The Effects of Long-Term Exposure to Elevated Levels of Corticosterone on Cognitive Performance and Hippocampal Cell Death of Neonatally Handled and Non-Handled Young Adult Rats

Rastko Kovacevic, ’96

Advisor: Cheryl McCormick

The present study examines the impact of chronically elevated corticosterone levels on neonatally handled and non-handled rats when the glucocorticoid negative feedback advantage of handled rats is neutralized. Forty-three male Long-Evans rats were used in the experiments in which the endogenous source of corticosterone in rats is supplemented for a period of 11 weeks with a relatively constant exogenous source (sustained release corticosterone pellets). The negative feedback mechanisms of animals are thus capable only of regulating the endogenous corticosterone secretion. The impact of chronic administration of corticosterone is evaluated on the basis of cognitive performance. The hippocampal cell loss is measured and correlated with behavioral data. Based on the studies that report that prolonged exposure to corticosterone may damage hippocampal neurons, it is expected that handled rats, who have more glucocorticoid receptors, will sustain a higher level of cognitive impairment as well as hippocampal neuron damage than non-handled rats following a long-term exposure to high levels of neurotoxic corticosterone they cannot control through negative feedback. Treatment-induced corticosterone values were in the medium to high basal range, but no effects of corticosterone treatment are detected. Both corticosterone treated and control handled animals, however, were found to perform more poorly on the spatial memory task. Behavioral and morphological measures were correlated and revealed a nearly significant correlation, which is in agreement with prior research. Results are discussed and possible interpretations of the data are offered.

Sex, Sickness, and Sinistrality: The Associations Among Gender, Hand Preference, and Immune Status as Indicated by Salivary sIgA Levels

Richard A. Epstein Jr.

Advisor: Cheryl McCormick

The present thesis investigates hypotheses derived from the studies of Geschwind and Behan (1982), which found associations among left-handedness and incidence of immune and developmental learning disorders. Salivary IgA levels were determined as a direct measure of immune function and found to be significantly higher in left-handers and women. Further, results mildly consistent with those of Geschwind and Behan (1982) were obtained from the self-report incidence of immune and developmental learning disorders. The results are discussed in relation to the Geschwind and Galaburda (1985a,b,c) theory which hypothesizes that the observed associations among left-handedness, immune disorders, and developmental learning disorders are due to the effects of abnormal levels of neonatal sex hormones.

Hemispheric Asymmetry in the Control of Sexual Behavior by Progesterone

Meredith Child, ’95

Advisor: Cheryl McCormick

Previous research has found hemispheric asymmetries in the effect of estrogen (E) on sexual behavior when placed in the ventromedial nucleus of the hypothalamus (VMH) (Davis, McEwen, & Pfaff, 1979; Roy & Lynn, 1987).  Hemispheric asymmetry in control of sexual behavior by E may be mediated by an asymmetric distribution of progesterone receptors in the hypothalamus (McCormick & Singh, submitted).  The present studies utilized a within-subjects design to examine whether progesterone (P) implants affect sexual behavior differently when in the right versus the left VMH or frontal cortex.  The effects of unilateral lesions in the VMH and frontal cortex on sexual behavior was investigated.  For implant studies, ovariectomized rats primed with estradiol benzoate 28 hours prior to testing were given cannula inserts of P into the VMH or frontal cortex four hours prior to behavioral testing.  One week later the procedure was repeated alternating the side of P implant  Receptive and proceptive sexual behaviors were tested in a paced-mating chamber The majority of females did not lordose when mounted by a male.  However, when implants of P were placed in the right hemisphere of the VMH the female spent more time with the male.  Further, females exhibited significantly fewer squeals per time with the male with implants on the right. P implants in either side of the frontal cortex did not influence sexual behavior.  Unilateral lesions were made with infusions of ibotenic acid in the implant animals. Lesions of the VMH or frontal cortex did not produce marked effects on sexual behavior.  The results show modest evidence of a right bias in the control of sexual behavior by P in the VMH, which is consistent with the side bias in the effects of E found in previous studies.

Organizational and Activational Effects of Sex Hormones on the Hypothalamic-Pituitary-Adrenal Axis in the Rat

Brinley Furey, ’95

Advisor: Cheryl McCormick

There are sex differences in many parameters of the hypothalamic~pituitary adrenal axis (HPA). For example, females secrete higher levels of corticosterone than do males following stress. Activational effects of sex hormones are known to underlie some of the sex differences. For example, removal of the ovaries in adulthood decreases the Stress response in females. However, it is unknown whether some of the sex differences are related to the organizational effects of sex hormones during early development. In the present study, male and female neonatal rats were either gonadectomized on the first day of life (neonatal GDX) or underwent sham surgery. At approximately three months of age, jugular catheters were placed in the animals to allow for repeated sampling. At that time, half of the sham animals were gonadectomized (adult GDX) or underwent sham surgery. In addition, at this time, a portion of the neonatal and adult gonadectomized animals received hormone implants. Five days following surgery, HPA function was assessed by determining plasma corticosterone levels prior to, and at several intervals following, twenty minutes of restraint stress. Plasma corticosterone levels were also measured for all groups across the circadian rhythm. Results indicated a near significant difference between adult GDX males with replacement and neonatal GDX males with replacement in corticosterone levels following stress (p=07). This difference indicates that males who were gonadectomized on the first day of life did not respond to testosterone as efficiently as males who were gonadectomized as adults. This result suggests an organizational effect of testosterone on the HPA axis early in development. Adult GDX females and neonatal GDX females, with and without replacement, did not differ significantly from each other, indicating a completely activational effect of estrogen on the HPA axis. Due to small sample size, no significant group differences were observed in corticosterone levels across the circadian cycle.

Mother~Young Interactions in Litters Treated with Endotoxin or Saline

Megan Mahoney, ’95

Advisor: Cheryl McCormick

Endotoxin treatment of neonates has long-term effects on the development of rats. However, the causal mechanisms of endotoxin are unknown. The reaction of dams to treatment of the pups may be a factor in endotoxin effects. To investigate how mother-young interactions were affected by endotoxin treatment newborn litters were selected for one of two treatments: (1) endo toxin-treatment (i.p. injection of .005 mg Salmonella enteritidis lipopolysaccharidelml saline; .1 cclg body weight) or (2) saline-treatment (i.p. injection .9% saline; .1 cc/g body weight). In study one, pups were injected on day zero and litters were culled to six animals, three of each sex. On day zero, as the acute effects of endotoxin accrued and dissipated, litters were videotaped for eight hours, and then for two hours daily on days one through five~ Preliminary selective retrieval tests on days seven and ten suggested that endotoxin dams preferentially select males over females. In study two, newborn litters underwent the same treatments. However, litters were culled to four pups, two of each sex, on day three. Retrieval tests were conducted, four trials/day, on days four, eight, and twelve. Many of the dams in either treatment did not retrieve. In retrieving animals, sex preferences were not evident in either group, and there was a tendency for saline dams to have shorter latencies to retrieve. On days three, seven, and eleven, pup ultrasound production was recorded in a five minute period. On day three both treatment groups called at the same rate but endotoxin pups had a significantly lower number of calls than saline pups on days seven and eleven (p=.0001; p=.001 1 respectively). The results from study one and study two suggest that endotoxin treatment may be altering stimuli on pups in a specific manner, which in turn alters maternal care toward the young. The corticosterone data suggest that neonatal isolation causes changes in the HPA axis that are short lived. The fact that the effects of isolation do not last until adulthood is in contrast to the research indicating that neonatal handling or maternal deprivation cause permanent changes in HPA function. Possible reasons for the changes in the effects of neonatal isolation are discussed. This study gives evidence to the malleability of the HPA axis especially during early life.

Prefrontal Cortex Modulation of Dopamine in Schizophrenia

Tammy Moscrip, ’95

Advisor: John Kelsey

The original dopamine (DA) hypothesis for schizophrenia was based on the observation that the most effective drugs in treating schizophrenia were DA receptor blockers, suggesting that schizophrenia is due to increased DA transmission in the limbic system. However, these drugs are usually more effective in ameliorating the positive symptoms than in treating the negative symptoms. The negative symptoms, rather than representing increased DA activity may be due to decreased activity, especially in the prefrontal cortex (PFC). Particularly intriguing is the hypothesis that the observed hypofrontality represents decreased DA transmission in the PFC. Moreover, animal studies suggest that decreased DA transmission in the PFC can reciprocally initiate excess DA activity in subcortical regions, thereby producing the positive symptoms. To examine this hypothesis I performed bilateral 6-OHDA lesions of the PFC of 20 male Long Evans rats. I then measured the activity and social interaction patterns which would potentially represent positive (excess activity) and negative (social withdrawal) symptoms, respectively. The PFC lesions decreased social interaction as expected. However, they also decreased, rather than increasing, activity. Both the typical (haloperidol) and atypical (clozapine) neuroleptics decreased activity as expected. However, they both also decreased social interaction. Finally, the PFC lesion decreased the sensitivity to the suppressive effects of both haloperidol and clozapine on activity and social interaction. Thus, the role of the prefrontal cortex dopamine system in mediating schizophrenia remains unclear.

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