LAUSR

As a young boy walks out of a theater with his two wealthy parents, his life is changed in an instant: a mugging goes awry, shots are fired in the night, and his parents are murdered in front of his eyes. He becomes an orphan, haunted by the memory of the event. He retreats inward, struggling for years to come to term with the events, before ultimately learning to channel his anguish constructively. Meanwhile, a different man decides to forgo a stable job to pursue his dream to become a comedian. He knows his family is depending on him, but his jokes fall flat. His wife and child die in a freak accident. A series of bad decisions lead to utter ruin and physical deformity. Having lost everything, the man is driven to despair. Unable to recover from his loss, he descends into madness. Though the orphan and the comedian both face extraordinary trauma, their subsequent paths diverge markedly: the boy goes on to become the Dark Knight, dedicating his life to fighting injustice; the comedian becomes the Joker, singularly bent on wreaking as much havoc on the world (and himself) as possible. How can we explain such different trajectories? When, in a letter to a friend, Benjamin Franklin famously penned that “in this world nothing can be said to be certain, except death and taxes,” he perhaps should have added one more inevitability: stress (1). Stress may be broadly defined as a systemic physiologic response to a perceived threat. In the face of danger, increases in blood pressure, heart rate, and glucose availability enable a potentially life-saving “fight-orflight” response. Stress also impacts the brain, modulating functions such as cognition, memory formation, and pain perception. Yet this remarkable ability to enter a state of physical and mental readiness almost instantaneously is not without consequence: for superheroes and mortals alike, stress changes people. On one hand, in keeping with the idea that “what doesn’t kill me makes me stronger,” manageable stress can have an inoculating effect, increasing one’s future capacity for tolerating similar adversity in the future. However, excessive stress can overwhelm compensatory systems and precipitate debilitating psychopathology including, most notably, posttraumatic stress disorder (PTSD). In this respect, the stressed brain is not unlike an exercised muscle: manageable doses can fortify the system, whereas an overload can cause permanent damage. Understanding the varied responses to stress starts with understanding the neurobiology of stress itself. The two most well-described elements of the stress response are the sympathetic nervous system and the hypothalamicpituitary-adrenal axis. Sensing danger, these two systems