Medical Neuroscience Department Theses and Dissertations

Permanent URI for this collection

https://hdl.handle.net/1805/1721

Browse

Now showing 1 - 10 of 87

Role of the Dorsomedial Hypothalamus in Responses Evoked from the Preoptic Area and by Systemic Administration of Interleukin-1β
(2009-06-23T21:35:36Z) Hunt, Joseph L.; DiMicco, Joseph A.; Cummins, Theodore R.; Rusyniak, Daniel; Vasko, Michael R.
Recent studies in anesthetized rats suggest that autonomic effects relating to thermoregulation that are evoked from the preoptic area (POA) may be mediated through activation of neurons in the dorsomedial hypothalamus (DMH). Disinhibition of neurons in the DMH produces not only cardiovascular changes but also increases in plasma adrenocorticotropic hormone (ACTH) and locomotor activity mimicking those evoked by microinjection of muscimol, a GABAA receptor agonist and neuronal inhibitor, into the POA. Therefore, I tested the hypothesis that all of these effects evoked from the POA are mediated through neurons in the DMH by assessing the effect of bilateral microinjection of muscimol into the DMH on the changes evoked by microinjection of muscimol into the POA in conscious rats. In addition, I tested the hypothesis that neurons in the DMH mediate a specific response that is thought to signal through the POA, the activation of the HPA axis evoked by systemic administration of the inflammatory cytokine IL-1β. After injection of vehicle into the DMH, injection of muscimol into the POA elicited marked increases in heart rate, arterial pressure, body temperature, plasma ACTH and locomotor activity and also increased Fos expression in the hypothalamic paraventricular nucleus (PVN), a region known to control the release of ACTH from the adenohypophysis, and the raphe pallidus, a medullary region known to mediate POA-evoked sympathetic responses. Prior microinjection of muscimol into the DMH produced a modest depression of baseline heart rate, arterial pressure, and body temperature but completely abolished all changes evoked from the POA. Microinjection of muscimol just anterior to the DMH had no effect on POA-evoked autonomic and neuroendocrine changes. Inhibition of neuronal activity in the DMH only partially attenuated the increased activity of the HPA axis following systemic injections of IL-1β. Thus, neurons in the DMH mediate a diverse array of physiological and behavioral responses elicited from the POA, suggesting that the POA represents an important source of inhibitory tone to key neurons in the DMH. However, it is clear that the inflammatory cytokine IL-1β must employ other pathways that are DMH-, and possibly POA-, independent to activate the HPA axis.
Effects of Nicotine Exposure in Adolescent Rats on Acquisition of Alcohol Drinking and Response to Nicotine in Adulthood
(2009-09-30T19:25:40Z) Bracken, Amy L.; McBride, William J.; Chambers, R. Andrew; Murphy, James M.; Rodd, Zachary A.
Nicotine is one of the most widely abused drugs in the world, and most smokers begin smoking during their adolescent years. Adolescence is a unique developmental period during which vulnerability to the effects of drug exposure is especially high. This dissertation uses rodent models to investigate the persistent effects of adolescent nicotine exposure on both neurobiological and behavioral measures of drug sensitivity in adulthood. The aims of this dissertation were to 1) determine whether nicotine would be self-administered into the posterior ventral tegmental area (pVTA), a neuroanatomical component of the mesolimbic dopamine (DA) system, which is known to be involved in reward and reinforcement; 2) investigate whether adolescent nicotine exposure would alter the sensitivity of the mesolimbic DA system as measured by DA release in the nucleus accumbens (NAc) in response to nicotine microinjections into the pVTA; 3) examine the effects of adolescent nicotine exposure on behavioral sensitization to nicotine in adulthood; and 4) investigate whether adulthood alcohol drinking behavior, in both Wistar and alcohol-preferring (P) rats, would be augmented by nicotine exposure during adolescence. Results of this dissertation demonstrated that 1) the pVTA is a neuroanatomical site that supports nicotine self-administration; and that adolescent nicotine exposure results in 2) increased nicotine-stimulated DA release in the NAc during adulthood; 3) augmented behavioral sensitization to nicotine in adult animals; and 4) enhanced acquisition of alcohol drinking behavior in adult Wistar and P rats. Overall, this dissertation provides insight into the diverse and persistent changes, in both neurobiology and behavior, caused by exposure to nicotine during the critical developmental period of adolescence.
Neuroprotective Effect Of Thyrotropin-Releasing Hormone (TRH) Against Glutamate Toxicity In Vitro
Yard, Michael; Kubek, Michael J.; Lahiri, Debomoy K.; Murrell, Jill Renee, 1964-
Acute and chronic activation of both ionotropic and metabotropic glutamate (glut) receptors is implicated in many neurodegenerative disorders including AD, dementia, epilepsy, stroke and neurotrauma. TRH and glut receptors (ionotropic & metabotropic) receptors are differentially coexpressed in granule and pyramidal neurons of the hippocampus. The author shows TRH to be protective when added to cultured pituitary adenoma (GH-3) cells and neuron-like pheochromocytoma (PC12) cells either prior to, during, or after glut-induced toxicity (Endo. Soc. Abs. 01), and also shows that the possible neuroprotective mechanism may involve heterologous downregulation of the metabotropic glut receptors, using superfused hippocampal slices and noting a reduction of Gαq/11 (SFN Abs. 02). He has also demonstrated that TRH protected against glut toxicity in fetal cortical cultures (Endo. Soc. Abs. 04). To extend these studies he used 14-day cultured rat fetal hippocampal neurons (Day E17) to determine if TRH is protective against toxicity induced by specific ionotropic and metabotropic glut agonists. Neuronal viability and integrity were assessed by trypan blue exclusion and LDH release after 18 hrs following 30 min exposure to glut agonists. Ten µM dihydroxyphenylglycine (DHPG, a Group 1 receptor agonist) + 30 µM N-methyl-D-aspartate (NMDA)-induced toxicity (42% vs contr. P<0.05); whereas, concurrent and continued treatment with 10 uM but not 1uM 3Me-HTRH resulted in less neuronal death and damage (86% vs contr P<0.05; 53% vs contr. P>0.05) respectively. DHPG treatment alone (10 µM) for 30 min. was non-toxic by both criteria (90% vs contr. P<0.05). The data suggest that TRH may be a selective modulator of glut-induced toxicity.
Cytosolic phospholipase A2 expression patterns in brain following the traumatic brain injury
(2010-06-01T16:58:17Z) Yang, Shuangni; Cummins, Theodore R.; Chen, Jinhui; Xu, Xiaoming
Effects of omega-3 fatty acids on rodent models of bipolar disorder and alcoholism
(2010-07-20T15:16:10Z) Case, Natalie J.; Oxford, Gerry S.; Niculescu, Alexander B.; Czachowski, Cristine L.
Our laboratory has previously identified the clock gene D-box Binding Protein (DBP) as a candidate gene for bipolar disorder and alcoholism using a Convergent Functional Genomics (CFG) approach. In subsequent work, we established mice with a homozygous deletion of DBP as a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. In the present study, we found that the omega-3 fatty acid, DHA, may have mood stabilizing capabilities in stressed DBP knockout mice, and reduces alcohol consumption in these mice as well as in the alcohol preferring (P) rats. Given their potential health benefits and their relative lack of negative side-effects, omega-3 fatty acids may become an important supplement for bipolar patients and co-morbid alcoholics, a potential that warrants continued research.
THE EFFECT OF ETHANOL ON IMPULSIVITY IN HIGH ALCOHOL PREFERRING MICE
(2010-07-21T20:19:33Z) Oberlin, Brandon G.; Grahame, Nicholas; Fetterman, J. Gregor; Kareken, David; McBride, William J.
Impulsivity is associated with addiction in many human studies. Delay discounting (DD) is often used to measure impulsive choice in humans and animals. In DD testing, a small immediate reward is pitted against a larger delayed reward, and relative preference is assessed. The relative contribution of ethanol to impulsivity in alcoholism is not well-understood, therefore I will test the hypothesis that ethanol exposure will increase impulsivity in High Alcohol Preferring (HAP) mice as measured in an adjusting amount DD task. Selectively bred HAP mice were exposed to ethanol and tested in DD in 3 different experiments. Experiment 1: ad lib homecage ethanol drinking for 21 days and 17 days were used to expose mice to ethanol. Additionally, mice were tested in DD while “currently drinking” vs. “abstinent”. In experiment 2, to achieve higher blood alcohol concentrations, mice were injected with 3.5 g/kg ethanol 8 times and tested before and after in DD. In both experiments 1 and 2, mice were tested at only 2 delays (0.5 sec and 10 sec), to maximize sensitivity to detect shifts in choice behavior. In experiment 3, mice responded for 8% ethanol or 0.01% saccharin at a full range of delays: 0, 1, 2, 4, and 8 sec. Experiment 1 did not reveal any impact of ethanol drinking on impulsivity. Experiment 2 revealed a strong trend of reduced impulsivity in the 10 sec delay group after ethanol injections. Experiment 3 revealed reduced impulsivity at the 8 sec delay in the group responding for ethanol, and also revealed a significant correlation between higher ethanol drinking and reduced impulsivity. These data were unexpected, and imply that the a priori hypothesis not only should be rejected, but that the opposite hypothesis may be true: ethanol decreases impulsivity, at least with high dose exposure and in responding for it as a reinforcer. This effect was similar to the effect observed in other studies with amphetamine, which consistently decreases impulsivity. Ethanol may have been exerting an amphetamine-like effect on impulsivity at the doses tested here. There is no evidence in the data generated in these studies that ethanol increases impulsivity.
Nf1-DEFICIENT MICE DISPLAY SOCIAL LEARNING DEFICITS THAT ARE RESCUED BY THE DELETION OF PAK1 GENE
(2011-03-16) Spence, John Paul; Shekhar, Anantha, 1957-; Clapp, D. Wade; Johnson, Philip L.; Yang, Feng-Chun
Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that affects roughly 1 in 3500 individuals. In addition to physical features (e.g., neurofibromas), developmental disorders are also common that can affect cognition, learning, attention and social function. The NF1 gene encodes neurofibromin, a GTPase activating protein (GAP)-like protein that negatively regulates Ras GTPase activation. Mutation at the NF1 locus increases the output of MAPK and PI3K signal transduction from the cellular membrane to the nucleus. Similar to humans, Nf1+/- mice show spatial learning abnormalities that are potentially correlated with increases in GABA-mediated inhibition and deficits in long-term potentiation in the hippocampus. Here, we demonstrate for the first time that Nf1+/- mice exhibit a selective loss of long-term social learning / memory and increased GABAergic inhibition in the basolateral amygdala, a critical brain region for regulating social behaviors. Next, utilizing a genetic intercross, we show that the co-deletion of p21-activated kinase type 1 (Pak1-/-), which positively regulates MAPK activation, restores Nf1+/--dependent MAPK hyperactivation in neurons cultured from the frontal cortex. We found that the co-deletion of Pak1 in Nf1+/- mice (Nf1+/- / Pak1-/-) also restores the deficits in long-term social learning / memory seen in Nf1+/- mice and normalizes the increases in GABA-mediated inhibition in the BLA, as compared to Nf1+/- mice. Together, these findings establish a role for Nf1 and Pak1 genes in the regulation of social learning in Nf1-deficient mice. Furthermore, proteomic studies identify dysregulation of F-actin and microtubule dynamics in the prefrontal cortex, and implicate proteins associated with vesicular release as well as neurite formation and outgrowth (e.g., LSAMP, STXBP1, DREB). In the BLA, disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) was identified, and ADAM22 may play a role in the regulation of AMPA receptors. Finally, due to the increased co-occurrence of NF1 and autism, these findings may also have important implications for the pathology and treatment of NF1-related social deficits and some forms of autism.
Paclitaxel alters the function of the small diameter sensory neurons
(2011-07-08) Gracias, Neilia; Vasko, Michael R.; Brustovetsky, Nickolay; Hingtgen, Cynthia M., 1966-; Hudmon, Andrew; Kelley, Mark Richard, 1957-
Although paclitaxel is a commonly used anti-neoplastic agent for the treatment of solid tumors, therapy often results in a number of side effects, the most debilitating of which is peripheral neuropathy. Peripheral neuropathy is defined as a pathology of peripheral nerves, and, depending on the type of nerves damaged, the neuropathy can be classified as sensory, motor, or autonomic neuropathy. In the case of peripheral neuropathy induced by paclitaxel, the symptoms are experienced in the extremities and are sensory in nature. Patients undergoing chemotherapy with paclitaxel often report sensory disturbances such as burning, tingling, numbness, a diminished sensation to pain and temperature, loss of vibration sense, loss of proprioception, and loss of deep tendon reflexes. Electrophysiological abnormalities including decreased sensory nerve action potential amplitude and conduction confirm damage to large myelinated fibers. However, the involvement of damage to small diameter sensory neurons in the etiology of paclitaxel – induced peripheral neuropathy is still controversial. Therefore, experiments were performed to determine if paclitaxel alters the function of small diameter sensory neurons and to examine the mechanisms responsible for the change in function. vi Sensory neuron mediated vasodilatation in paclitaxel – injected animals was examined as an indirect measure of calcitonin gene related peptide (CGRP) release and therefore of sensory neuron function. CGRP release was also directly measured from central terminals in the spinal cord. To examine mechanisms of paclitaxel – induced sensory neuron damage, CGRP release and neurite length was examined in paclitaxel – treated sensory neurons in culture. The results demonstrate that (1) paclitaxel decreases the ability of small diameter sensory neurons to produce an increase in blood flow in the skin; (2) paclitaxel alters the release of CGRP from the small diameter sensory neurons; (3) paclitaxel causes the neuronal processes of isolated sensory neurons to degenerate. This dissertation provides novel information showing that paclitaxel alters the function of small diameter sensory neurons and thus provides a better understanding of the mechanisms mediating the sensory disturbances characteristic of peripheral neuropathy resulting from chemotherapy with paclitaxel.
NEUROPROTECTIVE STUDIES ON THE MPTP AND SOD1 MOUSE MODELS OF NEURODEGENERATIVE DISEASES
(2012-02-29) Fontanilla, Christine V.; Farlow, Martin R.; Du, Yansheng; Jin, Xiaoming; Xu, Zao C.
The main, underlying cause of neurodegenerative disease is the progressive loss of neuronal structure or function, whereby central and/or peripheral nervous system circuitry is severely and irreversibly damaged, resulting in the manifestation of clinical symptoms and signs. Neurodegenerative research has revealed many similarities among these diseases: although their clinical presentation and outcomes may differ, many parallels in their pathological mechanisms can be found. Unraveling these relationships and similarities could provide the potential for the discovery of therapeutic advances such that a treatment for one neurologic disease may also be effective for several other neurodegenerative disorders. There is growing awareness that due to the complexity of pathophysiological processes in human disease, specifically targeting or inactivating a single degenerative process or a discrete cellular molecular pathway may be ineffective in the treatment of these multifaceted disorders. Rather, potential therapeutics with a multi-target approach may be required to successfully and effectively control disease progression. Recent advances in neurodegenerative research involve the creation of animal disease models that closely mimic their human counterparts. The use of both toxin- exposure and genetic animal models in combination may give insight into the underlying pathologic mechanisms of neurodegenerative disorders (target identification) leading to the development and screening of prospective treatments and determination of their neuroprotective mechanism (target validation). Taken together, ideal candidates for the treatment of neurodegenerative disease would need to exert their neuroprotective effect on multiple pathological pathways. Previous studies from this laboratory and collaborators have shown that the naturally-occurring compound, caffeic acid phenethyl ester (CAPE), is efficacious for the treatment against neurodegeneration. Because of its versatile abilities, CAPE was chosen for this study as this compound may be able to target the pathogenic pathways shared by two different animal models of neurodegeneration and may exhibit neuroprotection. In addition, adipose-derived stem cell conditioned media (ASC-CM), a biologically-derived reagent containing a multitude of neuroprotective and neurotrophic factors, was selected as ASC-CM has been previously shown to be neuroprotective by using both animal and cell culture models of neurodegeneration.
Elucidating mechanisms that lead to persistent anxiety-like behavior in rats following repeated activation of corticotropin-releasing factor receptors in the basolateral amygdala
(2012-03-16) Gaskins, Denise; Shekhar, Anantha, 1957-; Harris, Robert A. (Robert Allison), 1939-; Hingtgen, Cynthia M., 1966-; Truitt, William A.
Anxiety disorders are estimated to impact 1 in 4 individuals within their lifetime. For some individuals, repeated episodes of the stress response leads to pathological anxiety and depression. The stress response is linked to increased levels of corticotropin-releasing factor (CRF) in the basolateral nucleus of the amygdala (BLA), a putative site for regulating anxiety and associative processes related to aversive emotional memories, and activation of CRF receptors in the BLA of rats produces anxiety-like behavior. Mimicking repeated episodes of the stress response, sub-anxiogenic doses of urocortin 1 (Ucn1), a CRF receptor agonist, are microinjected into the BLA of rats for five consecutive days, a procedure called priming. This results in 1) behavioral sensitization, such that a previously non-efficacious dose of Ucn1 will elicit anxiety-like response after the 3rd injection and 2) the development of a persistent anxiety-like phenotype that lasts at least five weeks after the last injection without any further treatment. Therefore, the purpose of this thesis was to identify mechanisms involved in the Ucn1-priming-induced anxiogenesis. The first a set of experiments revealed that the anxiety-like behavior was not due to aversive conditioning to the context or partner cues of the testing environment. Next, Ucn1-priming-induced gene expression changes in the BLA were identified: mRNA expression for Sst2, Sst4, Chrna4, Chrma4, and Gabrr1 was significantly reduced in Ucn1-primed compared to Vehicle-primed rats. Of these, Sst2 emerged as the primary receptor of interest. Subsequent studies found that antagonizing the Sstr2 resulted in anxiety-like behavior and activation of Sstr2 blocked acute Ucn1-induced anxiety-like responses. Furthermore, pretreatment with a Sstr2 agonist delayed the behavioral sensitization observed in Ucn1-induced priming but did not stop the development of persistent anxiety-like behavior or the Ucn1-priming-induced decrease in the Sstr2 mRNA. These results suggest that the decrease in Sstr2 mRNA is associated with the expression of persistent anxiety-like behavior but dissociated from the mechanisms causing the behavioral sensitization. Pharmacological studies confirmed that a reduced Sstr2 mediated effect in the BLA is likely to play a role in persistent anxiety and should be investigated further.

Browse

Browsing Medical Neuroscience Department Theses and Dissertations by browse.metadata.dateaccessioned

Results Per Page

Sort Options