Stephanie L. Baker

Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared

The chronic mild stress (CMS) paradigm was developed in order to simulate in animals the symptom of anhedonia, a major feature of depression. Typically, changes in hedonic status are interpreted from a decrease in either intake or preference for a mild sucrose solution. Although the incidence of clinical depression is significantly higher in women than in men, the study of this disorder in most animal models of depression has been based on the responses of male rodents. The purpose of this study was to compare the effects of 6 weeks of CMS administration among male and female rats of two rat strains, Sprague-Dawley (SD) and Long Evans (LE), with respect to physiological (body, adrenal gland, and spleen weight) and biochemical (plasma corticosterone levels) indices of stress as well as evaluations of 1 and 24 h sucrose intake and preference. Estrous cycle was tracked throughout the study. Overall, our results indicate a slower rate of weight gain in animals, greater in males, exposed to the chronic stressor regime. Furthermore, CMS is shown to disrupt estrous cycling, predominantly in the Long Evans strain of rats. The main behavioral finding was a significant reduction in 24 h sucrose intake in female treated groups, which was not accompanied by alterations in preference. Corticosterone levels were elevated in CMS-treated animals relative to the singly housed control groups, but exposure to a subsequent stressor was not influenced by the stress history. Taken together, the effects of chronic stressor exposure are evident, based on physiological and biochemical indices, although none of the measures distinguished any striking gender specific reactions. The usefulness of sucrose intake or preference as behavioral indices of CMS-induced anhedonia in males and females is modest at best.

Effects of gestational stress: 1. Evaluation of maternal and juvenile offspring behavior

In both humans and animals, stress experienced during gestation is associated with physiological changes and disruptions in emotional function and cognitive ability in offspring; however, much less is known about the effects of such stress in mothers. In animal models, physical restraint is commonly employed to induce stress during gestation and results in elevated postpartum maternal anxiety and changes in maternal care. The purpose of the current study was to evaluate the consequences of restraint stress applied on gestation days 10 through 19 in mother rats and their juvenile offspring. Progeny were reared by birth mothers. Preterm anxiety was assessed in the elevated plus maze and maternal behavior in the retrieval test. Cognitive (T-maze) and anxiety measures (elevated plus maze and emergence) were applied to a subset of male and female offspring at 30-31 days of age. Weight and litter characteristics were also recorded. Mother rats exposed to stress during gestation had attenuated weight gain, elevated anxiety-like behavior, and reduced maternal care. Stressed mothers also had fewer pups and an elevated offspring mortality rate. The consequences of gestational stress in offspring were subtle and gender-dependent. Only juvenile females displayed marginal effects of gestational stress in the form of elevated anxiety-like behavior and attenuated weight gain. In the current study, although gestational stress had robust effects in the mother rat, these did not translate to similar changes in offspring behavior. The importance of focusing research on maternal responses to gestational stress is highlighted by these findings.

Strain and gender specific effects in the forced swim test: Effects of previous stress exposure

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.

Bisphenol-A: Epigenetic Reprogramming and Effects on Reproduction and Behavior

Bisphenol A (BPA) is a synthetic compound used in the production of many polycarbonate plastics and epoxy resins. It is one of the most widely produced chemicals in the world today and is found in most canned goods, plastics, and even household dust. Exposure to BPA is almost universal: most people have measurable amounts of BPA in both urine and serum. BPA is similar in structure to estradiol and can bind to multiple targets both inside and outside the nucleus, in effect acting as an endocrine disruptor. Research on BPA exposure has accelerated in the past decade with findings suggesting that perinatal exposure to BPA can negatively impact both male and female reproduction, create alterations in behavior, and act as a carcinogen. BPA can have both short term and long term effects with the latter typically occurring through epigenetic mechanisms such as DNA methylation. This review will draw on both human and animal studies in an attempt to synthesize the literature and examine the effects of BPA exposure on reproduction, behavior, and carcinogenesis with a focus on the potential epigenetic mechanisms by which it acts.

Behavioral and physiological effects of chronic mild stress in female rats

Anhedonia, a core symptom of clinical depression, refers to the loss of interest in normally rewarding stimuli; the chronic mild stress paradigm, an animal model of depression, was designed with this as an underlying feature. The procedure consists of the administration of a variety of ecologically relevant stressors over long durations. Its effects have been thoroughly investigated in male but not female rats. This study examines the appropriateness of stressors designed to evaluate the development and progression of depression in two strains of female rats, the effectiveness of two measures of anhedonia, and the relationship between stress reactivity and the estrous cycle. Changes in hedonic status were indexed for three weeks following a three week baseline period using two standard behavioral measures of anhedonia: sucrose intake and preference and thresholds for brain stimulation reward. Decreases in 24 h sucrose intake were observed in both strains during the first week of stress manipulations, and continued to decline thereafter for the remainder of the stress phase; in contrast, sucrose preference was unaffected by the stressors, indicating an overall reduction in fluid intake. No changes in the thresholds for brain stimulation reward were observed. The cyclical pattern of estrous was altered in both strains with a significant reduction in the number of regular cycles as a consequence of both the stressors and brain stimulation reward. Furthermore, cyclicity was not reinstated in many animals even six weeks after stress manipulations and behavioral tests had ceased. While the physiological measures suggest that the mild stressors are disruptive to female rats, the results of the behavioral tests are not consistent with the notion that the stressors induce an anhedonic state.

The effects of gestational and postpartum environmental enrichment on the mother rat: A preliminary investigation

Environmental enrichment is known to influence an animals well-being, provide opportunities for activity, and encourage behaviours appropriate to the species. Female Long-Evans rats were co-housed during their gestational and postpartum times in a colony housing environment comprising numerous cages, with interconnecting tubes, surrounding a multileveled enclosure with many objects scattered throughout. A control group of rats were housed in standard cages. The effects of the physical and social enrichment were determined by evaluating group differences in body weight, litter characteristics, elevated-plus maze performance during the gestational and postpartum periods, and Morris water maze behaviour (postpartum only). Results showed that enriched females were leaner and maintained a constant postpartum weight. Group differences in litter characteristics were observed, with enriched females having heavier but fewer offspring. Behavioural trends were observed in the elevated-plus maze with enriched rats showing greater change in behaviours over time. In the Morris water maze probe test, enriched rats performed less thigmotaxic and more middle maze swimming, as well as an increased tendency to enter the quadrant where the platform was located in non-probe trials. A housing environment, with complex physical and social stimulation, offered more opportunity for environmental interactions producing heartier pups and leaner mothers that displayed differential behavioural responses compared to control mothers. Studying maternal-offspring interactions in a more naturalistic environment allows one to observe a greater repertoire of behaviours that accommodates adequate normal or natural cognitive development than can be observed in the typical standard housing laboratory condition that limits experience and environmental engagement.

Effects of gestational stress: 2. Evaluation of male and female adult offspring.

Physical restraint applied during gestation is a commonly employed animal model of human pregnancy stress. The consequences of such a paradigm have been extensively investigated in adult male rats using a variety of physiological and behavioral measures. The behavioral repertoire of female offspring, however, has been largely ignored. The current study examines adult offspring-male and female Long Evans rats (55-90 days of age) and is a follow-up report to the consequences of maternal restraint (gestation days 10 through 19) in mother rats and their juvenile offspring. Physiological measures included weight and estrous cycle regularity. Elevated plus maze and emergence tests were used to measure anxiety, and the T-maze test, cognition. Data were analyzed via hierarchical linear modeling to account for the nesting of offspring within litters. Compared to same-sex controls, males from stressed mothers displayed a progressive attenuated weight gain over experimental weeks while females from stressed mothers maintained a stable, lower weight throughout. Twenty-five percent of females in the stressed group and none in the control group displayed irregular cycles in the first week of testing; on subsequent weeks, this group discrepancy ranged from 1% to 11%. Subtle effects were observed in anxiety measures: an interaction between sex and stress group in the analysis of head dip behavior in the elevated plus maze and decreased emergence latencies in stress groups. Results demonstrate the importance of examining the effects of maternal stress in offspring of both sexes at various developmental stages.

Chronic paroxetine infusion influences macronutrient selection in male Sprague-Dawley rats.

Decreased intake and weight loss are among the side effects frequently reported with chronic selective serotonin reuptake inhibitor (SSRI) use in both humans and animals. In an earlier study, we documented that paroxetine administered for several weeks induced a weight loss of greater than 10% in some male Sprague-Dawley rats (Pharmacol. Biochem. Behav. 63 (1999) 435). As a follow-up to that work, we investigated in this study whether such treatment influenced dietary macronutrient selection. Animals were first habituated to foods containing principally either proteins, fats, or carbohydrates in a self-selection paradigm, after which they were implanted intraperitoneally with osmotic minipumps that delivered either paroxetine (7.5 mg/kg/day) or vehicle (50:50 ethanol:water) for 28 days; food intake and weight changes were documented during this period. No acute effects of the drug were apparent. By the fifth day of treatment, significant differences in weight gain between groups were observed and thereafter generally maintained for the remainder of the study, with animals receiving paroxetine showing about an 8% decrease in weight gain overall. Carbohydrate and fat intakes were significantly reduced, whereas preference was unchanged in fats and proteins and initially decreased in carbohydrates; in the latter, this pattern reversed and exceeded vehicle animals for the second half of the study. Several hypotheses are discussed with respect to specific and nonspecific effects of paroxetine on feeding and macronutrient selection.

In utero programming alters adult response to chronic mild stress: part 3 of a longitudinal study.

Exposure to stress before birth may lay the foundation for the development of sensitivities or protection from psychiatric disorders while later stress exposure may trigger either their expression or suppression. This report, part three of a longitudinal study conducted in our laboratory, aimed to examine the interaction between early and adult stress and their effects on measures of anxiety and depression. In parts one and two, we reported the effects of gestational stress (GS) in Long Evans rat dams and their juvenile and young adult offspring. In this third and final installment, we evaluated the effects of GS and chronic mild stress (CMS) in the adult female offspring at 6 month and 12 month time-points. The two by two design included a combination of GS and CMS and the appropriate control groups. Using Hierarchical Linear Modeling, main effects of GS on corticosterone level at the 12 month time-point was found while main effects of CMS were seen in body weight, sucrose preference, and corticosterone, and significant interactions between group at the 6 and 12 month time-points. The GS group had the lowest sucrose preference during CMS at 6 months supporting a cumulative effect of early and later life stress. The GS/CMS group showed lower corticosterone at 12 months than the GS/noCMS group indicating a possible mismatch between prenatal programming and later life stress. These results highlight the importance of early life factors in exerting potentially protective effects in models involving later life stress.

Effects of combined pre- and post-natal enrichment on anxiety-like, social, and cognitive behaviours in juvenile and adult rat offspring

HIGHLIGHTSPre‐ and post‐natal enrichment improves learning and memory in rat offspring.Enriched rats spend less time in elevated‐plus maze open arms.Enriched offspring rats show more pro‐social behaviour than control offspring rats.Pre‐ and post‐natal enrichment results in lower body weights in rat offspring. ABSTRACT The pre‐ and post‐natal periods are characterized by unrivalled growth and are sensitive to environmental changes. A correctly stimulating early environment is essential for developing natural behaviors and maintaining affective wellness. Five litters of rat progeny were co‐housed through gestation until juvenile age in housing providing physical and social enrichment. Five control litters were housed separately in standard conditions. Half of the offspring were tested in the elevated plus‐maze and the social interaction test as juveniles (five weeks old) with the other half tested in the Morris water maze. As adults (11 weeks old), the testing groups were reversed. Weight was monitored weekly. Enriched offspring had leaner body weights. In the elevated plus‐maze, control juvenile progeny spent a higher percentage of time in the open arms, showed greater locomotor activity, less grooming, and more rearing (males only). In the social interaction test, enriched juvenile offspring were found to sniff their conspecific more, display more self‐grooming behaviour as well as show less locomotor activity and body contact. In the Morris water maze probe test, enriched rats demonstrated improved memory for the platform position and more effective search strategies with increased platform crossings, middle crossing as well as more time spent in the platform quadrant and less thigmotaxis behaviour. Adult female rat offspring also demonstrated superior memory for the platform position and crossed the maze middle more often. These results suggest that combined pre‐ and post‐natal environmental enrichment influences physiology and behaviour in offspring rats with some of those influences being long‐lasting.