, neural phenotypes, stress, anxiety, and other emotion-related traits are extremely complex and are defined by the interplay of multiple genetic, environmental, experiential, and epigenetic factors.

The work presented in this dissertation is a multi-scalar, integrative analysis of the molecular and neuroanatomic substrates that underlie emotion-related behavior. The amygdala is a principle component of the …

The Combined Effect Of In-Situ Tumor And Irradiation On Peritumoral Brain Vasculature, Janice Ann Zawaski

Theses and Dissertations (ETD)

In the USA, 200,000 brain tumors are diagnosed each year with glioma representing 8.4% of the 200,000. The standard treatment for glioma consists of surgical resection, when possible, followed by radiation therapy (RT) and/or chemotherapy. Radiation therapy is one of the most effective treatments of brain tumors; however, the therapeutic ratio of RT is limited by damage to the normal tissue. We hypothesize that tumor growth has an adverse effect on the peritumoral tissue through the angiogenic/inflammatory environment it creates rendering it susceptible to further damage by RT which may be prevented by using anti-angiogenic/anti-inflammatory agents. We have developed a …

Torsina And The Pathophysiology Of Dyt1 Dystonia, Yu Zhao

Theses and Dissertations (ETD)

The goal of my dissertation work was to examine the systems biology of torsinA, a DYT1 dystonia-associated protein, by using rodent model systems. TorsinA is a putative ATPase associated with a variety of cellular activities (AAA+). Deletion of glutamic acid residue 302/303 in TOR1A is causally associated with many cases of early-onset primary dystonia.

In our work, transient forebrain ischemia and sciatic nerve transection were used as central and peripheral neural perturbations, respectively, to gain insight into the in vivo role(s) of torsinA. Moreover, transgenic mouse models that overexpress either human mutant torsinA (hMT) or wild-type torsinA (hWT) were used …

Factors Influencing Topotecan Cns Penetration In Mouse Models, Jun Shen

Theses and Dissertations (ETD)

Camptothecin analogs such as topotecan are currently tested in clinical trials for brain tumors. However the clinical outcome is far below the expectations, which are derived from the promising preclinical studies. This discrepancy could be partially attributed to the presence of two barrier systems in the brain, the blood brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier (BCB). Further investigations have demonstrated multiple ATP-binding cassette (ABC) transporters are present at the two barriers. Camptothecin analogs are well known substrates for several of the transporters. This work defined the role of two ABC transporters, Bcrp1 and P-gp in determination of …

Neuroadaptive Changes In The Mesocortical Glutamatergic System During Nicotine Self-Administration And After Extinction In Rats, Fan Wang

Theses and Dissertations (ETD)

The mesocorticolimbic pathway is critical in almost all aspects of drug abuse, including nicotine. Though many of the neurochemical and molecular effects of nicotine have been well studied, nicotine’s long-term neuroadaptive effects, specifically within the mesocorticolimbic pathway, are largely undefined. Thus, in current study, we determined the neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration (SA), which emulates important aspects of nicotine intake by humans, and after extinction. In the initial study, after 18 days of nicotine SA, in the medial prefrontal cortex (mPFC), NMDA receptor subunit 2A (NR2A) and NR2B were increased by 67% and 83%, …

Role Of Medial Prefrontal Cortical Group Ii Metabotropic Glutamate Receptor In The Development Of Cocaine Sensitization, Xiaohu Xie

Theses and Dissertations (ETD)

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR_2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR_2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR_2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was …

Effect Of Background Synaptic Activity On Excitatory-Postsynaptic Potential-Spike Coupling, Veronika Zsiros

Theses and Dissertations (ETD)

Neurons receive large amount of synaptic inputs in vivo, which may impact the coupling between EPSPs and spikes. We mimicked the in vivo synaptic activity of the cell with the dynamic clamp system. We recorded from pyramidal cells in neocortical slices in vitro to investigate how timing and probability of spike generation in response to an EPSP is affected by background synaptic conductance under these conditions. We found that near threshold, background synaptic conductance improved the precision of spike timing by reducing the depolarization-related prolongation of the EPSP. In cells with ongoing spike activity and background synaptic conductances, an …

Developmental Expression Of Rat Target Of The Antiproliferative Antibody (Rtapa) Protein In The Brain, Clyde Dale Sullivan

Theses and Dissertations (ETD)

The present study defines the expression pattern of rTAPA (CD81) in the developing rat brain. rTAPA is a member of the tetramembrane spanning family of proteins, and like other members of this family, appears to be associated with the stabilization of cellular contacts. On immunoblots of the brain, rTAPA is present in higher levels than any other tissue examined: muscle, tendon, peripheral nerve, cartilage, liver, kidney, skin, and testicle. Immunohistochemical methods were used to define the distribution of rTAPA in the brain. This protein is expressed by ependyma, choroid plexus, astrocytes, and oligodendrocytes, and rTAPA is dramatically upregulated at the …