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The present experiments were designed to examine the hypothesis that the hippocampus and caudate nucleus are parts of independent memory systems which differ in the type of memory they mediate. In experiment 1, the mnemonic functions of the hippocampus and caudate were doubly dissociated; lesions of the caudate nucleus impaired acquisition of the "habit memory" component of the 4 x 4 radial maze task, but had no effect the "cognitive memory" component of the task. Lesions of the fimbria-fornix produced the opposite behavioral dissociation. In experiment 2, lesions of the caudate nucleus produced a transient deficit in cognitive win-shift radial maze behavior when rats were allowed to obtain food from maze arms on an unlimited basis prior to win-shift training. In contrast, lesions of the caudate had no effect on win-shift acquisition when rats were allowed to explore an empty maze prior to win-shift training. These results suggest that reinforcement contingencies may be important in determining the type of memory process initiated by a training experience. In experiments 3ab, systemic post-training injection of the dopamine (DA) agonist D-amphetamine (D-AMP) and the DA D2 receptor agonist LY 171555, but not the DA D1 receptor agonist SKF-38393, improved acquisition on both a habit memory win-stay radial maze task, and a cognitive memory win-shift radial maze task. In experiments 4ab, the mnemonic functions of the hippocampus and caudate nucleus were doubly dissociated using post-training intracerebral injections of these same DA agonists. Post-training intracaudate injection of D-AMP, LY 171555, and SKF-38393 improved acquisition of win-stay, but not win-shift radial maze behavior. Post-training intrahippocampal injection of these DA agonists produced the opposite behavioral dissociation. Taken together, the results are consistent with the hypothesis that the caudate nucleus mediates the acquisition of habit memory, while the hippocampus mediates the acquisition

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Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Stress is known to impair spatial navigation in rat models of declarative memory, and declarative memory in humans, but the effects on spatial navigation in humans are unclear. At least four models have been proposed to account for the cognitive effects of stress, based on the two different physiological stress response systems (the sympathetic-adrenal-medullary (SAM) and the hypothalamic-pituitary-adrenal (HPA) systems) and the effects of these responses on the hippocampus and (sometimes) other subcortical structures. In this dissertation, I examined the effects of an acute (experimental) stressor on human spatial navigation in three variations of virtual Morris water mazes designed to dissociate between hippocampus-dependent (allocentric) and hippocampus-independent (egocentric) forms of navigation. Results were considered in the light of all 4 models. Experiment 1 used a dual-strategy Morris water maze to test whether acute stress influences navigational strategy selection and whether this effect is mediated by the activation of the HPA or the SAM system. Surprisingly, stress increased hippocampus-based strategy selection, and did so in the presence of SAM but not HPA activation. Experiment 2 used new dual-strategy and place mazes to examine the effects of acute stress on both strategy selection and allocentric navigational performance. It also attempted to contrast the effects of stress at a short delay, which would favour mediation by the SAM system, and a longer, 30 minute delay (from stressor onset), which would favour mediation by the HPA system. Contrary to expectations, results revealed no effect of stress when tested immediately and sex-dependent impairments of performance (in females) and allocentric strategy selection (in males) at the delay. Experiment 3 used the same mazes as Experiment 2, plus a new cue maze to examine the effects of acute stress on strategy selection and both allocentric and egocentric navigational performance after a 30 minute delay. Results confirmed that stress reduces allocentric strategy selection and impairs allocentric performance, but also has sex-dependent effects on egocentric performance: in females, stress enhanced navigation (as expected) but in males, stress impaired it. None of the 4 models provided a good explanation for these results, suggesting that current accounts of the cognitive effects of stress may be inadequate. / Graduate

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Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) offer unique, noninvasive methods of measuring, respectively, in vivo quantitative neuroanatomy and neurochemistry. The main purpose of the present study was to identify and compare the neuroanatomical and neurochemical abnormalities that are associated with prenatal exposure to alcohol in both fetal alcohol syndrome (FAS)-diagnosed children and those diagnosed with fetal alcohol effects (FAE). MR data of three age-, gender- and race-balanced groups of children, FAS-diagnosed, FAE-diagnosed and non-exposed controls, were compared. Effects of prenatal alcohol exposure, regardless of diagnosis, were found in the caudate nucleus. Specifically, a significantly smaller caudate nucleus was found for the FAS and FAE participants compared to the controls. In addition, the metabolite ratio of N-acetyl-aspartate to creatine (NAA/Cr), an indicator of neuronal function, in left caudate nucleus of both the FAS and FAE participants was elevated compared to the control group. Analysis of absolute concentrations revealed that the increase in the ratio of NAA/Cr was due to an increase in NAA alone. Although its exact function in the CNS is unknown, NAA is believed to be a neuronal marker due to its exclusive localization to neurons. Some also speculate a role for NAA in myelination. Elevated NAA in the prenatal alcohol-exposed participants could indicate a lack of normal program cell death, dendritic pruning and/or myelination during development. The present study demonstrates that prenatal alcohol-exposed children, with or without facial dysmorphology, have abnormal brain anatomy and chemistry.

Epidemiological studies implicate pesticide exposure as a possible etiologic factor in idiopathic Parkinson's Disease, which results from degeneration of nigrostriatal neurons, along with reduced levels of the neurotransmitter, dopamine. Behavioral and neurochemical analyses in C57BL6 mice were performed following a subchronic dosing regime with the organochlorine insecticide heptachlor or the pyrethroid deltamethrin. Results were compared to those induced by the established parkinsonian neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the end of the treatment period, mice were assessed for effects on behavior, as well as levels of striatal dopamine, nerve terminal respiration, and synaptosomal dopamine transport. The primary behavioral effect of deltamethrin was incoordination, while heptachlor caused hyperexcitability and increased locomotion. The major neurochemical effect observed for both compounds was upregulation of the presynaptic dopamine transporter (DAT) by 70% and 100% for deltamethrin and heptachlor, respectively. The insecticides exerted only modest effects on striatal levels of dopamine and its metabolite, dihydroxyphenylacetic acid. However, doses of heptachlor higher than those which caused induction of DAT (e.g. greater than or equal to 25 mg/kg), when administered subchronically, were found to cause convulsions in some animals and caused marked, dose-dependent depression of basal striatal tissue respiration rates. No synergism was observed between the effects of insecticides and MPTP. Enhanced transport was thought to be a compensatory effect from increased release of transmitters by the insecticides, <i>in vivo</i>. Striatal dopamine, GABA and glutamate nerve terminals were differentially sensitive to the releasing effects of heptachlor compared to cortical serotonin terminals, and responded in the following rank order of sensitivity: dopamine > GABA > glutamate > serotonin. Additional experiments to characterize the mechanism(s) by which cyclodienes facilitate release of neurotransmitters in synaptosomes demonstrated a lack of distinct Ca²⁺ component and no involvement of retrograde DAT activity, suggesting that released label was of vesicular origin, but did not require Ca²⁺. Insecticidal toxicants, such as organochlorines and pyrethroids, which augment dopamine release and increase the maximal rate of dopamine uptake, may inundate the cytosol of nigrostriatal neurons with high concentrations of free dopamine, which has been shown by other researchers to induce apoptosis and may thereby contribute to the development of Parkinson's disease. Funding for this work was provided under grant number HHHREP 94-01 by the Hawaii Heptachlor Foundation, a non-profit organization. The Hawaii Heptachlor Foundation may be contacted at the following address: Ocean View Center PH#3, 707 Richards St., Honolulu, HI 96813. / Ph. D.