Current Neuropharmacology - Volume 16, Issue 3, 2018

Background: Stress is a common reaction to an environmental adversity, but a dysregulation of the stress response can lead to psychiatric illnesses such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety disorders. Yet, not all individuals exposed to stress will develop psychiatric disorders; those with enhanced stress resilience mechanisms have the ability to adapt successfully to stress without developing persistent psychopathology. Notably, the potential to enhance stress resilience in at-risk populations may prevent the onset of stress-induced psychiatric disorders. This novel idea has prompted a number of studies probing the mechanisms of stress resilience and how it can be manipulated. Methods: Here, we review the neurobiological factors underlying stress resilience, with particular focus on the serotoninergic (5-HT), glutamatergic, and γ-Aminobutyric acid (GABA) systems, as well as the hypothalamic-pituitary axis (HPA) in rodents and in humans. Finally, we discuss stress resiliency in the context of aging, as the likelihood of mood disorders increases in older adults. Results: Interestingly, increased resiliency has been shown to slow aging and improved overall health and quality of life. Research in the neurobiology of stress resilience, particularly throughout the aging process, is a nascent, yet, burgeoning field. Conclusion: Overall, we consider the possible methods that may be used to induce resilient phenotypes, prophylactically in at-risk populations, such as in military personnel or in older MDD patients. Research in the mechanisms of stress resilience may not only elucidate novel targets for antidepressant treatments, but also provide novel insight about how to prevent these debilitating disorders from developing.

Background: Chronic stress affects health and the quality of life, with its effects being particularly relevant in ageing due to the psychobiological characteristics of this population. However, while some people develop psychiatric disorders, especially depression, others seem very capable of dealing with adversity. There is no doubt that along with the identification of neurobiological mechanisms involved in developing depression, discovering which factors are involved in positive adaptation under circumstances of extreme difficulty will be crucial for promoting resilience. Methods: Here, we review recent work in our laboratory, using an animal model lacking the LPA1 receptor, together with pharmacological studies and clinical evidence for the possible participation of the LPA1 receptor in mood and resilience to stress. Results: Substantial evidence has shown that the LPA1 receptor is involved in emotional regulation and in coping responses to chronic stress, which, if dysfunctional, may induce vulnerability to stress and predisposition to the development of depression. Given that there is commonality of mechanisms between those involved in negative consequences of stress and in ageing, this is not surprising, considering that the LPA1 receptor may be involved in coping with adversity during ageing. Conclusion: Alterations in this receptor may be a susceptibility factor for the presence of depression and cognitive deficits in the elderly population. However, because this is only a promising hypothesis based on previous data, future studies should focus on the involvement of the LPA-LPA1 pathway in coping with stress and resilience in ageing.

Background: Resilience is the ability to achieve a positive outcome when we are in the face of adversity. It supposes an active resistance to adversity by coping mechanisms in which genetic, molecular, neural and environmental factors are involved. Resilience has been usually studied in early ages and few is known about it during aging. Methods: In this review, we will address the age-related changes in the brain mechanisms involved in regulating the stress response. Furthermore, using the EE paradigm, we analyse the resilient potential of this intervention and its neurobiological basis. In this case, we will focus on identifying the characteristics of a resilient brain (modifications in HPA structure and function, neurogenesis, specific neuron types, glia, neurotrophic factors, nitric oxide synthase or microRNAs, among others). Results: The evidence suggests that a healthy lifestyle has a crucial role to promote a resilient brain during aging. Along with the behavioral changes described, a better regulation of HPA axis, enhanced levels of postmitotic type-3 cells or changes in GABAergic neurotransmission are some of the brain mechanisms involved in resilience. Conclusion: Future research should identify different biomarkers that increase the resistance to develop mood disorders and based on this knowledge, develop new potential therapeutic targets.

Background: Many studies have been shown an important role of glutamatergic system as well microglial activation in the pathophysiology of major depressive disorder (MDD). In humans most resistant to the development of psychiatric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflammation in resilience. Methods: We conducted a review of computerized databases from 1970 to 2017. Results: There is an association between microglial activation and glutamatergic system activation with stress vulnerability and resilience. Conclusions: Glutamate neurotransmission, including neurotransmitter synthesis, signalling, and glutamate receptor functions and expression all seem to be involved with both stress vulnerability and resilience. Moreover, inflammation and microglial activation mediate individual differences in resilience and the risk of stress-induced MDD.

Background: In adulthood, depression is the most common type of mental illness and will be the second leading cause of disease by 2020. Major depression dramatically affects the function of the central nervous system and degrades the quality of life, especially in old age. Several mechanisms underlie the pathophysiology of depressive illness, since it has a multifactorial etiology. Human and animal studies have demonstrated that depression is mainly associated with imbalances in neurotransmitters and neurotrophins, hypothalamic-pituitary-adrenal axis alterations, brain volume changes, neurogenesis dysfunction, and dysregulation of inflammatory pathways. Also the gut microbiota may influence mental health outcomes. Although depression is not a consequence of normal aging, depressive disorders are common in later life, even if often undiagnosed or mis-diagnosed in old age. When untreated, depression reduces life expectancy, worsens medical illnesses, enhances health care costs and is the primary cause of suicide among older people. To date, the underpinnings of depression in the elderly are still to be understood, and the pharmacological treatment is the most commonly used therapy. Objective: Since a sedentary lifestyle and poor eating habits have recently emerged as crucial contributors to the genesis and course of depression, in the present review, we have focused on the effects of physical activity and omega-3 fatty acids on depressive illness in the elderly. Results: A growing literature indicates that both exercise and dietary interventions can promote mental health throughout one's lifespan. Conclusion: There thus emerges the awareness that an active lifestyle and a balanced diet may constitute valid low-cost prevention strategies to counteract depressive illness in the elderly.

Gene-environment interactions (GxE) can have lasting consequences on brain structure and function, potentially contributing to diverse neuropsychiatric phenotypes. This has been extensively demonstrated by studies examining GxE in childhood and early adulthood, whereas much fewer studies have addressed this question in late life. The relative paucity of studies examining GxE in late life may stem from the working hypothesis that brains become less malleable to environmental inputs as life progresses. However, while some components of brain plasticity decline with increasing age, others are retained and may even become more pronounced in old ages. Moreover, the micro- and macro-structural brain changes that accrue as a result of aging-related morbidities are likely to accentuate the susceptibility of neural circuits to environmental stressors as life advances. Supporting this hypothesis, psychosocial stress can increase the risk for late-life neuropsychiatric syndromes, especially when afflicting genetically predisposed individuals. This article reviews evidence showing how gene-stress interactions can impact the aging brain and related phenotypes in late life, and it discusses the potential mechanisms underlying such GxE and their implications for the prevention and treatment of late-life neuropsychiatric syndromes.