Early life overfeeding programs reproductive development in the female rat

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Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50

depressive mood, and IFN-gamma, a proinflammatory cytokine associated with tumor progression. http://dx.doi.org/10.1016/j.bbi.2015.06.059

Abstract # 1548 Association of stress-induced increases of inhibitory kappaB gene expression with depressive symptoms D. Goldblatt a, C. McInnis a, M.V. Thoma a,b, D. Gianferante a, L. Hanlin a, X. Chen a, D. Wang a,c, N. Rohleder a

increased frequency of the mini-excitatory postsynaptic currents (mEPSC) without any changes in amplitude compared to the controls; this was indicative of increased glutamate release. This was associated an increase in the synaptic spines in the principal neurons of the BLA. AMPA: NMDA ratio was increased in EAE mice and there was an alteration in the AMPA receptor subunit composition, with an increase in GluA2 subunit. In conclusion, emotional and cognitive deficits observed in EAE (and possibly MS) were associated with an increased dendrite spines, enhanced glutamatergic transmission and changes in AMPA receptor composition in the BLA. http://dx.doi.org/10.1016/j.bbi.2015.06.061

a

Brandeis University, 415 South St, Waltham, MA 02453, United States University of Zürich, Switzerland c USC Davis School of Gerontology, United States b

Rationale: Depressive symptoms are associated with exaggerated inflammatory and altered cortisol stress responses. Cortisol has been shown to stimulate IkB gene expression, which counteracts pro-inflammatory cytokine production. Increased inflammation is a risk factor for disease, highlighting the need to understand factors controlling inflammation. No studies have examined IkB expression in response to acute stress in relation with depressive symptoms. Methods: We recruited n = 48 healthy individuals and exposed them to the Trier Social Stress Test (TSST). Stress responses of plasma Interleukin-6, salivary cortisol, as well as inhibitory kappa-B (IkB) gene expression in peripheral blood, were measured before, as well as 30, and 120 min after stress. We also assessed self-reported depressive symptoms, post-stress mood, and stress appraisals. Results: Stress exposure induced increases in IL-6 and cortisol (IL-6: F = 42.41, p < 0:001; cortisol: F = 15.98, p < 0:001). IkB expression increased after stress with a peak at 30 min and recovery at 120 min (F = 13.11, p < 0:001). Depressive symptoms were positively related with IkB expression 30 min after stress (beta = 0.30, p = 0.05), and this relationship was mediated by decreases in positive affect. Conclusions: These show that in individuals with more depressive symptoms, acute stress translates into upregulated gene expression of inhibitory kappaB, which might be mediated through stronger decreases in mood. Higher IkB might allow better down regulation of inflammation, but could also be a response to stronger inflammatory reactivity in general. http://dx.doi.org/10.1016/j.bbi.2015.06.060

Abstract # 1549 Glutamatergic transmission is enhanced in the amygdala in experimental autoimmune encephalomyelitis S. Acharjee a,b, A. Benedkitsson b, Q. Pittman a a

University of Calgary, Physiology and Pharmacology, 2146 Health Science Centre, 3330 Hospital Drive NW, Calgary, United States b Mount Royal University, Canada Multiple sclerosis (MS) is often associated with co-morbidities like neuropsychiatric and cognitive impairments, affecting around 50% of the patients. We investigated these abnormalities in an animal model of MS, called experimental autoimmune encephalomyelitis (EAE) during the early onset of the disease. We have shown that at this presymptomatic stage, the EAE mice show emotional and cognitive deficits in absence of motor deficit. Whole-cell recording was carried out in the principal neurons of basolateral amygdala (BLA) to investigate the neuronal correlates of these behaviour changes. Investigation into glutamatergic synaptic transmission revealed

Abstract # 1550 Alpha2-adrenergic blockade emulates the enhancing effect of chronic stress on breast cancer progression D.M. Lamkin a, S.W. Cole a, E.K. Sloan a,b a

Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, United States b Monash University, Australia Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of beta-adrenergic receptors. Catecholamines also signal alpha-adrenergic receptors, and greater alpha-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of alpha-adrenergic receptors can result in elevated catecholamine levels, which may increase alpha-adrenergic signaling, because pre-synaptic alpha2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of alpha-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective alpha-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective beta-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective alpha2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective alpha1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that alpha2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of beta-adrenergic signaling on tumor progression-relevant biology. http://dx.doi.org/10.1016/j.bbi.2015.06.062

Abstract # 1551 Early life overfeeding programs reproductive development in the female rat L. Sominsky, I. Ziko, J.M. Barwood, S.J. Spencer School of Health Sciences, Health Innovations Research Institute, RMIT University, Melbourne, VIC 3083, Australia

Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50

Early life nutrition is crucial for the development of the hypothalamic-pituitary-gonadal (HPG) axis. Overweight and obese girls are significantly more likely to experience early menarche. Together, childhood obesity and precocious puberty have deleterious impact on adult health. Our laboratory has demonstrated that neonatal overfeeding, whereby rats are suckled in small litters (of 4; SL), compared to those suckled in control litters (of 12; CL), results in accelerated growth, advanced onset of puberty, as well as altered peripheral and central immune profiles, including increased levels of circulating leptin. Leptin, an adipocyte-derived hormone and pro-inflammatory cytokine, is essential to the establishment of the hypothalamic neural circuits controlling food intake, along with its critical role in reproductive physiology at all levels of the HPG axis. Here, we examined the role of leptin and its receptor in the prepubertal and adult ovary, along with other indices of ovarian follicular maturation and function. Neonatal overfeeding (SL) differentially altered the expression of the leptin receptor in the neonatal and adult ovary, potentially reflective of developmental and functional differences. Moreover, neonatally overfed females exhibited alterations in other markers of ovarian function, indicative of advanced follicular maturation and therefore a potential for premature reproductive senescence. Our data suggest neonatal overfeeding alters leptin-mediated development of the HPG axis, potentially leading to long-term changes in reproductive efficiency. http://dx.doi.org/10.1016/j.bbi.2015.06.063

Abstract # 1552 BDNF Met allele as a risk factor for inflammation-induced depression in breast cancer survivors L.N. Dooley, P.A. Ganz, S.W. Cole, J.E. Bower University of California, Los Angeles, CA, United States Inflammation may contribute to the development of depression in a subset of individuals. However, risk factors that render certain individuals more vulnerable to depression following an inflammatory stimulus have not been determined. Drawing from animal studies showing that reductions in neural plasticity may mediate effects of inflammation on depressive symptoms, we hypothesized that individuals genetically predisposed to lower levels of neural plasticity may be more susceptible to inflammation-induced depression. More specifically, the current study examined whether the Met allele of the BDNF Val66Met polymorphism, which predisposes individuals to reduced levels of plasticity, moderates the association between inflammation and depressive symptoms. We tested this hypothesis in a sample of 111 women with early-stage breast cancer who had recently completed treatment with surgery, radiation and/or chemotherapy, which can activate inflammatory pathways. Participants provided blood draws for genotyping and assessment of circulating inflammatory markers, and completed a questionnaire assessing depressive symptoms, including somatic, affective, and cognitive components of depression. Results revealed a significant interaction between BDNF genotype and CRP in predicting depressive symptoms (p = .036), such that women carrying at least one Met allele displayed a stronger association between CRP and cognitive depressive symptoms than those without a Met allele. A similar interaction emerged for IL-1ra (p = .055). Results support the hypothesis that the BDNF Met allele may be a risk factor for inflammation-induced depression among breast cancer survivors. http://dx.doi.org/10.1016/j.bbi.2015.06.064

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Abstract # 1553 Early life programming of pain: Neuroimmune to endocrine symphony I. Zouikr a,b,c, M.H. James d, E.J. Campbell c, A.F. Ahmed b, J.C. Horvat b, P.M. Hansbro b, V.L. Clifton e, K.W. Beagley f, R.F. Thorne b, C.V. Dayas c, D.M. Hodgson a a

Laboratory of Neuroimmunology, School of Psychology, University of Newcastle, Newcastle, Australia, School of Psychology, The University of Newcastle, Newcastle, NSW 2308, Australia b Hunter Medical Research Institute (HMRI), Newcastle, Australia c School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, Australia d Brain Health Institute, Rutgers University, NJ, USA e Robinson Institute, University of Adelaide, Adelaide, SA, Australia f Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia Chronic pain constitutes a major challenge for clinical and experimental scientists. This is due to the failure of current drugs targeting neurons only. We now know that pain can result from the interaction between the immune, endocrine, and nervous systems. Neonatal LPS exposure can alter neuroendocrine responses in adult rats. How neonatal LPS exposure program future pain responses is unknown. Rat pups were exposed to either LPS or saline (0.05 mg/kg, IP) on postnatal days (PND) 3 and 5. At PND 22 and PND80-97, rats received a hind paw injection of formalin. One hour later, blood and hippocampus were collected to measure circulating IL-1b, CORT, and hippocampal IL-1b. Paw tissue was collected to assess mast cell degree of degranulation. Additionally, 1.5 h following behavioral scoring brains were immunolabeled for Fos in the PAG. LPS-treated rats exhibited hyperalgesia at PND 22 ( p < 0:1) and PND 80-97 (p < 0:5). The LPS-induced hyperalgesia observed at PND 22 coincides with enhanced circulating IL-1b and mast cell degranulation, increased CORT as well as decreased Fos-labeling in the PAG. At PND80-97, LPS-treated rats had increased hippocampal IL-1b and enhanced Fos-labeling in the PAG. No changes were observed in peripheral IL-1b or CORT. Together, these data demonstrate the importance of the neonatal microbial environment in programming future inflammatory pain responses via developmentally regulated actions on the immune, endocrine, and supraspinal neural pathways. http://dx.doi.org/10.1016/j.bbi.2015.06.065

Abstract # 1554 Experimental endotoxemia induces increased functional connectivity between the thalamus and the default mode network in healthy men F. Labrenz a, K. Wrede b, H. Engler a, M. Schedlowski a, S. Elsenbruch a, S. Benson a a

Inst. of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Essen, Germany b Department of Neurosurgery, University Hospital Essen, Germany While functional MRI studies revealed altered task-related BOLD responses during experimental endotoxemia, little is known how systemic inflammation affects resting state activity of the brain. In this randomized, placebo-controlled study, healthy men received either low-dose (0.4 ng/kg) lipopolysaccharide (LPS) (N = 20) or saline (N = 25). Resting state activity was measured at baseline and 3.5 h post-injection. In multi-subject independent component analysis (ICA), 13 out of 30 components were identified which displayed