Stress is experienced when stimuli pose a perceived or actual threat to an organism. Exposure to a stressor initiates physiological and behavioral responses that are aimed at restoring homeostasis. In particular, stress activates the hypothalamic-pituitary-adrenal axis, leading to release of glucocorticoids, and engages the autonomic nervous system, causing release of norepinephrine. These “stress hormones” have widespread effects, because most cells express respective receptors that initiate cell-type-specific molecular signaling pathways. In the brain, acute stress promotes neuronal activation, resulting in alertness and adaptive behavioral responses. However, chronic or uncontrolled stress exposure can have deleterious effects on neuronal function, including loss of synaptic connections, which leads to behavioral and cognitive impairments. Stress responses also influence the function of brain-resident microglia and peripheral immune cells that interact with the brain, and alterations in these neuroimmune systems can contribute to the neurobiological and behavioral effects of chronic stress. Ongoing research is aimed at uncovering the molecular and cellular mechanisms that mediate stress effects on neuroimmune systems, and vice versa.
Eric S. Wohleb
The demonstration of steroid binding proteins in brain areas outside of the hypothalamus was a key neuroendocrine discovery in the 1980s. These findings suggested that gonadal hormones, estradiol and testosterone, may have additional functions besides controlling reproduction through the hypothalamic–pituitary–gonadal axis (HPG) and that glucocorticoids may also influence neural functions not related to the hypothalamic–pituitary–adrenal axis (HPA). In the past 30 years, since the early 1990s, a body of neuroendocrine studies in animals has provided evidence for these hypotheses, and in 2020, it is generally accepted that steroid hormones exert robust influences over cognition—both learning and memory. Gonadal hormones, predominantly estrogens, enhance learning and memory in rodents and humans and influence cognitive processes throughout the lifespan. Gonadal hormones bind to classical nuclear estrogen receptors and to membrane receptors to influence cognition. In contrast to the generally positive effects of gonadal hormones on learning and memory, adrenal hormones (glucocorticoids in rodents or cortisol in primates) released during chronic stress have adverse effects on cognition, causing impairments in both learning and memory. However, emerging evidence suggests that impairments may be limited only to males, as chronic stress in females does not usually impair cognition and, in many cases, enhances it. The cognitive resilience of females to stress may result from interactions between the HPG and HPA axis, with estrogens exerting neuroprotective effects against glucocorticoids at both the morphological and neurochemical level. Overall, knowledge of the biological underpinnings of hormonal effects on cognitive function has enormous implications for human health and well-being by providing novel tools for mitigating memory loss, for treating stress-related disorders, and for understanding the bases for resilience versus susceptibility to stress.
Kevin T. Larkin, Alaina G. Tiani, and Leah A. Brown
Based on its distinctive innervation between the brain and body, the vagal nerve has long been considered to play an important role in explaining how exposure to stress leads to numerous psychiatric disorders and cardiac diseases. In contrast to activation of the sympathetic nervous system during exposures to stress, the vagal nerve is responsible for parasympathetic regulation of visceral activity including cardiac functioning that often but not always co-occurs during periods of stress. Although methods exist to measure vagal nerve influences on the heart directly, most of the literature on both human and animal participants’ responses to stress employs the measurement of heart rate variability (HRV). HRV, the tendency for the heart rate to increase and decrease in adaptation to the changing physiological and external environment, can be easily detected using surface electrodes; several HRV parameters have been shown to be valid indicators of parasympathetic nerve activity. Theories of the evolutionary heritage of the vagal nerve, like Porges’ polyvagal theory and the subsequent neurovisceral integration perspective of Thayer and colleagues that traces the autonomic regulation of the heart into higher cortical regions, have served as important conceptual works to guide empirical work examining the effects of stress on both tonic and phasic vagal activity. A number of methodological approaches have been employed to evaluate whether exposure to stress affects vagal tone, including use of animal models, case-control samples of humans exposed to stressful living situations, and samples of humans diagnosed with a range of psychiatric disorders. Findings from studies comprising this literature support a relation between exposure to stress and reduced cardiac vagal tone. Both humans and animals typically exhibit reductions in daily HRV when exposed to a range of stressful situations or contexts. The relation between stress and phasic alterations in vagal functioning, the magnitude of the acute change in HRV in response to an acute stressor, is more complicated, likely involving significant moderating variables that have yet to be elucidated. In sum, considerable evidence supports an important neuroregulatory role of the vagal nerve in modulating the body’s response to environmental stress and potentially serving as an avenue for understanding how exposure to stress increases risk for psychiatric disorders as well as cardiovascular disease.
Georgia E. Hodes
In the late 20th century, the discovery that the immune system and central nervous system were not autonomous revolutionized exploration of the mechanisms by which stress contributes to immune disorders and immune regulation contributes to mental illness. There is increasing evidence of stress as integrated across the brain and body. The immune system acts in concert with the peripheral nervous system to shape the brain’s perception of the environment. The brain in turn communicates with the endocrine and immune systems to guide their responses to that environment. Examining the groundwork of mechanisms governing communication between the body and brain will hopefully provide a better understanding of the ontogeny and symptomology of some mood disorders.
Jeffrey S. Darling, Kevin Sanchez, Andrew D. Gaudet, and Laura K. Fonken
Microglia, the primary innate immune cells of the brain, are critical for brain maintenance, inflammatory responses, and development in both sexes across the lifespan. Indeed, changes in microglia form and function with age have physiological and behavioral implications. Microglia in the aged brain undergo functional changes that enhance responses to diverse environmental insults. The heightened sensitivity of aged microglia amplifies proinflammatory responses, including increased production of proinflammatory cytokines and chemokines, elevated danger signals, and deficits in debris clearance. Elevated microglia activity and neuroinflammation culminate in neuropathology, including increased risk for neurodegenerative diseases and cognitive decline. Importantly, there are sex differences in several age-related neuroinflammatory pathologies. Microglia coordinate sex-dependent development within distinct brain structures and behaviors and are, in turn, sensitive to sex-specific hormones. This implies that microglia may confer differential disease risk by undergoing sex-specific changes with age. Understanding how aging and sex influence microglial function may lead to targeted therapies for age- and sex-associated diseases and disorders.
Kristen Delevich and Linda Wilbrecht
Puberty onset marks the beginning of adolescence and an organism’s transition to adulthood. Across species, adolescence is a dynamic period of maturation for brain and behavior. Pubertal processes, including the increase in gonadal hormone production, or gonadarche, can influence a broad array of neural processes and circuits to ultimately shape adult behavior. Decades of research in rodent models have shown that gonadal hormones at puberty promote adult-typical patterns of behavior across social, affective, and cognitive realms. Importantly, hormonal activation of sex-specific patterns of adult behavior relies on sexual differentiation of the brain around the time of birth, mediated by testicular hormones in males – and lack thereof in females. While it was originally believed that gonadal hormones play a purely activational role at puberty, studies in the early 21st century provide examples where the timing and relative levels of gonadal hormones exert long-lasting, or organizational effects on brain and behavior. In this way, adolescent exposure to gonadal hormones can orchestrate brain and body changes in unison and in some cases tune how the brain responds to gonadal hormones in adulthood. Notably, many of the effects of puberty on behavior may occur indirectly by altering sensitivity to environmental events and an organism’s ability to respond to or learn from experience. These insights from the animal literature provide a framework for understanding how puberty may influence the maturation of complex behaviors and modify risk or resilience to mental health disorders during human adolescence. In sum, puberty interacts with genetics, early life organizational effects of gonadal hormones, experience, and learning processes to shape behavior in adulthood.
Jill E. Schneider
During the evolution of animals, survival and reproduction depended upon mechanisms that maintained internal homeostasis in the face of environmental change. These environmental changes included fluctuations in ambient temperature, food availability, humidity, day length, and population density. Most, if not all, of these variables have effects on the availability of energy, and most vertebrate species have mechanisms that sense energy availability and adjust behavioral priorities accordingly. For example, when the availability of food and potential mating partners is stable and abundant, brain mechanisms often inhibit ingestive behavior, increase energy expenditure, and give priority to courtship and mating. In response to severe energy shortages, brain mechanisms are likely to stimulate foraging, food hoarding, and overeating. These same deficits often delay reproductive development or inhibit adult reproductive behavior. Such adaptations involve the integration of sensory signals with peripheral hormone signals and central effectors, and they are key to understanding health and disease, particularly obesity, eating disorders, and diabetes. The link between energy balance and reproduction recurs repeatedly, whether in the context of the sensory-somatic system, the autonomic nervous system, or the neuroendocrine cascades. Peripheral signals that are detected by receptors on vagal and splanchnic nerves are relayed to the caudal hindbrain. This brain area contains the effectors for peripheral hormone secretion and for chewing and swallowing, and this same brain area contains receptors for humoral and metabolic signals from peripheral circulation. The caudal hindbrain is therefore a strong candidate for integration of multiple signals that control the initiation of meals, meal size, energy storage, and energy expenditure, including the energy expended on reproduction. There are some differences between the reproductive and ingestive mechanisms, but there are also many striking similarities. There are still gaps in our knowledge about the nature and location of metabolic receptors and the pathways to their effectors. Some of the most promising research is designed to shed light on how hormonal signals might be enhanced or modulated by the peripheral energetic condition (e.g., the level of oxidizable metabolic fuels).
Divine C. Nwafor, Allison L. Brichacek, Sreeparna Chakraborty, Catheryne A. Gambill, Stanley A. Benkovic, and Candice M. Brown
The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.
Caleigh Guoynes and Catherine Marler
How hormones and neuromodulators initiate and maintain paternal care is important for understanding the evolution of paternal care and the plasticity of the social brain. The focus here is on mammalian paternal behavior in rodents, non-human primates and humans. Only 5% of mammalian species express paternal care, and many of those species likely evolved the behavior convergently. This means that there is a high degree of variability in how hormones and neuromodulators shape paternal care across species. Important factors to consider include social experience (alloparental care, mating, pair bonding, raising a previous litter), types of care expressed (offspring protection, providing and sharing food, socio-cognitive development), and timing of hormonal changes (after mating, during gestation, after contact with offspring). The presence or absence of infanticide towards offspring prior to mating may also be a contributor, especially in rodents. Taking these important factors into account, we have found some general trends across species. (1) Testosterone and progesterone tend to be negatively correlated with paternal care but promote offspring defense in some species. The most evidence for a positive association between paternal care and testosterone have appeared in rodents. (2) Prolactin, oxytocin, corticosterone, and cortisol tend to be positively correlated. (3) Estradiol and vasopressin are likely nuclei specific—with some areas having a positive correlation with paternal care and others having a negative association. Some mechanisms appear to be coopted from females and others appear to have evolved independently. Overall, the neuroendocrine system seems especially important for mediating environmental influences on paternal behavior.
Edo Ronald de Kloet and Marian Joëls
The glucocorticoid hormones cortisol and corticosterone coordinate circadian events and are master regulators of the stress response. These actions of the glucocorticoids are mediated by mineralocorticoid receptors (NR3C2, or MRs) and glucocorticoid receptors (NR3C1, or GRs). MRs bind the natural glucocorticoids cortisol and corticosterone with a 10-fold higher affinity than GRs. The glucocorticoids are inactivated only in the nucleus tractus solitarii (NTS), rendering the NTS-localized MRs aldosterone-selective and involved in regulation of salt appetite. Everywhere else in the brain MRs are glucocorticoid-preferring. MR and GR are transcription factors involved in gene regulation but recently were also found to mediate rapid non-genomic actions. Genomic MRs, with a predominant localization in limbic circuits, are important for the threshold and sensitivity of the stress response system. Non-genomic MRs promote appraisal processes, memory retrieval, and selection of coping style. Activation of GRs makes energy substrates available and dampens initial defense reactions. In the brain, GR activation enhances appetitive- and fear-motivated behavior and promotes memory storage of the selected coping style in preparation of the future. Thus, MRs and GRs complement each other in glucocorticoid control of the initiation and termination of the stress response, suggesting that the balance in MR- and GR-mediated actions is crucial for homeostasis and health.