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Cancer is a life-changing disease that introduces an abundance of psychosocial stress into patient's lives. Exposure to psychosocial stress over periods of weeks or more has a maladaptive effect on the human immune system. Chronic psychosocial stress means elevated activates the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenomedullary (SAM) axes which over time induce deleterious physiological effects in the form of glucocorticoid resistance, chronic low-level inflammation, and inhibition of leukocyte telomerase activity. Because these down-stream physiologic effects of psychosocial stress have oncogenic implications, the effective management of chronic stress inherent to a cancer diagnosis should positively impact the efficacy of current cancer therapies. Mindfulness is an age-old concept that has recently gained traction in the medical community for its utility as a cognitive therapy in treating patients with mental health disorders. Although the study of mindfulness as a complementary cancer therapy is in its relative infancy, other examples of mind-body medicine have already been documented to help treat many psychological side effects of cancer including anxiety, depression, sleep deprivation, and pain. It has been theorized that mindfulness acts by providing a cognitive strategy to buffer the harmful effects of psychosocial stress. Mindfulness elicits discrete effects on human psychology and physiology that are conducive to the efficacy of current cancer treatments. Mindfulness techniques have shown promise in providing relief for many of the psychological side effects of a cancer diagnosis. In this thesis, we explore the psychological and physiological effects of mindfulness practice that counter-act many of the harmful consequences of chronic stress exposure specifically immunosuppression, chronic inflammation, and telomerase activity.

Evidence suggests that toxic stressors introduced early in development have prolonged effects on neuronal function due, in part, to the maturation of the hypothalamic- pituitary- adrenal (HPA) axis during adolescence. Early life stress has been implicated as a driver of mood and anxiety disorders, like depression and post-traumatic stress disorder - the extent to which appears to be sex dependent. While it is known that early life stress results in several consequences in adulthood, the mechanisms by which these changes manifest are unclear. Stress-induced changes in mood and behavior are often associated with alterations in inflammatory reactivity in both the brain and in the periphery. Previous work from our lab, and others, demonstrates that both male and female rats respond to chronic adolescent stress (CAS) but may differ in inflammatory markers within the brain and periphery and in the induction of negative affective-like behaviors. Inflammatory reactivity has been targeted as a means of identifying how these sex differences arise in studies of chronic stress in adults. Circulating concentrations of inflammatory cytokines have not been directly employed as predictors of behavioral outcomes of stress exposure in adolescence but may be a useful tool in uncovering mechanisms that protect or predispose an organism from the effects of chronic stress. To further assess immunological and behavior deficits following chronic stress in adolescence, the current work used a model of chronic adolescent stress where male and female adolescent mice were exposed to a predator stress for 15 consecutive days. In late adolescence, these mice were treated with an acute inflammatory challenge with lipopolysaccharide (LPS)to elicit an inflammatory response. We predicted that chronic, predatory stress experienced during adolescence would induce negative anxiety-like behaviors and alter circulating proinflammatory levels. Furthermore, we expected females to be more susceptible to the effects of adolescent stress than males. We observed that, chronic, predatory stress during adolescence increased anxiety-like behaviors in males and females, but did not alter social behaviors during late adolescence. Predatory stress also impacted circulating levels of TNFα, but no sex differences in LPS-induced cytokine concentrations were apparent.

Captive animals are sometimes very inactive, which can elicit concern for their welfare. However, inactivity is difficult to interpret in terms of welfare, since while some forms reflect chronic fear (hiding), apathy, or depression-like states, others reflect positive states (e.g. relaxation). This thesis aimed to determine whether high levels or particular sub-types of inactivity indicate poor welfare in fur-farmed mink (Neovison vison), and to identify the specific psychological states involved. These questions were addressed by studying individual differences within populations on three commercial farms, and comparing mink in standard, non-enriched cages to those in enriched cages. Two hypotheses were tested on farms: that the most inactive mink experience chronic stress, and that this would impair reproduction. Inactive females did have smaller litters, a difference that was not attributable simply to their greater body fat. However, there was no evidence of endocrine stress nor increased fear in “glove tests”, and their kits also grew more quickly. This suggests that inactive females do not experience more chronic stress than active females do. Tests of responsiveness to stimuli (measured in terms of contact and orientation) showed that, compared to mink in enriched cages, non-enriched mink were more responsive to all types of stimuli, especially neutral ones. This finding is inconsistent with the hypothesis that inactive individuals in these conditions are apathetic or depressed; instead, it supports the alternative hypothesis that non-enriched cages induce boredom. However, this boredom-like hyper-responsiveness did not co-vary with inactivity levels. Finally, non-enriched cages did not consistently elevate total inactivity. However, they did induce specific types: inactivity in the nest box, lying alert (vs. sleeping), and lying belly down rather than curled up were all more common than in enriched cages. Inactivity in the nest box may reflect hiding; it seemed linked to fearfulness in glove tests and to endocrine stress responses. In sum, while non-enriched conditions induce poor welfare, they do not increase overall inactivity; furthermore, within populations, the welfare of highly inactive individuals is no more compromised than that of their more active counterparts. However, subtypes of inactivity provide more information about welfare than total inactivity. / NSERC (PGS)

The “two-hit” schizophrenia hypothesis suggests genetic and environmental abnormalities interrupt early CNS function. This increases vulnerability of a “second hit” and schizophrenia onset. Chronic stress and decreased Reelin signaling are reportedly associated with schizophrenia. Heterozygous Reeler Mice (HRM) show a 50% reduction in Reelin and display major schizophrenia phenotypes. Receptor-Associated Protein (RAP) blocks ligand-association to Reelin receptor Apolipoprotein E receptor 2 (ApoER2). In this study, we sought to replicate major heterozygous reeler mouse (HRM) phenotypes using in vivo RAP studies to establish an experimental in vitro model. Using an in vitro model, we investigated the effects of chronic stress and decreased Reelin signaling on AMPAR subunit expression. Implantable Alzet osmotic pumps allowed bilateral ventricular 7nM RAP perfusion in 12-14 week-old mice. An assay revealed significant Dab-1 phosphorylation reduction in RAP-perfused animals. These results correspond with learning and memory and associative-fear conditioning abnormalities. Overall activity, sensory perception, and nociception remained unaltered. RAP-perfused mice displayed deficits in pre-pulse inhibition to acoustic startle, and therefore sensory-gating deficits. A significant decrease in Glur1 and Glur2/3 expression was observed in primary hippocampal/cortical neurons following chronic RAP and CORT exposure. Collectively, our results show postnatal Reelin signaling disruption produces physiological, biochemical, and behavioral phenotypes similar to the HRM model. The exact mechanism of Reelin-dependent AMPAR insertion remains unclear. Glur1 and Glur2/3 appear to be inserted by differing mechanisms. Glur1 is reported to be inserted with Reelin activation of phosphoinositol-3-kinase (PI3K) signaling. Glur2/3, whose mechanism of insertion is unknown, has not been shown to be inserted via PI3K. Our findings also demonstrate the usefulness of in vitro RAP use, in which apolipoprotein E receptor 2 (ApoER2) expression is predominant compared to other lipoprotein receptors that may be affected with RAP application.

Depression is an extremely common, devastating psychiatric syndrome with profound effects on the structure of neurons and the proteins that they express. However, the pathophysiology of depression remains unclear despite decades of extensive research efforts, and this lack of understanding makes it difficult to develop effective treatments. It is extremely problematic that conventional antidepressant drugs do not work for many patients, and those that do respond require weeks to months of continuous treatment before adequate therapeutic improvement is achieved. Therefore, there is a clear unmet need to develop mechanistically novel antidepressant compounds that are well-tolerated, more effective, and faster acting. Subjecting rats to repeated-corticosterone (CORT; stress hormone analogous to cortisol for humans) injections produces a depressive-like phenotype that can be used to make inferences about the human condition and screen compounds for antidepressant properties. Our laboratory has previously found that stress downregulates hippocampal reelin in a similar manner to that seen in depression patients, and that drugs with antidepressant actions recover this deficit. This provided a rationale to administer reelin directly into the hippocampus, which rescued behavioral and neurochemical deficits, but intrahippocampal infusions are not clinically viable. Reelin is expressed in the periphery and blood as well as the brain, so the aims of the collection of studies described here are to evaluate the antidepressant-like properties of peripheral intravenous (i.v.) reelin. In the first experiment, the antidepressant-like effects of several dosages of reelin (3/5μg given every 5/10 days) were evaluated in rats that were exposed to 3-weeks of daily CORT (40mg/kg) injections. I found that all the dosages of reelin attenuated CORT-induced despair-like behavior in the forced-swim test (FST) and normalized alterations in serotonin (5-HT) transporter (SERT) membrane protein clustering (MPC) in blood lymphocytes. Reelin treatment also increased reelin-immunoreactive (IR) cell counts in the hippocampal dentate gyrus (DG) subgranular zone (SGZ), but it had less of an effect on neurogenesis as measured by the number and maturation rate of doublecortin (DCX)-IR cells. Interestingly, the lowest dosage used also rescued the number of reelin-IR cells in the hypothalamic paraventricular nucleus (PVN). This suggested that the restoration of SGZ-reelin plays a pivotal role in attenuating depressive-like behavior and that 3μg every 10 days was the most effective dosage that was tested. Using the lowest dosage that showed to be effective in the first experiment, I then evaluated if male and female rats responded similarly to i.v. reelin using a larger battery of behavioral tests. Post-mortem tissue analyses focused on reelin and receptors that bind gamma-aminobutyric acid (GABA) and glutamate in the SGZ, which have been implicated in psychiatric disorders and the mediation of fast-acting antidepressant responses. I found that reelin rescued the FST- behavioral and neurochemical alterations induced by CORT similarly in both sexes, indicating that it may have therapeutic effects by normalizing inhibitory/excitatory transmission. I also evaluated the effect of i.v. reelin on neurogenesis in females and found that, akin to males, the regulation of adult-born cells by peripheral reelin is unlikely to mediate the antidepressant-like effects. The goal of the third experiment was to examine whether the antidepressant-like effects of peripheral reelin are achieved in a rapid manner. I found that a single 3μg injection after 3 weeks of CORT significantly decreased behavioral deficits in the FST 24 hours later in both sexes. Reelin also partially rescued cognitive deficits and expression levels of reelin, GluN2B, and mitochondrial-related pro-apoptotic factors bcl-2 associated X protein (BAX) and cytochrome C (CytC) in the DG. In addition, a single injection of reelin fully recovered the number of GluA1-expressing cells and partially recovered SERT cluster size in males, whereas reelin partially recovered GluA1-IR cell counts and fully recovered SERT cluster sizes in females. Reelin had modest effects on DCX-IR cells in both sexes. The final chapter summarizes and discusses my findings, which suggest that the antidepressant-like effects of peripheral reelin are associated with the recovery of neurochemical deficits that strengthen neurotransmission, at least in the hippocampus. Therefore, developing reelin-based therapeutics with antidepressant activity would be a fruitful area of research, although additional mechanistic, pharmacokinetic, and pharmacodynamic studies are essential. / Graduate

Post-traumatic stress disorder (PTSD) is characterized by fear extinction deficit; chronic stress worsens this deficit. Using a Chronic Unpredictable Stress (CUS) model, we previously found that CUS increased fear extinction deficit in female mice and knockout of Ciliary Neurotrophic Factor (CNTF) attenuated it. The amygdala, specifically the medial amygdala, is strongly associated with fear conditioning and extinction. CUS increased CNTF and reduced Urocortin 3 (UCN3) in the medial amygdala, suggesting CNTF-mediated UCN3 inhibition may be involved in CUS-induced deficit of fear extinction. The medial amygdala connects to the hypothalamic paraventricular nucleus (PVN) via posterior bed nucleus of stria terminalis (pBNST) and mediates the stress response (Fig. 1). The objective of this project is to determine whether CUS affects CNTF, UCN3, and CNTF-related cytokine leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) in the pBNST and hypothalamic PVN. Hippocampal CNTF expression was also examined as a brain region outside of the medial amygdala-pBNST-hypothalamic PVN circuitry. 4 groups (5 mice/group) of CNTF+/+ and CNTF-/- mice were treated with 4 weeks of CUS or control handling. At the end, fresh brain samples were collected. The hypothalamic PVN, pBNST and hippocampus were punched out from 600-700 um cryostat frozen sections. CUS was applied for 4 weeks. The control mice were handled daily for 4 weeks. RNA was extracted from tissue using QIANGEN Rneasy mini kit. BCA assay was performed to analyze protein concentration, then 10% SDS gel was used to run the protein samples. Statistical analysis included one-way ANOVA followed by Bonferroni multiple comparison or 2-tailed T test. p <0.05 was defined as significant difference. In the pBNST, CUS did not affect CNTF and UCN3 mRNA expression. However, UCN3 protein was upregulated by CUS in CNTF+/+ but not CNTF-/- mice, suggesting CNTF inhibits UCN3 expression, possibly through post-transcriptional mechanism. CUS did not alter LIF and IL-3 in the pBNST. CUS did not alter CNTF mRNA expression in the PVN and further study will measure UCN3 mRNA and protein in the PVN. Finally, there was no CUS effect on CNTF, LIF and IL-6 mRNA in the hippocampus. These results and further studies are useful in development of therapeutic medications and drug targets in the case of chronic stress.

Long-distance translocation (LDT), the relocation of an animal outside of its home range, is a popular strategy for mitigating conflict between humans and venomous snakes. While LDT has been demonstrated to prevent a snake’s return to the location of capture, it may result in increased mortality, magnitude and frequency of movements, and activity range sizes. Thus, it has generally been discouraged. However, the effects of LDT on stress physiology and thermoregulation have gone largely unstudied in reptiles. To elucidate these effects, we conducted an experimental LDT on Western Rattlesnakes (Crotalus oreganus) on Vandenberg Air Force base in California. Fourteen snakes were monitored, beginning in mid July 2012 and ending in early September. Each was implanted with a radio transmitter and iButton temperature data logger within the coelomic cavity. In late August, seven snakes were translocated to similar habitat, approximately 30 kilometers away, where they were monitored for 9-13 days. Prior to translocation, all snakes were tracked every other day, while after translocation all snakes were tracked every day. A ‘Before-After Control-Impact’ (BACI) experimental design was used, with a dedicated control group, but also with the translocated group serving as control prior to the act of translocation. We collected data on snake body temperatures (T­b) and temperatures (T­e) of physical operative temperature models (OTMs) that simulated non-thermoregulating snakes and allowed for a comparison of habitat thermal quality between our two study sites. Together, T­b and T­e allowed for a formal assessment of thermoregulatory effectiveness. Additionally, blood concentrations of corticosterone (CORT), the primary stress hormone in reptiles, and testosterone (T), a metric of male reproductive ability that is often negatively associated with CORT, were assayed just prior to translocation and again at the end of the study. During each of the two sampling periods, in addition to baseline hormone concentrations, stressed hormone concentrations were assayed following the application of an acute stressor (the baseline blood draw plus one hour’s captivity in a plastic bucket). We also studied the effect of LDT on the CORT and T response (stressed concentration minus baseline concentration). Furthermore, we evaluated how LDT impacted a suite of behaviors related to defense and movement, as well as snake body mass and body condition index (BCI). Finally, we assessed the effects of LDT on movements and spatial use (activity range size). We sought to assess the effects of LDT on movements, spatial use, and behavior in order to facilitate comparison with other translocation studies, as well as to evaluate those impacts in a physiological context. In addition to assessing the impact of LDT on CORT and T separately, we evaluated a relationship between the two steroid hormones, and, using a model selection approach, we evaluated relationships between CORT and T and movements and spatial use. The thermal quality of the habitat at our two sites did not differ and we found no effect of LDT on snake body temperature or thermoregulatory effectiveness. We found that spatial use increased following LDT, since the average 100% minimum convex polygon (MCP) activity range size of our translocated snakes was greater than that of our control snakes during the post-translocation period. However, movements (mean distance moved per day and total distance moved) were unaffected by LDT. Translocation was not found to affect snake body mass or BCI, indicating that snake energy demands did not increase as a result of LDT. Of the behaviors that we recorded, many (rattling, tongue-flicking, fleeing, moving vs. stationary when found) were observed too infrequently to carry out satisfactory parametric analyses, though a qualitative assessment leads to the conclusion that LDT did not affect them. The effect of LDT on how often our snakes were visible was marginally significant, but post-hoc testing found no differences. Nonetheless, the translocated snakes tended to be visible more often than the controls, during the post-translocation period. We found no effect of LDT on the percentage of a snake’s body sunlit when visible. Our translocation was not found to any CORT metric, while for T, the only metric that was affected was the baseline concentration. Baseline T was found to be higher in translocated snakes than in control snakes following translocation. We found some evidence for a positive relationship between CORT and T for baseline and stressed concentrations. Our model selection procedure found little evidence for a relationship between snake movements and spatial use and either CORT or T. Our results are encouraging in that we did not find that LDT disrupts thermoregulation or results in a condition of chronic stress, as indicated by the CORT results. The positive effect of LDT on baseline T is somewhat mysterious, but studies on mammals suggest that increased T may aid in spatial learning and memory. Since the site that a snake is translocated to is entirely novel, an elevated capacity for spatial learning and memory could be beneficial to a translocated snake. Our finding that spatial use increased following LDT agrees with other studies of LDT in snakes, but some studies have found that movements increased following LDT, while we did not. In addition to snake movements being unaffected, we translocated our snakes within a relatively thermally benign climate in coastal central California. Translocations carried out in more extreme climates, with either cold winters or hot summers may indeed result in an effect on thermoregulation and a state of chronic stress. Consequently, we advocate further study of the physiological effects of LDT on other snake species in a variety of climates. Additionally, while it was our goal to study the short-term effects of LDT, more long-term studies, which follow the snakes through the entire active season and the winter hibernation period, may be informative.

Childhood obesity has been prevalent for a number of years despite programs designed to educate children and families on healthy diets and activities. Multiple disciplines have reported chronic stress can interfere with normal neuroendocrine functions in the body which include energy balance. Research into alternate mechanisms contributing to childhood obesity is just beginning to include psychosocial factors’ and their influence on biology. Healthy coping strategies can reduce the effects of stress and influence perceptions of what is stressful. Warm, secure relationships with parents, family connectedness, and a secure stable environment all contribute to the buffering of chronic stress as well as promote the ability to cope with stress. Through the years, changes in the family environment through divorce, single parenthood, and cohabitation may play a role in the child’s ability to cope with stress. Therefore, the purpose of this study was to explore relationships between the child’s perceptions of chronic stress, coping strategies, family connectedness, family characteristics, and weight in 4th and 5th grade children. This study used a cross sectional and correlational design. The conceptual framework guiding this study was the Bio-Psycho-Social Model for Health integrating the three dimensions (biological, psychological, and sociological) as they relate to obesity in children. Well established instruments were used to measure chronic stress, coping, family connectedness, and weight. Results did not reveal a relationship between chronic stress and children’s weights. The ‘frequency the family sat down to eat dinner together’ was significantly related to weight: the more dinners together the lower the body mass indices and accounted for 14.7% variance in children’s body mass indices. Frequency of family meals was also correlated with the frequency of cooking dinner and negative trending of both ‘frequency’ and ‘helpfulness’ of coping strategies: possibly suggesting less need for the coping strategies. Parents’ education was positively correlated with more sleep on school nights for children. The findings suggest the importance of family time together is related to lower body mass indices in children. / text

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