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Author

Ron Sullivan

Date of Award

5-1995

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Supervisor

Henry Szecntman

Abstract

There is evidence that a number of psychiatric disorders, particularly depression and schizophrenia, are frequently associated with lateralized disturbances of brain function, or alterations in normal patterns of lateralized function. It is also known that many such disturbances, especially in schizophrenia, involve central dopamine (DA) systems. Several studies in recent years have established that lower animals often exhibit lateralization of brain function, both on the neurochemical and behavioral level. Central DA systems appear to be particularly asymmetrical. Left/right hemispheric asymmetries in rats have been reported at the population level for a variety of DA-modulated behaviors which may variously reflect motor, sensory, spatial, or stress/arousal processes. However, the directions of reported population asymmetries can vary across studies, depending in part upon the particular processes predominantly reflected in the measured behavior, and consequently leading to difficulties in interpretation. Given the potential relevance to both normal and abnormal brain function in humans, it is of much interest to determine what paraliels exist between lateralization in humans and lower animals.

The objectives of the present thesis were twofold. First, we sought to determine which DA-mediated behaviors exhibit left/right hemispheric asymmetries at the population level in rats, by employing specific paradigms to measure motor, sensorimotor, spatial and stress-related processes. The basic approach was to compare the effects of unilateral DA-depleting lesions (with 6-hydroxydopamine), in left or right brain structures of male rats. Behavioral and neurochemical asymmetries were also examined in nonlesioned controls. A second objective was to study the role of interhemispheric connections in the expression of behavioral asymmetries characteristic of rats with unilateral lesion-induced DA depletion. Specifically, we describe the effects of sectioning the corpus callosum in unilaterally lesioned (6-OHDA) rats, on motor and sensorimotor asymmetries.

Regarding the first objective, hemispheric population asymmetries were not found for any of three measures of motor activation, in rats with left or right lesions of the substantia nigra. These measures included ipsiversive turning behavior in response to amphetamine, contraversive turning in response to apomorphine and spontaneous locomotor measures in activity monitors. Similarly, groups did not differ in a measure of sensory/spatial bias, namely the orientation to edges during exploration of a large openfield. The same animals did differ however, in the performance of the Morris water maze task for spatial localization, suggesting that right brain mechanisms may be preferentially involved in successful task performance. A follow-up study with the water maze paradigm, using nonlesioned rats distinguished by the preferred direction of amphetamine-induced turning (and by inference the hemisphere of greater DA activity), further supported a preferential role for right brain DAergic mechanisms in this task. An additional test of population hemispheric asymmetry which focused on stress mechanisms, compared the effects of mesocortical DA depletion (left, right or hilateral) on the development of restraint stress-induced gastric pathology. Rats depleted of DA in the right anterior midline cortex, developed significantly more severe stress pathology than did nonlesioned controls. In contrast, left or bilateral cortical DA depletion resulted in nonsignificant trends for increased pathology. All three lesion types resulted in significant and unique effects on DAergic systems in subcortical brain structures, which may have in part contributed to the asymmetric effects on development of stress pathology.

Regarding the second objective of the study, it was found that corpus callosum section eliminated the asymmetrical orientation to openfield edges in unilaterally lesioned rats. Conversely, there was no effect of callosotomy on asymmetries in direction of turning behavior, either drug-induced or externally cued in the behavioral competition for food. Taken together with the report that callosal section potentiates lateralization of emotional expression, the findings emphasize the anatomical dissociability of these functional asymmetries, despite their mediation by DAergic systems at various levels.

Based on these and other literature reports, it is proposed that the most fundamental processes exhibiting consistent left/right hemispheric population biases in rats, are those related to stress. The greatest degree of functional asymmetry is found in the cortex, which modulates sutcortical structures in a highly asymmetrical manner. The data extend recent suggestions that the right cortex is preferentially involved in the mediation of high arousal states (such as uncontrollable stress). Other studies have shown that activation of mesocortical DA by stress initially favors the left brain, and later predominates in the right brain as stress is prolonged. Given the evidence that cortical DA facilitates coping ability, and based on a variety of neurochemical and behavioral reports of DAergic asymmetries, it is suggested that a normal left brain DAergic dominance may exist at the population level, for both rats and humans. Such an asymmetry is proposed to confer an adaptive advantage in the rapid execution of responses to minor stressors. Finally, it is proposed that disturbances in patterns of cortical activity may lead to (psycho)pathological states which are associated with vulnerability to stress.

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