The social deficits that characterize autism spectrum disorder (ASD) often result in teasing, bullying, or social rejection, which in turn interfere with one's ability to get along with others, make friends, and develop independent living skills. These negative social experiences also contribute to emotional problems such as depression, and this may be particularly difficult for higher functioning people living with ASD. Research shows that just about everyone experiences an emotional problem sometime in their life. However, people with ASD are much more likely to experience such problems and at a younger age and continue to experience them at least intermittently throughout their lives. For example, more than half of all adults with ASD have impairing depression. Unfortunately, coping with depression only compounds the adverse consequences of social deficits resulting in a great deal of stress for people with ASD, their family, and friends and becomes a major health concern for many. Although just about everyone recognizes the impact that emotional problems can have on the lives of people with ASD, we know very little about what causes them or what makes them worse. In the past decade we have witnessed major advances in our understanding of the biological and environmental factors that likely contribute to depression in typically developing people, and the proposed study seeks to use this information to better the lives of people living and coping with ASD. Scientific research shows that "immune system hormones" called cytokines play an important role in the severity of emotional problems such as depression. For example, scientists have found that the same cytokines that are involved in inflammation (like when you get an infection or fever) are also involved in depression and reactions to stress. Stress can either help or hurt the ability of the immune system to work properly. The amount of stress in your life, how long the stress lasts, how close the stress hits you, and how well you cope, all affect how well your immune system holds up when you deal with stress. Unfortunately, although we now know that the immune system plays a key role in both physical and mental health, we know almost nothing about how stress affects the immune system and problems with depression in people with ASD. Before we can help fix a problem, however, it is necessary to know where to look. Right now, although we have some good clues as to which cytokines are likely involved in depression, we do not know which regions in the brain are associated with depression in people with ASD, or how these brain regions respond to environmental stressors such as social rejection. Therefore, the main reason for conducting this study is to use brain imagining technology to better understand how the immune system and environmental stressors contribute to depression symptoms in higher functioning adults with ASD. A major contribution of this study is the establishment of a game plan by identifying factors that need to be considered when trying to develop more effective intervention strategies for depression in people with ASD. This study addresses two important areas of interest identified by the Fiscal Year 2013 (FY13) autism Research Program (ARP). The first area is "understanding factors underlying the heterogeneity of clinical expression or response to treatment of ASD." The term "heterogeneity" refers to the fact that people with ASD are highly different from each other. It is true that they all share problems with social functioning, but they also differ in many other ways just as people without ASD. One important difference is intellectual ability. The present study focuses on high functioning individuals as they are much more likely to initiate social interactions with others. It also focuses on adults (18-45 years) because this age group is more likely to experience depression and has not received anywhere near the same degree of attention by researchers as younger individuals. Emotional problems are also heterogeneous even if they have the same name. For example, depression is made up of several different types of problems such as social withdrawal and loss of interest in pleasurable activities. The second FY13 ARP area of interest is "condition co-occurring with ASD." Several experts in ASD have concluded that depression is the most common co-occurring psychiatric problem that poses life adjustment challenges for adults with ASD. The proposed study seeks to better understand heterogeneity, the biology of depression, and the role of environmental stressors in order to use this information to predict which people with ASD will respond to different behavioral and pharmacological interventions and the kinds of services they will likely need. The short-term benefits of this study include helping clinicians to identify and classify (diagnose) depression in people with ASD and to recognize potential risk factors for emotional problems (stress, cytokine levels) so steps can be taken to improve the effectiveness of the interventions that are likely to help them the most. Results will also help researchers identify people who might be ideal participants for treatment studies. Longer-term benefits include the much sought-after goal of actually discovering new therapies based on information about how the brain works and then matching patients to treatments.