Making sense of the costs of adversity throughout the lifespan on aging in humans and other animals.

Social adversity, particularly early in life, can cause lifelong damage to health; by now, numerous studies examine this relationship in non-human species, producing some important themes: A) Captive animals readily lack ethological validity, giving a special place to studies of natural populations; one must appreciate though, that animal studies typically benefit humans who themselves lack ecological validity, namely Westernized subjects. B) Animal studies of the links between social adversity and psychiatric maladies potentially produce anthropomorphism; however, long-term study of our closest relatives demonstrates how convincingly another primate can, for example, experience grief, rather than display "grief-like" behavior. C) Are long-term consequences of social adversity best viewed as maladaptive and pathological, or as adaptive preparation for similar adversity later in life?; the growing literature casts light on when adversity's consequences are the purview of medicine or natural history. D) Studies examining sustained adversity and aging can increasingly distinguish between aging versus diseases of aging or cohort effects, and between aging effects arising from direct physiological mechanisms or indirect behavioral ones.

2022 ISPNE Bruce McEwen Lifetime Achievement award: Stress, from molecules to societies.

The International Society for Psychoneuroendocrinology meeting in Chicago in 2022 was thrilled to recognize Dr. Robert Sapolsky with the Bruce McEwen Lifetime Achievement award. This is the second year for the award to be named to honor Bruce McEwen and it marks the completion of a special issue edited by Blazej Miziak and Robert Paul Juster in the journal Psychoneuroendocrinology dedicated to Bruce's legacy and the unfathomable contribution of Allostatic Load to the stress field. Yet, as our award winner writes, Bruce's legacy is more than scientific as he was well known for mentorship and being an exemplary person, theorist, and scientist. Perhaps understandably for a career favored by humble introverts and shy reclusives, the science shines in the spotlight and personal reflections are cut to accommodate word count limits. For scholars entering the field, stargazing at larger than life luminaries in the field is thrilling yet intimidating as it feels impossible that these experts have the same doubts and distractions as the rest of us primates. Thus, Psychoneuroendocrinology is thrilled to kick off the first perspectives piece in the Cell to Selves series with Dr. Robert Sapolsky sharing that, like his Baboon troops in Kenya, he too sometimes has a bad-hair day. This paper is a written version of a lecture I gave on September 8th, 2022, when receiving the first Bruce McEwen Lifetime Achievement Award from the ISPNE. This was a bittersweet honor; Bruce was my graduate advisor at Rockefeller University and over the next forty years, he was my mentor, teacher and father figure. His death in 2020 left a hole in my life.

Glucocorticoids, the evolution of the stress-response, and the primate predicament.

The adrenocortical stress-response is extraordinarily conserved across mammals, birds, fish, reptiles, and amphibians, suggesting that it has been present during the hundreds of millions of years of vertebrate existence. Given that antiquity, it is relatively recent that primate social complexity has evolved to the point that, uniquely, life can be dominated by chronic psychosocial stress. This paper first reviews adrenocortical evolution during vertebrate history. This produces a consistent theme of there being an evolutionary tradeoff between the protective effects of glucocorticoids during an ongoing physical stressor, versus the adverse long-term consequences of excessive glucocorticoid secretion; how this tradeoff is resolved depends on particular life history strategies of populations, species and vertebrate taxa. This contrasts with adrenocortical evolution in socially complex primates, who mal-adaptively activate the classic vertebrate stress-response during chronic psychosocial stress. This emphasizes the rather unique and ongoing selective forces sculpting the stress-response in primates, including humans.

The Jaw Epidemic: Recognition, Origins, Cures, and Prevention.

Contemporary humans are living very different lives from those of their ancestors, and some of the changes have had serious consequences for health. Multiple chronic "diseases of civilization," such as cardiovascular problems, cancers, ADHD, and dementias are prevalent, increasing morbidity rates. Stress, including the disruption of traditional sleep patterns by modern lifestyles, plays a prominent role in the etiology of these diseases, including obstructive sleep apnea. Surprisingly, jaw shrinkage since the agricultural revolution, leading to an epidemic of crooked teeth, a lack of adequate space for the last molars (wisdom teeth), and constricted airways, is a major cause of sleep-related stress. Despite claims that the cause of this jaw epidemic is somehow genetic, the speed with which human jaws have changed, especially in the last few centuries, is much too fast to be evolutionary. Correlation in time and space strongly suggests the symptoms are phenotypic responses to a vast natural experiment-rapid and dramatic modifications of human physical and cultural environments. The agricultural and industrial revolutions have produced smaller jaws and less-toned muscles of the face and oropharynx, which contribute to the serious health problems mentioned above. The mechanism of change, research and clinical trials suggest, lies in orofacial posture, the way people now hold their jaws when not voluntarily moving them in speaking or eating and especially when sleeping. The critical resting oral posture has been disrupted in societies no longer hunting and gathering. Virtually all aspects of how modern people function and rest are radically different from those of our ancestors. We also briefly discuss treatment of jaw symptoms and possible clinical cures for individuals, as well as changes in society that might lead to better care and, ultimately, prevention.

Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more.

The authors highlight, from a firsthand perspective, Bruce S. McEwen's seminal influence on the field of stress neurobiology and beyond, and how these investigations have yielded important insights, principles and critical questions that continue to guide stress research today. Featured are discussion of: 1) the important inverted-U relationship between stress/glucocorticoids and optimal physiological function, 2) stress adaptation and the role of adaptive stress responses, 3) mechanisms by which the short-term stress response promotes heightened immune function and immunity, and 4) the far reaching impact of the theoretical framework of allostasis and allostatic load-concepts that have created new bridges between stress physiology, biomedical sciences, health psychology and sociology.

Adult-generated neurons born during chronic social stress are uniquely adapted to respond to subsequent chronic social stress.

Chronic stress is a recognized risk factor for psychiatric and psychological disorders and a potent modulator of adult neurogenesis. Numerous studies have shown that during stress, neurogenesis decreases; however, during the recovery from the stress, neurogenesis increases. Despite the increased number of neurons born after stress, it is unknown if the function and morphology of those neurons are altered. Here we asked whether neurons in adult mice, born during the final 5 days of chronic social stress and matured during recovery from chronic social stress, are similar to neurons born with no stress conditions from a quantitative, functional and morphological perspective, and whether those neurons are uniquely adapted to respond to a subsequent stressful challenge. We observed an increased number of newborn neurons incorporated in the dentate gyrus of the hippocampus during the 10-week post-stress recovery phase. Interestingly, those new neurons were more responsive to subsequent chronic stress, as they showed more of a stress-induced decrease in spine density and branching nodes than in neurons born during a non-stress period. Our results replicate findings that the neuronal survival and incorporation of neurons in the adult dentate gyrus increases after chronic stress and suggest that such neurons are uniquely adapted in the response to future social stressors. This finding provides a potential mechanism for some of the long-term hippocampal effects of stress.

Speculations on the Evolutionary Origins of System Justification.

For centuries, philosophers and social theorists have wondered why people submit voluntarily to tyrannical leaders and oppressive regimes. In this article, we speculate on the evolutionary origins of system justification, that is, the ways in which people are motivated (often nonconsciously) to defend and justify existing social, economic, and political systems. After briefly recounting the logic of system justification theory and some of the most pertinent empirical evidence, we consider parallels between the social behaviors of humans and other animals concerning the acceptance versus rejection of hierarchy and dominance. Next, we summarize research in human neuroscience suggesting that specific brain regions, such as the amygdala and the anterior cingulate cortex, may be linked to individual differences in ideological preferences concerning (in)equality and social stability as well as the successful navigation of complex, hierarchical social systems. Finally, we consider some of the implications of a system justification perspective for the study of evolutionary psychology, political behavior, and social change.

The mTOR cell signaling pathway is crucial to the long-term protective effects of ischemic postconditioning against stroke.

Ischemic postconditioning (IPostC) protects against stroke, but few have studied the pathophysiological mechanisms of its long-term protective effects. Here, we investigated whether the mTOR pathway is involved in the long-term protective effects of IPostC. Stroke was induced in rats by distal middle cerebral artery occlusion (dMCAo) combined with 30 min of bilateral common carotid artery (CCA) occlusion, and IPostC was induced after the CCA release. Injury size and behavioral tests were measured up to 3 weeks post stroke. We used rapamycin and mTOR shRNA lentiviral vectors to inhibit mTOR activities, while S6K1 viral vectors, a main downstream mTOR gene, were used to promote mTOR activities. We found that rapamycin administration abolished the long-term protective effects of IPostC. In addition, IPostC promoted the presynaptic growth associated protein 43 (GAP-43) and the postsynaptic protein 95 (PSD-95) levels at 1 week post-stroke, which were reduced by rapamycin. Furthermore, rapamycin reduced phosphorylated mTOR (p-mTOR) protein levels measured at 3 weeks after stroke. These results were confirmed by mTOR shRNA transfection. Moreover, we found that injection of S6K1 viral vectors promoted GAP-43 and PSD-95 protein levels. We conclude that mTOR may play a crucial, protective role in brain damage after stroke and contribute to the protective effects of IPostC.

Doubled-Edged Swords in the Biology of Conflict.

Considerable advances have been made in understanding the biological roots of conflict, and such understanding requires a multidisciplinary approach, recognizing the relevance of neurobiological, endocrine, genetic, developmental, and evolutionary perspectives. With these insights comes the first hints of biological interventions that may mitigate violence. However, such interventions are typically double-edged swords, with the potential to foster conflict rather than lessen it. This review constitutes a cautionary note of being careful of what one wishes for.

Psychiatric distress in animals versus animal models of psychiatric distress.

The realm of human uniqueness steadily shrinks; reflecting this, other primates suffer from states closer to depression or anxiety than 'depressive-like' or 'anxiety-like behavior'. Nonetheless, there remain psychiatric domains unique to humans. Appreciating these continuities and discontinuities must inform the choice of neurobiological approach used in studying any animal model of psychiatric disorders. More fundamentally, the continuities reveal how aspects of psychiatric malaise run deeper than our species' history.

Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors.

BACKGROUND: Despite strong evidence linking fibroblast growth factor 2 (FGF2) with anxiety and depression in both rodents and humans, the molecular mechanisms linking FGF2 with anxiety are not understood. METHODS: We compare 1) mice that lack a functional Fgf2 gene (Fgf2 knockout [KO]), 2) wild-type mice, and 3) Fgf2 KO with adult rescue by FGF2 administration on measures of anxiety, depression, and motor behavior, and further investigate the mechanisms of this behavior by cellular, molecular, and neuroendocrine studies. RESULTS: We demonstrate that Fgf2 KO mice have increased anxiety, decreased hippocampal glucocorticoid receptor (GR) expression, and increased hypothalamic-pituitary-adrenal axis activity. FGF2 administration in adulthood was sufficient to rescue the entire phenotype. Blockade of GR in adult mice treated with FGF2 precluded the therapeutic effects of FGF2 on anxiety behavior, suggesting that GR is necessary for FGF2 to regulate anxiety behavior. The level of Egr-1/NGFI-A was decreased in Fgf2 KO mice and was reestablished with FGF2 treatment. By chromatin immunoprecipitation studies, we found decreased binding of EGR-1 to the GR promoter region in Fgf2 KO mice. Finally, we examined anxiety behavior in FGF receptor (FGFR) KO mice; however, FGFR1, FGFR2, and FGFR3 KO mice did not mimic the phenotype of Fgf2 KO mice, suggesting a role for other receptor subtypes (i.e., FGFR5). CONCLUSIONS: These data suggest that FGF2 levels are critically related to anxiety behavior and hypothalamic-pituitary-adrenal axis activity, likely through modulation of hippocampal glucocorticoid receptor expression, an effect that is likely receptor mediated, albeit not by FGFR1, FGFR2, and FGFR3.

Reducing social stress elicits emotional contagion of pain in mouse and human strangers.

Empathy for another's physical pain has been demonstrated in humans [1] and mice [2]; in both species, empathy is stronger between familiars. Stress levels in stranger dyads are higher than in cagemate dyads or isolated mice [2, 3], suggesting that stress might be responsible for the absence of empathy for the pain of strangers. We show here that blockade of glucocorticoid synthesis or receptors for adrenal stress hormones elicits the expression of emotional contagion (a form of empathy) in strangers of both species. Mice and undergraduates were tested for sensitivity to noxious stimulation alone and/or together (dyads). In familiar, but not stranger, pairs, dyadic testing was associated with increased pain behaviors or ratings compared to isolated testing. Pharmacological blockade of glucocorticoid synthesis or glucocorticoid and mineralocorticoid receptors enabled the expression of emotional contagion of pain in mouse and human stranger dyads, as did a shared gaming experience (the video game Rock Band) in human strangers. Our results demonstrate that emotional contagion is prevented, in an evolutionarily conserved manner, by the stress of a social interaction with an unfamiliar conspecific and can be evoked by blocking the endocrine stress response.

Toxoplasma gondii is dependent on glutamine and alters migratory profile of infected host bone marrow derived immune cells through SNAT2 and CXCR4 pathways.

The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both "hypermotility" and "enhanced migration" to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium-dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF-1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility.

Glucocorticoids increase excitotoxic injury and inflammation in the hippocampus of adult male rats.

BACKGROUND/AIMS: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. METHODS: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether nonsteroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (1) chemokine production (CCL2 and CINC-1), (2) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-ß), and (3) NF-κB activity. RESULTS: Concurrent treatment with minocycline, but not indomethacin, prevented GC endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-κB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus - factors that normally restrain inflammatory responses. CONCLUSIONS: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part by increasing the neurotoxicity of CNS inflammation.

Mammalian target of rapamycin cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke.

BACKGROUND AND PURPOSE: Whether the mammalian target of rapamycin (mTOR) pathway is protective against brain injury from stroke or is detrimental is controversial, and whether it is involved in the protective effects of ischemic postconditioning (IPC) against stroke is unreported. Our study focuses on the protective role of mTOR against neuronal injury after stroke with and without IPC. METHODS: We used both an in vitro oxygen-glucose deprivation model with a mixed neuronal culture and hypoxic postconditioning, as well as an in vivo stroke model with IPC. Rapamycin, a specific pharmacological inhibitor of mTOR, and mTOR short hairpin RNA lentiviral vectors were used to inhibit mTOR activity. A lentiviral vector expressing S6K1, a downstream molecule of mTOR, was used to confirm the protective effects of mTOR. Infarct sizes were measured and protein levels were examined by Western blot. RESULTS: We report that stroke resulted in reduced levels of phosphorylated proteins in the mTOR pathway, including S6K1, S6, and 4EBP1, and that IPC increased these proteins. mTOR inhibition, both by the mTOR inhibitor rapamycin and by mTOR short hairpin RNA, worsened ischemic outcomes in vitro and in vivo and abolished the protective effects of hypoxic postconditioning and IPC on neuronal death in vitro and brain injury size in vivo. Overexpression of S6K1 mediated by lentiviral vectors significantly attenuated brain infarction. CONCLUSIONS: mTOR plays a crucial protective role in brain damage after stroke and contributes to the protective effects of IPC.