Figure 2.3 Schematic representation of pathways important in hypothalamic control of energy balance and sleep. VLPO, ventrolaterol preoptic nucleus; DMH, dorsomedial hypothalamus; TRH, thyrotropin releasing hormone; CRF, corticotrophin releasing factor; PVN, paraventricular nucleus; SCN, suprachiasmic nucleus; LH, lateral hypothalamus; HPA, hypothalamus‐pituitary‐adrenal axis; AgRP, agouti‐related peptide; NPY, neuropeptide Y; POMC, pro‐opiomelanocortin; CART, cocaine and amphetamine related transcript; MCH, melanin‐concentrating hormone; TNF‐α, tumor necrosis factor alpha; IL1‐β, interleukin 1 beta; IL‐6, interleukin‐6; LCFA, long chain fatty acids.

      2.3.2 How We Sleep: Light–Day Cycle, Circadian Clock, and Hypothalamic Linkages to Metabolic Control and Sleep

      The 24‐hour rotation of the Earth creates a light‐dark cycle that has conditioned the biology and temporal behavior of humans and other mammals to synchronize activities with the 24‐hour clock. This control is exerted in the hypothalamus at the level of the suprachiasmatic nucleus (SCN) (Figure 2.3). In response to temporal cues (or zeitgeber for “time giver”), the SCN executes control of central clock gene function through both endocrine and autonomic outputs. The SCN inputs to the arcuate nucleus, PVN, and LH to cyclically regulate feeding, energy storage, and body temperature [13, 14]. Signals from the SCN are also relayed to the dorsomedial hypothalamus (DMH), which sends significant output to the ventrolateral preoptic nucleus (VLPO), which directly promotes sleep. Its activity is highest during sleep and inhibited by NE and serotonin arising from the arousal network. Thus, timing of sleep, feeding, nutrient intake, times of arousal, and energy expenditure are regulated cyclically (e.g., the early rise of cortisol at the beginning of the day just before activity) [14]. In addition to the SCN, most peripheral cells and tissues express autonomous clocks that function in synchrony with the SCN through the action of a regulatory cassette of clock genes. This regulatory cassette consists of a class of transcriptional activators (Clock/BMAL1) that, in addition to controlling the expression of numerous genes involved in carbohydrate and lipid metabolism, induce the expression of their own repressors (Per1‐3/Cry1‐2) [13].

Besides receiving signals from the SCN, these peripheral clocks are influenced by surrogate zeitgebers other than light, including food availability, glucocorticoids, and temperature. Because of these linkages, it is easy to understand how disruption of this network by environmental changes, such as shift work, jet lag, light pollution, changes in eating patterns, and sleep deprivation, may lead to metabolic imbalance and weight gain. These changes all have the common effect of altering hypothalamic control of processes involved in energy storage and expenditure. Indeed, studies of shift work provide important insights into the linkages between circadian rhythm and metabolism. Studies of individuals experiencing circadian misalignment reveal significantly higher rates of hypoleptinemia, insulin resistance, inverted cortisol peaks, and increased blood pressures. All of these measures are frequently used biomarkers of allostatic load and consistent with the association between poor sleep health and metabolic syndrome, diabetes, and obesity (Figure 2.3) [13, 14].

      Notably, these influences appear bidirectional, as patients with diabetes show dampened circadian oscillation of both glucose and insulin. Thus, synchronization of activity, feeding behavior, and sleep with light–dark cycles has significant influence on metabolic imbalance and obesity. As mentioned above, many aspects of these regulatory circuits are likely to have bidirectional effects, since glucocorticoids have a strong influence on the expression of multiple clock genes in the SCN and peripheral tissues [13].

      2.3.3 How We Feel: Stress and the Role of HPA Axis in Memory and Mood

      A critically significant adaptive function for promoting and maintaining survival is the memory system. The active process of recollection and embedding of past adverse experiences provides a means of assuring that similar events can be appropriately avoided or circumnavigated. The release of glucocorticoids through the HPA axis in response to stress also influences pathways and mechanisms that govern multiple aspects of memory [15]. Cortisol has access to many areas of the brain that express both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) [9]. While GRs are ubiquitous throughout the brain, MRs are mostly concentrated in the limbic regions, including the hippocampus and the amygdala. GR activation is associated with consolidation, the transition of short‐term to long‐term memory. MR activation is associated with evaluation and response to stressful experiences.

      Research indicates that glucocorticoids have complicated influences on memory consolidation and retrieval. Moreover, chronic elevation of glucocorticoid in combination with NE has a strong influence on neurogenesis through their influence on neuronal plasticity by promoting dendritic remodeling at the cellular level [5]. Such influences are complex and sometimes paradoxical. While glucocorticoids play a role in the consolidation of memory of emotionally arousing experiences, they can also impair retrieval of primary learned or memorized events. Learning and memory processes take place in complex networks of regions in the brain that may act in parallel or competition. Studies suggest that emotional stress can promote rerouting of systems of memory and