Mild Early Life Stress Enhances Prefrontal-Dependent Response Inhibition in Monkeys Karen J. Parker, Christine L. Buckmaster, Katharine R. Justus, Alan F. Schatzberg, and David M. Lyons Background: Severely stressful early experiences have been implicated in the pathophysiology of psychiatric disorders. In contrast, exposure to mild early life stress (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stressors. Herein we extend this research to examine the effects of mild early life stress on cognition. Methods: Squirrel monkeys were randomized to a mild intermittent stress (IS; n = 11) or nonstress (NS; n = 9) condition from 17 to 27 weeks postpartum. At 1.5 years of age, monkeys were assessed for response inhibition on a test previously shown to reflect prefrontal-dependent cognitive function. Results: IS monkeys demonstrated fewer response inhibition errors compared with NS monkeys. There were no rearing-related differences in aspects of performance that did not require inhibitory control. Compared with NS monkeys, IS monkeys had lower basal plasma pituitary-adrenal stress hormone levels. No rearing-related differences on neuroendocrine measures obtained 15 minutes after testing were found. Conclusions: Results from this experiment provide the first evidence that exposure to mildly stressful early experiences improves prefrontal-dependent response inhibition in primates. Combined with our previous data, findings from this animal model suggest that exposure to mild early life stress may enhance the development of brain systems that regulate emotional, neuroendocrine, and cognitive control. Key Words: Cognitive, HPA axis, response inhibition, prefrontal cortex, primate, stress inoculation, stress resistance I n keeping with Selye’s (1974) classical theory that stressors may serve a beneficial function provided that the type and degree of stress are not excessive, data have begun to accumulate which suggest that exposure to mild forms of early life stress provide later resistance to psychosocial adversity (Garmezy et al 1984; O’Leary 1998; Rutter 1987). In children, for example, prior mildly stressful life events are associated with diminished emotional distress during hospital admission (Stacey et al 1970) and attenuated fearfulness in a day care setting (Holmes 1935). In adolescents, prior childhood exposure to mildly stressful events is associated with decreased cardiovascu- lar response to psychologically stressful laboratory tests (e.g., mental arithmetic, video game performance, hand submersion in ice water) (Boyce and Chesterman 1990). These protective effects conferred in childhood may be enduring, as women (Forest 1991) and men (Khoshaba and Maddi 1999) better cope with adverse events (e.g., death or divorce of spouse, major accident or illness, job stress) if they have previously experi- enced and successfully coped with stressful circumstances in childhood. Although these retrospective, correlational studies provide important preliminary evidence that mild early life stress may protect against adverse stress-related health outcomes, until recently, little research had causally linked mildly stressful early experiences to the manifestation of stress resistance. Because opportunities for controlled studies of stress responsivity in children are uncommon, we previously tested whether exposure to mild stress early in life (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stres- sors in primates (Parker et al 2004). Young squirrel monkeys in these experiments were randomized to a mild intermittent stress (IS) or nonstress (NS) postnatal rearing protocol. Results from these experiments revealed that later in life, IS monkeys demon- strate lower plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations under undisturbed conditions and exhibit diminished anxiety and blunted pituitary-adrenal hormone re- sponses to emotionally challenging circumstances compared with NS monkeys. Exactly how pervasive the effects of mild early life stress are in organizing human and primate development is as yet un- known. However, insofar as mild early stress decreases the development of characteristics associated with psychiatric disor- ders (e.g., anxiety, stress sensitization), other functional domains impaired in patients with depressive and anxiety disorders merit investigation. One such domain is cognition. Patients with de- pressive and anxiety disorders, for example, exhibit significant prefrontal-dependent cognitive deficits (Austin et al 2001; Kuelz et al 2004). These include impaired response inhibition on a variety of tests such as the Stroop Color Word Test, the Go/Nogo Task, and the Wisconsin Card Sorting Test (Bannon et al 2002; Kaiser et al 2003; Malloy et al 1989; Merriam et al 1999; Schatzberg et al 2000; Trichard et al 1995). In addition to poor performance on these neuropsychological tests, the inability to inhibit inappropriate thoughts (e.g., negative ideation), actions (e.g., compulsive engagement in ritualistic behavior), and emo- tions (e.g., panic, anxiety, feelings of worthlessness) are gener- ally considered to be defining features of these psychiatric disorders. Thus, in this study, we examine the effects of mild early life stress on prefrontal-dependent cognitive function. In recent years, test paradigms designed to assess prefrontal- dependent response inhibition in children have been modified for use in primates (Diamond 1990; Lyons et al 2000; Wallis et al 2001). Studies of both Old World and New World monkey species generally confirm anatomical specificity for these func- tional tests, with some species differences and performance variation (Hauser 1999). Structural prefrontal cortical lesions in adult rhesus macaques and marmosets have been shown to From the Department of Psychiatry and Behavioral Sciences, Stanford Uni- versity Medical School, Stanford, California. Address reprint requests to Karen J. Parker, Ph.D., Department of Psychiatry and Behavioral Sciences, 1201 Welch Road, MSLS Room P104 - Mail Code 5485, Stanford University Medical School, Stanford, CA 94305-5485; E- mail: kjparker@stanford.edu. Received May 12, 2004; revised September 21, 2004; revised December 10, 2004; accepted December 10, 2004. BIOL PSYCHIATRY 2005;57:848 – 855 0006-3223/05/$30.00 doi:10.1016/j.biopsych.2004.12.024 © 2005 Society of Biological Psychiatry