Evidence for sex-specific shifting of neural processes underlying learning and memory following stress Kevin D. Beck a,b, ⁎, Victoria N. Luine c a Neurobehavioral Research Lab (129), VA New Jersey Health Care System, East Orange, NJ 07018, United States b Stress and Motivated Behavior Institute, Department of Neurology and Neuroscience, UMDNJ — New Jersey Medical School, Newark, NJ 07103, United States c Department of Psychology, Hunter College of the City University of New York, New York, NY,10021, United States abstract article info Article history: Received 7 January 2009 Received in revised form 3 April 2009 Accepted 9 April 2009 Keywords: Sex differences Stress Learning Memory Hippocampus Caudate Acetylcholine Monoamines Ovarian hormones Recent human research has been focused upon determining whether there is evidence that stress responses cause qualitative changes in neural activity such that people change their learning strategies from a spatial/ contextual memory process through the hippocampus to a procedural stimulus–response process through the caudate nucleus. Moreover, interest has shifted to determining whether males and females exhibit the same type of stress-induced change in neural processing of associations. Presented is a select review of 2 different animal models that have examined how acute or chronic stressors change learning in a sex-specific manner. This is followed by a brief review of recent human studies documenting how learning and memory functions change following stressor exposure. In both cases, it is clear that ovarian hormones have a significant influence on how stress affects learning processes in females. We then examine the evidence for a role of acetylcholine, dopamine, norepinephrine, or serotonin in modulating this shifting of processing and how that may differ across sex. Conclusions drawn suggest that there may be evidence for sex-specific changes in amygdala and hippocampus neuromodulation; however, the behavioral data are still not conclusive as to whether this represents a common or sex-specific shift in how males and females process associations after stressor exposure. Published by Elsevier Inc. Stressor exposure is commonly associated with changes in learning and memory processing. These changes, however, are not necessarily homogenous in form. Research conducted over the past 15 years suggests that the changes in learning and memory following various stressful events are variable depending on the sex of the individual. Contrary to the view that these studies suggest that stress may cause different neurobiological changes in the male versus female brain, there are some theories proposing that a uniform shift in neural processing occurs in response to stressor exposure, which then leads to altered cognitive function. We questioned how sex differences could result from a uniform shift in neural activity. Thus, we examined the human and animal literature that specifically targeted identifying sex differences in neural processing, related to learning and memory. From these data, we attempted to reconcile the theory of a uniform shift in processing and the known sex differences in behavior following stressor exposure. In doing so, it is our hope to identify where further research will help determine whether males and females respond with similar or different neural processing following a stressful event. 1. Stress and neural processing It is now well established that highly arousing events (stress) cause changes in neural processing. These changes involve multiple neuro- transmitter systems that shape neuronal processing to occur in certain patterns across multiple areas. Presumably, the net result of this process is to create a state where the individual can focus neural resources to those stimuli that are most important to its immediate survival. For instance, neurochemical measures following stressor onset clearly show that acute exposure to various types of stressors causes an increase in release of norepinephrine, dopamine, serotonin and amino acids in limbic cortex and subcortical limbic structures [1–10]. In parallel, activation of the hypothalamic–pituitary–adrenal (HPA)-axis leads to an increase in circulating glucocorticoids [11–13]. Thus, the combination of increased monoamine signaling with increased adrenal hormone reception is representative of the prototypical fight-or-flight alarm state described in 1927 by Cannon [14] and later expanded upon by Selye [15]. Selye's concept that the initial arousal state provides biological resources such that maximal efficiency is attained to cope with the stressor but prolonged engagement with the stressor causes an eventual breakdown of these processes has been popular for many individuals studying how performance changes in response to stress. As depicted in Fig. 1 (panel A), the idea that stress responding occurs in stages or follows a continuum based on stress-response duration matches the Physiology & Behavior 99 (2010) 204–211 ⁎ Corresponding author. Neurobehavioral Research Laboratory (129), VA New Jersey Health Care System, 385 Tremont Avenue, East Orange, NJ 07018, United States. Tel.: +1 973 676 1000x3682; fax: +1 973 395 7114. E-mail address: beckkd@umdnj.edu (K.D. Beck). 0031-9384/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.physbeh.2009.04.011 Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb