Gretchen N. Neigh

Disease drivers of aging

It has long been known that aging, at both the cellular and organismal levels, contributes to the development and progression of the pathology of many chronic diseases. However, much less research has examined the inverse relationship—the contribution of chronic diseases and their treatments to the progression of aging‐related phenotypes. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatments on aging, putative mechanisms by which these effects are mediated, and the open questions and future research directions required to understand the relationships between these diseases and aging.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

Mutual regulation and balance between the endocrine and immune systems facilitate an organisms stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors.

Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment

Posttraumatic stress disorder (PTSD) is defined as a psychiatric disorder; however, PTSD co-occurs with multiple somatic manifestations. People living with PTSD commonly manifest dysregulations in the systems that regulate the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis, and development of a pro-inflammatory state. Additionally, somatic autoimmune and inflammatory diseases and disorders have a high rate of co-morbidity with PTSD. Recognition and understanding of the compounding effect that these disease states can have on each other, evidenced from poorer treatment outcomes and accelerated disease progression in patients suffering from co-morbid PTSD and/or other autoimmune and inflammatory diseases, has the potential to lead to additional treatment opportunities.

Sex Differences in Synaptic Plasticity: Hormones and Beyond

Notable sex-differences exist between neural structures that regulate sexually dimorphic behaviors such as reproduction and parenting. While anatomical differences have been well-characterized, advancements in neuroimaging and pharmacology techniques have allowed researchers to identify differences between males and females down to the level of the synapse. Disparate mechanisms at the synaptic level contribute to sex-specific neuroplasticity that is reflected in sex-dependent behaviors. Many of these synaptic differences are driven by the endocrine system and its impact on molecular signaling and physiology. While sex-dependent modifications exist at baseline, further differences emerge in response to stimuli such as stressors. While some of these mechanisms are unifying between sexes, they often have directly opposing consequences in males and females. This variability is tied to gonadal steroids and their interactions with intra- and extra-cellular signaling mechanisms. This review article focuses on the various mechanisms by which sex can alter synaptic plasticity, both directly and indirectly, through steroid hormones such as estrogen and testosterone. That sex can drive neuroplasticity throughout the brain, highlights the importance of understanding sex-dependent neural mechanisms of the changing brain to enhance interpretation of results regarding males and females. As mood and stress responsivity are characterized by significant sex-differences, understanding the molecular mechanisms that may be altering structure and function can improve our understanding of these behavioral and mental characteristics.

Editorial introduction: The effects of somatic disease and environmental insults on the stress response.

The majority of work examining relationships between stress and medical illness has focused on the impact of stress and alterations in HPA axis function on the development of diseases and disorders [15, 3]. Although it is well accepted that toxic stress can have profound and protracted consequences on numerous systems in the brain and body contributing to a number of medical, neurologic or mental illnesses, there is also substantial evidence that development of these illnesses can have equal consequences on the stress response and hypothalamic pituitary adrenal (HPA) axis function. Illness-induced dysregulation of stress systems may then influence other physiological systems creating a feed-forward cycle and leading to exacerbation of the primary disease or contributing to development of comorbid medical, neurologic or mental disorders. Furthermore, ecological or societal exposures such as environmental toxins, drugs of abuse, and poor nutrition also exert effects on the HPA axis that may further increase risk for development of disease secondary to these exposures (Fig. 1). Therefore, this edition integrates a body ofwork from experts in various fields of somatic or neurologic illness, drug addiction, metabolism and nutrition, and environmental toxins to discuss the consequences of these diseases or exposures on the HPA axis and the stress response. Major medical illnesses that involve pathophysiological processes such as inflammation can affect the stress response and HPA axis function to contribute to increased risk for behavioral comorbidities like depression. For example, cancer and its treatments have been associated with increases in inflammatorymarkers at rest and in response to stress in association with alterations in HPA axis function, which is thought to contribute to behavioral symptoms of depression, fatigue and cognitive dysfunction in cancer patients and survivors [4,14,24]. In this special issue, Leah Pyter reviews recent clinical and translational evidence that cancer can impact endocrine, immune, or behavioral responses to stress. Whereas the clinical work in this area has focused primarily on the effect of cancer therapies (e.g. radiation and chemotherapy), this review presents a unique perspective on how the tumors themselvesmay perturb physiological systems beyond their local microenvironment to contribute to alterations in immune, nervous, and metabolic systems [17,23]. Relevant literature from rodent cancer models are presented and integrated with the clinical literature, which indicate overall elevations in baseline glucocorticoids and decreased HPA axis responses to acute stressors, to make the case that alterations in stress responses by the cancer itself may interact with psychological and physiologic stressors during diagnosis and treatment to influence behavioral and physical health outcomes in cancer patients. In addition to cancer, inflammation as a result of chronic viral infections and their treatments has also been associated with increased risk

Chromosomal and Endocrinological Origins of Sex

Sexual differentiation begins in utero with the sex chromosomes dictating subsequent endocrine and physiological effects. Distinctly timed events influence each subsequent developmental phase. Although the sex-dependent developmental paths typically occur in predicted patterns, individual and environmental variations may produce alterations in the expected sex-typical profiles. As aging progresses, males and females experience varying endocrine fluctuations, some with far-reaching consequences and the roots of these variations may be grounded in prior developmental events. In order to understand, study, and treat diseases and disorders that are impacted by sex, an appreciation of the mechanisms of organizational differences between the sexes is essential.

Sex Differences in Neuroanatomy and Neurophysiology: Implications for Brain Function, Behavior, and Neurological Disease

Sex differences in neurophysiology and behavior are crucial to the understanding of neurological diseases. Alzheimer’s disease, Parkinson’s disease, anxiety, and depression are just a few of the known sexually dimorphic neurological disorders in terms of prevalence, symptom presentation, disease progression, etc. Steroid hormones, particularly estrogen, are thought to play a protective role in some of these diseases. Thus, it is pertinent to understand how steroid hormones affect the central and peripheral nervous systems in order to uncover the underlying mechanisms involved in these diseases. Steroid hormones act on sexually dimorphic brain regions, including several nuclei of the hypothalamus, to influence neuronal signaling (eg, neurotransmitter systems), physiological functions of the body, and sexually dimorphic behaviors like mating and aggression. This chapter discusses the roles of steroid hormones including estrogen, progesterone, and testosterone in neuronal signaling, body functions, behavior, and neurological disease.