published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Brain damage in the first week of life is behaviorally and anatomically devastating for a rat. I investigated the use of pre- and/or postnatal experience as interventions that might improve the outcomes in rats with postnatal day 4 (P4) frontal cortex lesions. Prenatal maternal tactile stimulation or maternal complex housing facilitated recovery in P4 lesion animals and produced changes in brain organization. Post-lesion tactile stimulation also was found to be beneficial possibly via experience dependent changes in FGF-2 expression. Levels of FGF-2 were increased in both skin and brain after tactile stimulation and correlated with behavioral and anatomical changes. Direct post-lesion administration of FGF-2 had similar effects. These results are the first demonstration that prenatal experience can be prophylactic for postnatal brain injury and that behavioral experience can act on brain organization via enhanced trophic factor expression originating in skin. / xxi, 221 leaves : ill. ; 28 cm.

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Postnatal handling of rat litters during the first week of life greatly decreases behavioural fearfulness to novelty in the adult offspring. Our first question was to what extent the Benzodiazepine/GABAA receptor complex, a system critical for the expression of fear, might be involved in mediating the observed reduced fearfulness in handled animals (H). Benzodiazepine receptor (BZ) binding was reduced in the amygdala and locus coeruleus (LC), regions important for the expression of fear in non-handled (NH) and maternally separated animals (MS). Moreover, levels of the mRNA for the gamma2 sub-unit of the GABAA receptor complex, which confers high affinity BZ binding, were higher in the amygdaloid nuclei as well as in the LC of handled compared with both NH and MS animals. / Studies with the handling paradigm have lead to the idea that variations mother-pup interactions may actually be the cause of the handling effects. As adults, the offspring of mothers which exhibited high levels of licking/grooming and arched-back nursing (LG-ABN) showed substantially reduced behavioral fearfulness in response to novelty compared to the offspring of low LG-ABN mothers. In addition, the adult offspring of the high and low LGABN mothers showed the same receptor and molecular profiles as H and NH adult offspring. Corticotropin releasing factor (CRF) and alpha2 norepinephrine receptor levels, additional receptor systems thought to be important in the expression of fearfulness, differed in these animals too. Adoption studies give further support to the maternal hypothesis in the finding that the expression mRNA for the gamma2 sub-unit of the GABAA receptor complex can be differentially expressed as a result of different offspring to mother combinations. / Taken together, these findings suggest that early life events (ie: naturally occurring differences in maternal care) during the first few days of life have long-term effects on the development of central neurotransmitter systems, which mediate the expression of fearfulness to novelty.

This series of experiments used the multiple learning and memory systems hypothesis of the mammalian nervous system to investigate the possibility that the amygdala, dorsal striatum, and hippocampal systems might, in certain situations, interact to produce behavior in the normal animal. Using variations of the conditioned-cue preference (CCP) task, evidence is presented showing that context-specific information acquired by the hippocampus interferes with acquisition of amygdala-based stimulus-reward learning. It was also demonstrated that there are amygdala-, dorsal striatum-, and hippocampus-based forms of place learning and that cue ambiguity and movement are important factors determining which of these learning and memory systems gain behavioral control in place learning situations. These findings provide evidence for interactions among learning and memory systems and implicate the amygdala and dorsal striatum in some types of non-hippocampal based place learning using distal cues.

Many of the physiological responses concomitant with exercise are understood. Similarly, many of the changes characterizing the aging process have been established. However, the combination of the two (ie. effects of aging on exercise or vice versa) presents a myriad of questions, of which many remain unanswered.The objective of this study was to establish the differences between previously untrained young and adult male Fischer 344 rats following an exhaustive swim for the following parameters: 1) muscle glycogen, an essential fuel substrate; 2) Glucose-6-phosphate dehydrogenase (G6PDH), a marker of inflammation and tissue damage; 3) citrate synthase (CS), an integral enzyme of the Kreb's cycle and a respiratory chain marker; 4) muscle protein; and 5) percent muscle dry weight.The rats were divided into two groups by age. Young (3 mo., n=16) and adult (12 mo., n=17) rats were randomly divided into sedentary (young sed (YSD) n=7 and adult sed (ASD) n=9) or exercised groups (young swimmers (YSW) n=8 and adult swimmers (ASW) n=8). Rats in the swimming groups were given a brief exposure to the water one week prior to their exhaustive swim to minimize the stress and confusion during the actual exercise bout. On the study days one randomly selected swimmer from each age group was swum to exhaustion and sacrificed via pneumothorax. One animal from each of the respective sedentary age groups was also randomly selected and sacrificed as above. The plantaris, rectus femoris, red vastus, soleus, triceps, and liver were surgically excised from each animal and frozen in liquid nitrogen for later analysis.While the younger animals had lower glycogen stores initially, following the exhaustive swim their reduction in muscle glycogen was approximately 150% that of the adult animals for any given muscle. Muscle glycogen levels in ASD and YSD rats were significantly higher than those of the YSW animals for all muscles with the exception of the YSD's soleus. However, the percent decrease in liver glycogen following the swim for the two age groups was almost identical (a reduction of 55.05% and 58.59% for the adult and young age groups, respectively).Although the adult animals were significantly heavier than the younger rats, this did not appear to cause a significant difference in their swim time to exhaustion. No significant differences were observed between the groups for muscle protein or G6PDH. Levels of CS were significantly higher in the YSD plantaris when compared to the ASW. Similarly, the ASD rectus femoris CS levels were significantly greater than those of the ASW. Although significant differences between groups in percent muscle dry weight existed for the plantaris, rectus femoris, and triceps such differences seemed to have little bearing on the two age group's swim to exhaustion times.On the basis of this study it was concluded that although starting with greater glycogen stores prior to exercise, adult animals use less of this substrate prior to exhaustion than do younger animals. While the mechanism for such a phenomenon was not discovered it is believed to be enzymatic in nature. Furthermore, the adult animals do not appear to exhibit significantly more tissue damage following an exhaustive swim than that seen in younger animals. / School of Physical Education

Systemic Lupus Erythematosus (SLE) is a multi-organ autoimmune disorder that may result in death due to cardiac dysfunction. This dysfunction often occurs due to an endocarditis, known as Libman-Sacks, which presents on heart valves. The condition is hard to clinically diagnose and is often observed postmortem. Heart damage has been observed in the NP-SLE Lewis rat model positive for SLE. However, research has not been done in this model on the correlation between SLE and Libman-Sacks endocarditis. Numbers of occurrence have ranged from 3-50% in SLE patients. The presence of Libman-Sacks endocarditis should likewise occur in 3-50% of NP-SLE Lewis rats. There will be seven NP-SLE Lewis rats, five negative serum control rats, and five saline injected control rats. By performing this controlled study in rats, the correlation between SLE and Libman-Sacks will be better understood. / Department of Physiology and Health Science

The present study determined whether dietary supplementation with reduced glutathione (GSH), glutathione ester (GSHE) or N-acetylcysteine (NAC) increased the mitochondrial level of GSH, the major antioxidant inside cells, in rat kidney cortex and medulla. Nine month-old female Lewis rats were given daily intraperitoneal injections of isotonic saline (n=6), or saline containing GSH (250mg or 0.81mmol/Kg of body wt; n=7), GSHE (12mg or 0.03mmol/Kg; n=8), or NAC (200mg or 1.22mmol/Kg; n=8) for four weeks. At the end of the injection period, the rats were anesthetized and the kidneys removed. The kidneys were separated into cortical and medullary sections, weighed, and homogenized. The sections were separated into cytosolic and mitochondrial fractions by differential centrifugation. The GSH levels were determined by a colorimetric assay. Cortical and medullary mitochondrial GSH levels were significantly increased by all three supplements. Cytosolic GSH levels were also significantly increased in both cortical and medullary sections. Thus, dietary supplementation can significantly increase the mitochondrial pool of GSH in the rat kidney. / Department of Physiology and Health Science