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Mother-infant separation (MS) is an early-life stressor which affects stress-related processes in brain and behaviors in rats. Changes associated with MS were investigated in the brain and behavior of two rat strains, Holtzman and Sprague-Dawley, at three points in development. The hypothesis was that MS would affect the prefrontal cortex (PFC), both in metabolic capacity and PFC-related behaviors across the lifespan. First, cytochrome oxidase (CO), an enzyme that directly reflects metabolic capacity in the brain, was quantified in two-week old Holtzman rats after MS, early handling (EH), or nohhandled controls. MS reduced CO activity in the PFC of female rats but not males. Path analysis of the CO data revealed a stronger descending influence of the medial PFC, a region associated with behavioral inhibition, in females; contrasted with a stronger descending influence of the lateral PFC, a region associated with motor output, in males. Second, adolescent rats were tested in the open field to assess MS effects on ambulatory activity and impulsivity. MS increased ambulatory activity and impulsivity in Sprague-Dawley males. In a separate study, MS reduced ambulation and impulsivity in Holtzman rats in the open field. Brains of Sprague- Dawley adolescents showed reduced PFC thickness in MS males relative to EH males. Across groups, male adolescents had reduced metabolic capacity relative to females in the PFC. Finally, extinction of Pavlovian fear, a PFC-related behavior, was not affected by sex or separation group in adult Holtzman rats. Across groups, males showed greater fear renewal than females, despite the extinction process. An unexpected finding was that EH attenuated fear renewal. Findings from these MS studies in Sprague-Dawley rats are similar to human psychopathology of ADHD, which is reported more frequently in young males and is related to PFC dysfunction. The opposite behavioral findings between Holtzman and Sprague-Dawley rats suggest that genetic predisposition can affect long-term responses to the same early-life stressor. Knowledge about baseline sex differences in brain and behavior gained from the studies on Holtzman rats may help future research to consider sex-dependent effects of disruptions during development, as it appears that some basic neural substrates are sexually dimorphic. / text

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Rats display considerable individual differences in performance of skilled reaching for food. Such variability in the normal performance of the rats intrudes upon the interpretation of many different experimental investigations in behavioral neuroscience. Understanding the origins of individual differences in skilled reaching performance of the rat provides insights into brain function, the evolution of skilled reaching, and also it helps optimizing preventative and therapeutic care. Although variability in skilled reaching is manifested in many studies, their origins remain poorly understood. The objective of the present thesis was to document the individual differences in skilled reaching for food in rats and to examine potential sources of individual differences in brain function. The present studies revealed that the difference in reaching success displayed by rats was a robust and constant feature in different conditions, emerged with practice and the motor cortex plays an important role in such variability / x, 241 leaves : ill., ; 29 cm

Analgesias induced by an interaction between restraint and morphine, an interaction between exposure to a novel environment and morphine, and by restraint alone were all shown to be dependent upon an increase in brain tryptophan uptake. Further investigation of the analgesia induced by an interaction between retraint and morphine revealed that the increase in brain tryptophan uptake was induced by sympathetic activity and that the nucleus raphe magnus, the nucleus raphe dorsalis, and the periaqueductal gray were critical to the analgesia. Examination of the endogenous opiod activity critical to analgesia induced by restraint alone revealed that the opioid activity was in the central nervous system and independent of tryptophan uptake. The findings reported in this thesis may be delineating a general mechanism for analgesia that involves stress, serotonin, and opioids.

The maternal consumption of alcohol during pregnancy produces a wide range of abnormalities in the offspring. The major objectives of this thesis were to investigate (1) the correspondence between prenatal ethanol-induced alterations in behavior and in hypothalamicpituitary- adrenal (HPA) activity, (2) the ability of early postnatal handling as an environmental manipulation to attenuate at least some of the adverse behavioral and physiological consequences of prenatal ethanol exposure, and (3) possible mechanisms mediating the HP A hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol and the possible influence of postnatal handling on those mechanisms. Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum fed control (C) treatment groups were tested as young adults (-35-120 d of age) or mid-aged adults (13-14 months of age). The first study investigated the effects of prenatal ethanol exposure (E) and postnatal handling (H) on behavior and HPA activity during a conditioned taste aversion (CTA) task. We tested the hypothesis that E animals which underwent postnatal handling would show improved conditioned aversion learning and reduced HPA activity compared to E animals that did not experience handling (nonhandled, NH). We found that prenatal ethanol exposure and postnatal handling independently resulted in an increased rate of consumption of a saccharin solution over five preexposure days. In addition, we found that handling differentially affected posttoxicosis consumption of the conditioned solution as well as corticosterone (CORT) levels in E, PF and C animals. H-E animals showed increased posttoxicosis intake compared to H-PF and H-C animals during reexposure under non-deprived conditions; CORT levels were lower in PF and C than E males compared to their N H counterparts during reexposure under food- and waterdeprived conditions. Thus, E animals were less able to utilize environmental cues in the present study, displaying a more rapid reduction in neophobia compared to PF and C animals and, following postnatal handling, showing a decreased acquisition of conditioned aversion and an increased CORT response during reexposure to the conditioned solution. The second study examined spatial learning and memory in young adult (2 months) and mid-aged (13-14 months of age) H and N H E and control animals utilizing a Morris water maze. We investigated the hypothesis that postnatal handling would improve spatial navigation in E animals compared to E animals that did not experience handling and/or attenuate differences among E and control animals, and that this effect might be age-dependent. We also examined whether performance deficits in mid-aged animals would correspond to increases in CORT levels on the last day of testing. Young E males showed impairments in spatial navigation compared to young PF and C animals, taking longer to find the hidden platform over the course of testing and displaying an alteration in search pattern when the platform was removed. Interestingly, differences in young E, PF and C animals in escape latency and in distance traveled prior to finding the platform were apparent in H but not in N H animals. There were no differences in performance on the Morris water maze in mid-aged E, PF and C animals, but CORT levels were elevated in mid-aged E compared to C animals, supporting previous data indicating that E animals demonstrate HPA hyperresponsiveness to stressors. Lastly, although mid-aged animals had longer escape latencies and an altered search pattern compared to young animals, handling did not appear to attenuate impairments associated with aging. The third study investigated the hypothesis that postnatal handling might attenuate stress-induced ACTH and/or CORT differences among E, PF and C animals. Furthermore, the ability pf postnatal handling to modulate HPA feedback deficits in E animals was examined during exposure to a restraint stressor following dexamethasone (DEX) administration. Both E females and males showed increased ACTH and CORT compared to PF and/or C animals following saline administration. Administration of DEX to block HPA activity significantly suppressed both plasma ACTH and CORT in all animals. However, E females exhibited increased and/or prolonged elevations in ACTH and CORT compared to PF and C animals following DEX blockade. These data suggest that the insult of prenatal ethanol exposure affects both male and female offspring, but that there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyperresponsiveness. Postnatal handling reduced ACTH levels in both females and males following saline administration. Following DEX administration, H males had lower CORT than NH males. Postnatal handling resulted in a more rapid decrease in stress-associated CORT elevations in C females, and attenuated differences in CORT between PF and C females. However, postnatal handling did not attenuate deficits in negative feedback inhibition in E females; E females in both the H and N H treatments showed elevated CORT compared to their C counterparts, and H-E females also showed elevated CORT compared to H-PF females. Thus, postnatal handling did not attenuate the typical HPA hyperresponsiveness to stressors observed in E animals (saline condition), nor did it eliminate deficits in HPA feedback inhibition in E females (DEX condition). The fourth study examined whether the mechanisms resulting in HPA hyperresponsiveness in E animals are similar to those underlying the effects of postnatal handling. Differences in HPA responsiveness between H and NH animals appear to be dependent upon basal CORT activity and not stress-induced elevations in CORT. Therefore, we tested the hypothesis that differences in HPA activity among E and control animals would not occur following adrenalectomy (ADX) but could be reestablished following replacement with basal levels of exogenous CORT. In the absence of a CORT feedback signal or in the presence of a constant, basal CORT feedback signal, E, PF and C animals did not significantly differ in their abilities to regulate ACTH secretion, indicating that during the trough of the circadian rhythm, E, PF and C animals are equally capable of regulating HPA activity utilizing either CORT-independent feedback or feedback mediated through basal CORT activity. Thus, the effects of prenatal ethanol exposure on HPA function do not appear to be dependent upon the feedback signal provided by basal CORT levels. In conclusion, handling did not attenuate the effects of prenatal ethanol exposure examined in the present experiments. This may be because the effects of postnatal handling and prenatal ethanol exposure on HPA function are mediated through different mechanisms as well as the finding that handling is, at least partly, mediated through mother-pup interactions. Therefore, postnatal handling might exert differential effects on litters in which pup behavior has already been altered by prenatal treatments, underscoring the enduring effects of prenatal ethanol exposure.

Playing is a common behavior among juveniles of many mammalian species, including rats (Rattus norvegicus). The mechanisms underlying the change that occurs in the play fighting of male rats at puberty were the focus of this thesis. It was found that castration at weaning disrupted the formation of male-typical dominance relationships, but did not alter the pubertal changes in play fighting, whereas neonatal castration prevented the shift from juvenile- to adult-typical behaviour at puberty. This transistion is male specific and cannot be induced in females by exposing htme to more extreme social contexts, involving interactions with unfamiliar males. The change in play by males at puberty is not, then, a byproduct of other sex differences, but results from a highly specific mechanism in early infancy. The significance of this sex difference is explored with respect to the functions of play fighting in rats and other species. / xii, 137 leaves : ill. ; 28 cm.

This thesis used a rodent model of skilled forelimb training and intracortical microstimulation to examine the relationship between learning and cortical reorganization. This thesis examines how reorganization is related to the specific changes in forelimb movements during learning. It also examines the role that task reptition plays in driving motor cortex reorganization and showed that once the skilled motor task had been acquired it was necessary to repeat the task sufficiently to produce motor cortex reorganiztion. This thesis also examines reorganization following skilled reach training was related to the consolidation of motor skill, finding that animals that learned the skilled reaching task after five days of training also showed cortical reorganization, which persisted for one month. These experiments show that the distribution and subsequent redistribution of movement representations within motor cortex is related to changes in motor performance that occur during motor training. / viii, 108 leaves : ill. ; 28 cm.

Play fighting in kindling-prone (FAST) and kindling-resistant (SLOW) rats: Potential genetic controls over the components of play. Even though the behavioral components of play fighting have been well characterized in the rat, little is known about the underlying neurobehavioral mechanisms that control them. FAST and SLOW lines of selectively-bred rats were used to determine whether the components of play fighting were dissociable. Differences in their respective play profiles suggest tht there are genetic differences in the expression of differnt components of play. The effects of gene-environment interactions on the components of play suggest that playful attack and playful defense may be differentially labile, and that socially-relevant envionmental manipulations may have a greater impact on social interactions in adulthood than in the juvenile phase. Furthermore, these findings suggest that the genetic constraints on each of the components of play fighting give each component a unique pattern of context-dependent change. Future experiments using FAST and SLOW, as well as other selectively-bred lines of rats may provide insight into the proximate mechanisms regulating play fighting. / viii, 125 leaves ; 28 cm.