deep reach. The hypothalamus plays a

deep reach. The hypothalamus plays a key role in enabling communication from brain to periphery. Located in the lower central region of the brain, the hypothalamus receives neural input on brain and body states (e.g., pain, sadness, fear, hunger) and in response signals brain regions that control the autonomic nervous system and the pituitary and adrenal glands. Signals to the autonomic nervous system permit modulation of heart rate, blood pressure, and numerous other factors that serve to maintain homeostasis. Signals to the pituitary gland (located at the base of the brain, just below the hypothalamus) prompt the release of hormones that ultimately permit modulation of almost every endocrine gland in the body, including the adrenal glands (one is situated on top of each kidney). The adrenal glands serve many functions, and one is to produce and secrete cortisol. Cortisol is frequently referred to as a “stress hormone” because circulating levels increase dramatically in response to any stimulus that requires, or might require, metabolic resources. Thus, cortisol increases blood sugar levels, increases blood pressure, and reduces immune responses and inflammation (hence the use of cortisone cream or injections to control inflammation of the skin after exposure to poison ivy). This complex web of physiological links may seem far removed from feelings of social isolation, but loneliness has repeatedly been observed to be a risk factor for elevated levels of cortisol, especially in the morning. For instance, in middle- aged adults, the more intense the degree of loneliness reported at day’s end over the course of three days in everyday life, the higher the spike in cortisol the subsequent morning. The conundrum is Page |44 that loneliness is associated with increased risk of chronic conditions that are characterized by heightened inflammation (e.g., atherosclerosis, elevated cholesterol levels, heart disease, diabetes, and even cognitive impairment). If cortisol dampens inflammation, why might elevated levels of cortisol in lonely individuals be associated with more rather than less inflammation? It turns out that communication among the hypothalamus, pituitary gland, and adrenal glands becomes dysregulated when chronically stimulated. Whereas cortisol effectively dampens immune and inflammatory responses on an acute basis, when circulating cortisol levels are chronically elevated, cells become resistant to its immunosuppressant and anti- inflammatory effects. This alteration happens at the level of DNA where the actions of genes in each cell of our body can be turned on (i.¢., expressed) or off. Recent evidence suggests that the effects of loneliness reach down to this level. Circulating leukocytes (white blood cells) from a small group of chronically lonely adults showed decreased expression of glucocorticoid response genes relative to expression rates in a matched group of socially connected adults. These genes are important because they activate the production of proteins that “hear” the anti- inflammatory signal sent by cortisol. Thus, despite higher levels of circulating cortisol in the lonely group, the cortisol signal may still not be heard. The lonely group also showed increased expression of genes carrying pro-inflammatory elements which, together with reduced expression of glucocorticoid response genes, provides a functional genomic explanation for elevated risk of HOUSE_OVERSIGHT_021290