stress-response pathway. The sympathetic system activates internal organs (such as heart, lungs, and liver) and mobilizes energy to respond to stressors. The parasympathetic nervous system does the opposite, preserving energy, putting a brake on the heart rate, increasing intestinal activity, relaxing muscles in the gastrointestinal system, and decreasing inflammation. Those functions have earned the parasympathetic system the nickname “rest and digest,” compared with the “fight or flight” of the sympathetic system. The stress response is adaptive (it promotes survival), but it is maladaptive if it is chronically activated over a long time. Long-term activation of the stress response can cause abnormalities in the brain or in other parts of the body.

Reticular Activating System

In response to any stimulus, including stimuli that are novel or potentially threatening, a primary brain system that is activated is the reticular activating system (RAS). Without activation of the RAS there would be no stress response or waking behavior; indeed, loss of RAS function results in a persistent vegetative state. The RAS works closely with the cholinergic, noradrenergic, and serotonergic systems of the brainstem and influences other brain areas, such as the cerebral cortex, hypothalamus, amygdala, and cerebellum. Novel and potentially threatening stimuli, such as a loud sound, induce a massive output from the RAS that does three things: it activates the pontine reticular formation to potentiate the startle response, which is part of a general protective system (the eyes close, flexion in humans lowers the head from danger, and muscles tighten in preparation for attack from an enemy); it activates the thalamus to trigger synchronization of fast rhythms between the thalamus and cortex that “awaken” the cortex, placing it in a “ready” position; and it participates with forebrain structures in activating the hypothalamus to trigger the HPA axis and the surge of epinephrine from the adrenal medulla. The “fight or flight” response is therefore a brainwide and bodywide response to novelty and threat that involves activation of the RAS with other coordinated brain systems.

The RAS is dysregulated in anxiety disorders and depression. In fact, some of the first symptoms of posttraumatic stress disorder (PTSD) and depression are sleep-wake problems (see Chapter 5). Both disorders are marked by increased vigilance and increased REM-sleep drive, which can result in vivid dreaming and REM-sleep intrusion into waking, for example, hallucinations (Pfaff 2005). In some cases, the RAS can be activated directly by inputs to the brainstem from the periphery, such as a loud sound, pain, touch, or signals from the gut via the vagus nerve. For the other senses, the sensory information reaches the RAS via the amygdala, which also can respond directly to a stimulus, such as a loud sound, pain, or touch.

Importance of the Amygdala

The stress response begins with sensory information about a stressor—its visual images, sounds, smells, touch, or other sensations (Figure 4-1). Information from sensory nerve cells in peripheral tissues is relayed to several regions of the brain, including the hypothalamus, thalamus, somatosensory cortex, nucleus of the solitary tract, ventral lateral medulla, and the parabrachial nucleus and insular cortex. Each of those regions sends signals to the amygdala (in the temporal lobes of the cerebrum) which integrates all the incoming sensory signals (Bonne et al. 2004) and to the hypothalamus. The amygdala consists of collections of cell types (nuclei) that form the “extended amygdala.” The extended amygdala consists of the central and basolateral nucleus of the amygdala, and the lateral bed nucleus of the stria terminalis (BNST) (Alheid and Heimer 1988; Davis and Whalen 2001). The BNST also receives input from the

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