Anxiety and hypothalamic—pituitary—adrenal axis responses to psychological stress are attenuated in male rats made lean by large litter rearing Lauren J. Bulfin a , Melanie A. Clarke a , Kathryn M. Buller b , Sarah J. Spencer a, * a Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria 3800, Australia b Perinatal Research Centre, The University of Queensland Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia Received 7 December 2010; received in revised form 12 January 2011; accepted 28 January 2011 Psychoneuroendocrinology (2011) 36, 1080—1091 KEYWORDS Nutrition; Development; Stress; HPA; Lean; Obesity Summary An excellent strategy to treat overactive responses to stress is to exploit the body’s inherent stress-inhibitory mechanisms. Stress responses are known to differ between individuals depending upon their level and distribution of adiposity and their experiences in early life. For instance, we have recently shown that female rats made obese by overfeeding during the neonatal period have exacerbated responses to psychological stress. The converse may be true for those that are underfed during this period. In this investigation we hypothesized that rats made lean by neonatal underfeeding would have reduced anxiety and attenuated hypothalamic— pituitary—adrenal (HPA) axis responses to psychological stress. Our findings show that male (but not female) rats, made smaller by being suckled in a large litter, show reduced anxiety-related behaviour compared with those from normal litters when tested in the elevated plus maze. These smaller males also have attenuated activation of the paraventricular nucleus of the hypothalamus in response to the psychological stress, restraint, and corticosterone responses to restraint that return more quickly to baseline than controls. These findings are exciting from the perspective of understanding and potentially exploiting the body’s inherent stress-inhibitory mechanisms to treat overactive responses to stress. They also provide an indication that being lean may be able to ameliorate overactive stress responses. Understanding the mechanisms by which these stress responses are attenuated in lean animals will be important for future strategies to treat diseases associated with overactive HPA axes in humans. # 2011 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +61 3 9902 0114; fax: +61 3 9905 2547. E-mail addresses: Sarah.Spencer@med.monash.edu.au, Sarah.Spencer@monash.edu (S.J. Spencer). a vail abl e a t www.s cien cedir e ct.c om jou rn a l home pag e : ww w. el sev ier. com/ loca te /psyn eu en 0306-4530/$ — see front matter # 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2011.01.006