Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes bibliographical references (p. 153-165).

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants that are recognized as global environmental contaminants and a potential health risk. They have been shown to elicit neurodevelopmental toxicity through disruption of the cholinergic neurotransmitter system in rodent models, but the effects of environmentally relevant exposures in wildlife species are unknown. The objective of this study was to assess the effects of the commercial pentabrominated diphenyl ether mixture DE-71 on cholinergic parameters in captive mink (Mustela vison) following dietary exposure of adult females and in utero, lactational and dietary exposure of their offspring. Adult females were fed diets containing 0, 0.1, 0.5 or 2.5 μg/g DE-71 from four weeks prior to breeding through weaning of their kits at six weeks of age. A portion of the weaned kits were maintained on their respective diets through 27 weeks of age. Cholinergic neurochemical biomarkers, including muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (mAChR) binding, cholinesterase (ChE) activity and acetylcholine (ACh) concentration, were assayed in the cerebral cortex, and ChE activity measured in the plasma. Results indicated no significant effects of DE-71 on cholinergic parameters in the cerebral cortex, but a 3-fold increase in ChE activity in the plasma of adult females in the 2.5 μg/g DE-71 group. There were also no direct effects of DE-71 on mAChR or mAChR binding or ChE activity in the enzyme and receptor fractions from the whole brain of untreated mink following in vitro exposure to 0-23.6 nM DE-71. This study demonstrated that environmentally relevant exposures to DE-71 did not affect key parameters of the cholinergic neurotransmitter system in the brain of captive mink.

The pedunculopontine tegmental nucleus (PPTg) has been proposed to be critical in drug and food reward. It is a major source of cholinergic inputs to the substantia nigra and ventral tegmental area, areas important in reward, and is believed to modulate activity of dopamine neurons through a cholinergic mechanism. The firing rate of cholinergic PPTg cells is regulated by muscarinic autoreceptors that can be blocked to increase cell firing. If the PPTg modulates dopamine neurons involved in reward, then a muscarinic antagonist microinjected into the PPTg should be rewarding. To test this hypothesis, bilateral microinjections of scopolamine methyl bromide (5 $ mu$g or 20 $ mu$g) or 0.9% saline were used as reward treatments in the conditioned place preference test. On the test day, rats from both doses of drug avoided the drug-paired chamber, which suggests that cholinergic PPTg cells are not involved in reward.

In order to assess cognitive function in multiple sclerosis (MS) and the effect of cholinergic modulation, experiments were conducted using functional magnetic resonance imaging (fMRI) to assess the brain activation during cognitive tasks. A study comparing the processing of verbal working memory with an N-back task found that patients showed smaller increase in activation than healthy controls with greater task difficulty, suggesting a reduced functional reserve. Controls and patients showed differences of correlations between brain regions activated. Interactions between prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. The effect of Rivastigmine on the cognitive processing in MS patients was tested in a longitudinal study, involving serial fMRI scans. Changes in the brain activation patterns were demonstrated with drug administration, without any changes in behavioural measures. Rivastigmine may act to increase the functioning of the normal neural network reducing the need for previously recruited compensatory mechanisms in MS patients. A study on healthy subjects examined the effect of cholinergic inhibition on cognitive processing and brain activation. Changes in functional activation due to Hyoscine during verbal working memory were found analogous to that in MS patients without any changes in behavioural measures. Processes that potentially impair brain cognitive function may recruit similar compensatory functional adaptive mechanisms. Studies on rats and MS patients explored the effect of Rivastigmine on the relationship of the BOLD fMRI signal with the underlying neural activity. Rivastigmine may be influencing the cortical excitability after direct cortical stimulation but showed only a small effect on the BOLD signal under more physiological neural activity. The neural activity in response to visual stimulation is slightly increased with Rivastigmine in MS patients, a change not detected with functional imaging. These studies suggest that changes in BOLD signal do represent sufficiently large changes of underlying neural activity in the presence of Rivastigmine. The relationship of damage in MS to measures of connectivity was studied using diffusion tensor imaging (DTI). Correlation was found between measures of connectivity and callosal size, a measure of fibre loss. The distribution of lesions was spatially correlated with changes in connectivity due to MS. Thus DTI could be utilized to explore the connectivity changes associated with MS, and the relationship with changes in functional activation.

Cholinergic interneurons are relatively rare neurons in the rat striatum. These sparsely distributed neurons display a synchronous pause in their tonic firing pattern during reward-related learning. It has been hypothesised that a specialised fast-conducting crossed-corticostriatal pathway is involved in synchronising the pause in tonic firing of these interneurons. This study aimed to detail the innervation of cholinergic interneurons by mapping their proximal and distal inputs and to describe the innervation of the crossed-corticostriatal pathway in male Wistar rats. In vivo electrophysiological recording methods were used to label single crossed-corticostriatal neurons but inadequately labeled their axons. Thus, an anterograde neuronal tracing study was conducted. Biotinylated dextran amine (BDA; 1.2 [mu]l) was pressure-injected into the left cerebral hemisphere. Six days later, the rat was perfused-fixed and the brain sectioned. BDA-labelled axons were traced to both the ipsilateral and contralateral striata. Cholinergic interneurons in the right striatum were double-immunolabelled using an optimised protocol including a polyclonal rabbit anti-m2-muscarinic receptor antibody and a monoclonal goat anti-choline acetyltransferase antibody. All sections were processed for transmission electron microscopy. Serial ultrathin sections were montaged and distal (from non BDA-labelled tissue) and proximal synapses were each mapped separately. A reconstructed distal dendrite from a cholinergic interneuron, located 225 [mu]m from the soma, was analysed. It had an average width of 1 .25[mu]m and 0.726 synapses per [mu]m. This was compared to dendrites in the same tissue and from BDA-labelled tissue. Two dendrites were presumed to be distal profiles of either cholinergic or somatostatin interneurons, while the third was thought to belong to another interneuronal cell type. In terms of surface area, there were less somal synapses compared to those made onto the distal dendrite of the cholinergic interneuron. Somal synapse counts were similar to those reported previously from our laboratory, where symmetric synapses were most common. Crossed-corticostriatal BDA-labelled axons were found to course across proximal dendrites and somas of immunolabelled cholinergic interneurons. Varicosities from these axons were found in close proximity to proximal dendrites and somas of cholinergic interneurons. Of all cholinergic interneurons in an adjacent section, 77% showed closely associated proximal varicosities. Of these, 76% of varicosities were associated with the soma, 11% to proximal dendrites and 13% to both locations. Twenty-nine BDA-labeled axons were analysed using transmission electron microscopy. Most were observed making asymmetric synaptic contact with unlabelled spines. In two cases spines were traced to medium spiny projection neurons. Two axon segments were seen touching the proximal regions of separate cholinergic interneurons. At these contact sites interrupted membrane thickenings were observed. It is proposed here that synapses may form at these sites during reward-related learning. However labelling of the contact sites with a postsynaptic marker would be necessary to confirm their synaptic nature. The current study has gathered information about the distal and proximal innervation patterns of these neurons and described the termination pattern of the crossed-corticostriatal pathway in relation to these neurons for the first time. These findings support the crossed-corticostriatal pathway as one possible anatomical substrate for synchronising the pause response on both sides of the brain.

Thesis (Ph.D.) - University of St Andrews, April 2008.

Thesis (Ph. D.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 116-138).

Thesis (M.Sc.) - Carleton University, 2007. / Includes bibliographical references (p. 78-87). Also available in electronic format on the Internet.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xii, 103 p.; also includes graphics (some col.). Includes bibliographical references (p. 90-103). Available online via OhioLINK's ETD Center