Toward a mechanistic understanding of interindividual differences in cognitive changes after stress: reply to van den Bos Erno J. Hermans 1, 2 , Marloes J.A.G. Henckens 1 , Marian Joe¨ ls 3 , and Guille´n Ferna´ ndez 1, 2 1 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, 6525 EN, The Netherlands 2 Department for Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, 6525 EN, The Netherlands 3 Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands Understanding why some people are vulnerable to develop psychopathology while others are resilient is one of the key challenges for research into stress-related mental disor- ders. Therefore, we agree with Ruud van den Bos [1] that understanding interindividual differences in the response to stress is critical. Here, we outline how important dimen- sions of interindividual variability, such as coping style and sex, can be reconciled with our biphasic-reciprocal model of neural resource allocation under stress. We high- light the critical importance of neuroscientific insight not only for understanding mechanisms shared by all, but also to identify causal factors that produce interindividual differences. In his Letter [1] in response to our recent article in TiNS [2], van den Bos argues that our biphasic-reciprocal model of neural resource allocation under stress [2] does not take sex differences and interindividual differences in stress- coping styles into account. We acknowledge that individual differences in stress responsiveness, and particularly the long-term consequences thereof, certainly are striking, be it due to sex, coping style, early life adversity, or any of the other many factors influencing development of the stress system. For instance, only few people develop psychopa- thology after exposure to highly stressful life events, and sex ratios show that men tend to develop other types of stress-related psychopathology compared with women [3]. A full understanding of the cognitive changes after stress should also explain these differences. Van den Bos argues that a distinction can be made between animals or humans who exhibit proactive as opposed to reactive coping styles. Given that passive, reactive coping styles have been associated with relatively strong corticosteroid activity [4], he reasons that our model may describe the reactive coping style better than the proactive coping style. However, our model distinguishes between a predominant role of catecholaminergic activity in the acute phase of the stress response, as opposed to corticosteroids in the recovery phase [2]. In contrast to reactive animals, animals classified as having proactive coping styles exhibit stronger catecholaminergic activity and predominantly sympathetic autonomic nervous sys- tem activity in response to acute stress [4]. The catechol- aminergic response, in particular norepinephrine, has been shown to drive salience network activation during stress [5]. Therefore, one would expect stronger, rather than weaker, salience network activation in individuals with a proactive coping strategy. Thus, the proactive versus reactive dimension may be captured by a relative dominance of catecholaminergic versus corticosteroid ac- tivity, and our model could account for both coping styles by assuming a difference in the balance between the two phases and the underlying biological substrates. Another factor that explains variability in stress responses is sex. Van den Bos points out that recent findings reveal a qualitative difference in the effect of stress on men compared with women. While women be- come more anxious and vigilant during acute stress, men exhibit more habitual behavior and reward sensitivity [6]. These observations reveal a striking parallel with sex differences in stress-related psychopathology. Inter- nalizing disorders, such as anxiety disorders and depres- sion, are more prevalent in women, while externalizing disorders, such as addiction and aggression, are more common in men [3]. Acute stress can furthermore exacer- bate both internalizing (e.g., pathological fear) and exter- nalizing (e.g., substance abuse) symptoms [7]. Within our model [2], such findings are explained by a transient disruption of goal-directed cognitive control func- tions supported by the executive control network, which would result in a functional release of the salience network to fall back to its ‘default’ stress response strategy. One may speculate that this default strategy could differ be- tween men and women due to an altered balance within stress-sensitive neuromodulatory pathways, in particular between dopaminergic and noradrenergic systems (see, e.g., [6]). Noradrenergic projections are widespread and integrate affective, attentional, and sensory processes [5]. By contrast, dopaminergic innervation is more pro- nounced in the striatum, a brain region involved in regu- lating habitual behavior and reward sensitivity [3]. The distinct roles of these two neuromodulatory systems in the neural response to stress, as we pointed out in our article [2], remain to be explored, in particular in humans. Letter 0166-2236/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2015.05.002 Corresponding author: Hermans, E.J. (erno.hermans@donders.ru.nl). TINS-1148; No. of Pages 2 Trends in Neurosciences xx (2015) 1–2 1