Date of Award

12-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Anatomy and Neurobiology

Research Advisor

Robert S. Waters, Ph.D.

Committee

Joseph Callaway, Ph.D. Andrea Elberger, Ph.D. Robert Foehring, Ph.D. Akinniran Oladehin, Ph.D.

Abstract

The primary goal of this dissertation was to examine the long-term effect of prenatal alcohol exposure (PAE) on the primary somatosensory (SI) and primary motor cortex (MI). For over 30 years, PAE has been shown to produce a triad of symptoms (growth deficits, craniofacial dysmorphologies and central nervous system disruptions) diagnosed as fetal alcohol syndrome (FAS) in children and adults. Since low to moderate levels of prenatal alcohol exposure are less likely to produce FAS symptoms in children, the term “PAE” in this dissertation typically refers to heavy/abusive/chronic levels of prenatal alcohol exposure (in humans this equates to 5+ drinks/per occasion/1+ times per week) administered in a chronic binge-type fashion having a high potential to cause FAS. However, it must be pointed out that the most important factor in studies dealing with PAE in humans or animals is the peak blood alcohol level (BAL) and next are the temporal and spatial parameters dealing with high BALs. It is evident that children with FAS frequently show major deficits in information processing, which is one of the major functions of the sensorimotor system. Two major components of the sensorimotor system are the cortical input to layer IV primary sensory cortex (SI) and output from layers V and VI primary motor cortex (MI). Therefore, the focus of this dissertation is on PAE-related anatomical and physiological deficits in SI and MI that are likely to play a role in the multiple sensorimotor, behavioral, and learning disruptions seen in children with FAS.

The similarities in rodent and human cortical organization make rodents excellent models for elucidating the influence of PAE on the sensorimotor system. Of particular note is the highly organized human and rodent sensorimotor system with the sensory input and motor output arranged into structural and functional columns. However, one difference between humans and rodents is that the latter receives its sensory information in layer IV cortex into cell aggregates termed “barrels,” whereas humans have no such specific cortical structures per se. Each barrel in rodent cortex is spatially related to sensory receptors that innervate specific regions of the body surface, thus barrels produce a cortical somatic map. The longest studied and most easily identifiable barrel region is the posterior medial barrel subfield (PMBSF), representing mystacial vibrissae of the rodent. A second highly studied region of the barrel cortex is the forepaw barrel subfield (FBS), representing the forepaw.

One hallmark feature of PAE is the behavioral disruptions seen in fine motor control. These deficits may be due to disruptions in both SI and MI. Like SI, MI is also well organized into specific cortical regions associated with eliciting motor responses. Because SI and MI are highly organized, these cortical regions are very useful for studying the effect of prolonged PAE-related sensorimotor disruptions.

The primary goal of this dissertation was to examine the long-term consequences of PAE on SI and MI in 6-week-old (juvenile) or 7-month-old (adult) rats. To accomplish this goal, four major experiments were carried out utilizing a binge-type alcohol exposure paradigm on pregnant rat dams followed by an examination of the PAE pups as well as untreated control and nutritional control pups at six weeks and seven months of age.

Experiment 1: We tested the hypothesis (Chapter 2) that PAE would reduce the PMBSF area in juvenile and adult rats. Results indicated that PAE significantly reduced the PMBSF area, the total PMBSF barrel area, and interbarrel septa area in PAE juveniles and adult rats. Furthermore, PAE effects were asymmetrical across the PMBSF, as the areas of posterior barrels were less reduced than anterior barrel areas. By combining barrels into lateral-to-medial running “arcs” and calculating the area as a percent difference from respective chowfed (CF) or pairfed (PF) arcs, results suggested a split in the PMBSF between a more reduced anterior region and a less reduced posterior region. The areas of anterior arcs of PMBSF were always more reduced than the areas of posterior arcs. However, a similar asymmetric pattern was not identified in anterior to posterior running rows.

Experiment 2: The goal of Experiment 2 (Chapter 2) was to test the hypothesis that the rostrocaudal asymmetry identified in Experiment 1 was due, in part, to differential sensory experience across the mystacial pad. It is well established that numerous peripheral and CNS asymmetries already occur by way of variations in mystacial pad vibrissae lengths, base widths, vibrissae behavior, peripheral innervation patterns, and metabolic activity levels within cortical PMBSF barrels. It was hypothesized that trimming the mystacial pad would eliminate any differences between posterior and anterior vibrissae, in turn affecting the vibrissae cortical barrel representations and subsequent PMBSF asymmetries. To test this hypothesis, unilateral mystacial vibrissae were trimmed in EtOH and CF rats from postnatal day five (PD5) to PD42. EtOH rats sacrificed on PD42 had their individual PMBSF area and individual PMBSF barrel areas measured. These areas were then compared to respective PMBSF and barrel areas of the ipsilateral cortex from a CF group that had also undergone vibrissae trimming, and the percent change was calculated. Results indicated that vibrissae trimming did not affect the asymmetry identified in Chapter 2.

Experiment 3: We tested the hypothesis that PAE would significantly reduce the area of the FBS morphology and the area of the peripheral glabrous forepaw (Chapter 3). The FBS morphology and peripheral glabrous forepaw areas were significantly reduced in juvenile rats following PAE.

Experiment 4: This experiment was carried out to test the hypothesis that PAE would reduce the physiological/functional forepaw representation and also delay evoked response latency between periphery and SI (Chapter 4). Using carbon-fiber electrodes inserted into layer IV cortex, the physiological forepaw representation was mapped by lightly tapping the forepaw periphery (i.e., digits, or pads) with a dull insect pin and recording forepaw receptive fields in the cortex. PAE significantly reduced the representation of the entire glabrous forepaw surface as well as the physiological forepaw representation.

Experiment 5: We tested the hypothesis that PAE would reduce the size of the primary motor cortex (MI), specifically those regions responsible for contralateral vibrissae and forepaw movement (Chapter 5). Results indicated that PAE significantly reduced MI areas for mystacial vibrissae and forepaw motor cortex.

Results from Experiments 1 to 5 reinforce the hypothesis that PAE has a long-term effect on the sensorimotor system and provides new information on the effect of PAE on MI. The sensorimotor system is important for processing peripheral information and performing planned motor movements. Therefore, deficits in this system may be among the underlying mechanisms for reported clinical symptoms, such as the disturbances in balance, posture, fine motor control, attention, learning, reaction time, and other information disruptions often identified in children exposed to high levels of alcohol in utero.

DOI

10.21007/etd.cghs.2007.0048

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