Blood-brain biomarkers for stress susceptibility.

Posttraumatic stress disorder (PTSD) is a debilitating condition that arises in the aftermath of a highly traumatic event and was initially described as “shell shock” in combatants (1). Patients display three primary sets of symptoms: repeated flashbacks of the trauma, hyperarousal, and hyperanxiety (2). The condition was subsequently documented to occur in victims of sexual violence and natural disasters, among others (3). Further, there is extensive evidence that certain individuals have a higher predisposition to developing the condition (4), and there is also a higher prevalence of PTSD in women (5). In PNAS, Daskalakis et al. (6) explore the question of individual and sex differences using a combinationof behavioral analyses andhigh-throughput genomics in two brain areas involved in the pathophysiology of PTSD: the hippocampus and amygdala. The authors report that glucocorticoid receptor (GR) signaling is a convergent signaling pathway associated with individual differences in both sexes. Indeed, corticosteroid treatment after trauma exposure is shown to prevent the onset of PTSD-like symptoms. They also find a similar genomic profile for individual and sex variation in blood samples, highlighting the value of blood-based biomarkers as a diagnostic tool for changes in brain signaling. Two complementary strategies have facilitated our current understanding of PTSD. On the one hand, structural and functional imaging of the human brain, along with rigorous clinical assessments of PTSD etiology and psychopathology, has helped identify brain regions implicated in the behavioral symptoms. These top-down clinical studies in turn have inspired a bottom-up strategy that combines a range of neurobiological techniques and models to analyze the effects of trauma across biological scales: from molecular and cellular correlates at one end to behavioral and circuit-level analyses at the other (Fig. 1). Together, these approaches have contributed to animalmodels of stress that not only capture salient features of the disorder at the behavioral level but also provide insights into the underlying neuronal, endocrine, and genetic mechanisms. For instance, neuroimaging studies in patients show contrasting functional/ structural modulation of the hippocampus and amygdala. Reduced hippocampal volumes, compared with either trauma-exposed control subjects or trauma-unexposed healthy subjects, have been reported in PTSD patients (7). Further, hippocampal volumes have been inversely associated with PTSD symptom severity (7). Amygdala activation, by contrast, is positively correlated with the severity of PTSD symptoms (7). Consistent with these clinical observations, accumulating evidence from animal models shows that stress has opposite effects on these brain structures. In the hippocampus, stress causes dendritic atrophy, loss of spines, and impairs synaptic plasticity mechanisms like long-term potentiation (8). However, chronic stress strengthens the structural basis of synaptic connectivity through dendritic growth and spinogenesis in the basolateral amygdala (BLA) (9). Repeated stress also enhances long-term potentiation (LTP) in the BLA and facilitates fear and anxiety (9). Another striking characteristic of PTSD lies in the temporal domain. Although PTSD is triggered by a single intensely traumatic, often life-threatening event, some symptoms persist well beyond the original event. This aspect has been captured by several animal models wherein a single, brief exposure to severe stress, followed by extended periods of stress-free recovery, leads to a delayed and gradual buildup of behavioral abnormalities that is manifested well after the acute stressor and is accompanied by cellular changes in the brain (10–12). The animal model used by Daskalakis et al. (6) represents one such paradigm wherein enhanced arousal and anxiety behavior is assessed 7 d after a brief exposure to predator scent stress. Although animal studies have identified key spatiotemporal features of stress-induced plasticity in the amygdala and hippocampus (Fig. 1), they also underscore several unresolved issues. The study by Daskalakis et al. represents significant progress in addressing two of these important issues, i.e., the role of individual variation and sex differences. One of the major questions in the field stems from the observation that not all individuals exposed to a traumatic experience develop PTSD. What factors make some individuals more vulnerable or resilient to PTSD? Thus far, one of the most tangible ways of addressing this issue has been the use of arbitrarily selected cutoff for behavioral measures to Stress