Robert Sapolsky

Stanford Medicine | Stanford · Department of Biological Sciences

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...

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...

Social subordination induces proinflammatory gene expression profiles

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 u...

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...

It is a truism that the brain influences the body and that peripheral physiology influences the brain. Never is this clearer than during stress, where the subtlest emotions or the most abstract thoughts can initiate stress responses, with consequences throughout the body, and the endocrine transducers of stress alter cognition, affect and behavior....

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 b...

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. gondi...

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...

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 i...

The protozoan Toxoplasma gondii (T.gondii) manipulates the behavior of its rodent intermediate host to facilitate its passage to its feline definitive host. This is accomplished by a reduction of the aversive response that rodents show towards cat odors, which likely increases the predation risk. Females on average show similar changes as males. Ho...

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We...

Performance on many memory tests varies across the day and is severely impaired by disruptions in circadian timing. We developed a noninvasive method to permanently eliminate circadian rhythms in Siberian hamsters (Phodopussungorus) so that we could investigate the contribution of the circadian system to learning and memory in animals that are neur...

Norway rat pups were either handled (H) or undisturbed (nonhandled, NH) in the period between birth and weaning on Day 21. Following weaning, half of the animals in each group were housed socially (Soc), and half were housed in isolation (Isol). At 120-150 days of age, all animals were sacrificed, and the following regions were dissected and frozen...

Attention has long been focused on the relationship between stress and aging, both under the guise of stress as an accelerator of normal aging and of aging as a time of impaired ability to cope with stress. This review examines the considerable amount of evidence in support of these views. We address these ideas with respect to glucocorticoids, the...

Protein kinases Akt1 and Akt3 are considered to be more crucial to brain function than Akt2. We investigated the roles of Akt1 and Akt3 in stroke-induced brain injury and examined their interactions with the Akt/mTOR pathways. Focal ischemia was induced in rats. Lentiviral vectors expressing constitutively active Akt1 and Akt3 (cAkt1 and cAkt3) wer...

Inflammation is a major factor in the progression of damage after stroke and in the clinic, current therapies treat the clot, not the resulting damage. We have developed a novel method of protein delivery that exploits the migration ability of leukocytes after ischemic stroke (transient middle cerebral artery occlusion; tMCAO). In our studies, ex v...

Glucocorticoid stress hormones (GCs) are well known for being anti-inflammatory, but some reports suggest that GCs can also augment aspects of inflammation during acute brain injury. Because the GC receptor (GR) is ubiquitously expressed throughout the brain, it is difficult to know which cell types might mediate these unusual "proinflammatory" GC...

Research with experimental stroke models has identified a wide range of therapeutic proteins that can prevent the brain damage caused by this form of acute neurological injury. Despite this, we do not yet have safe and effective ways to deliver therapeutic proteins to the injured brain, and this remains a major obstacle for clinical translation. Cu...

Relative in vitro T cell stimulatory capacity of optimized, transgene loaded-DCs. DCs derived from adult rat bone marrow using standard methods (adult) or from pup bone marrow using the modified method (pup) were tested for their ability to stimulate T cell proliferation in a mixed leukocyte reaction (MLR). LPS-treated DCs were used as a positive c...

Quantification of ischemic damage following treatment with protein-loaded DCs. (A) Quantification of infarct area for each treatment group, expressed as the percent damage/total hemisphere area. * indicates significance by two-tailed t-test, P = 0.034. Error bars denote SEM. n = 14, 15, 15, 17 for vehicle, GFP-DCs, hBDNF-DCs, and tBH4-DCs, respecti...

Mass spectrometry analysis of standard and modified DC cultures. (XLS)

Plasmid map for lentiviral backbone, pHR-IG, and transgene inserts. Plasmid features are indicated with arrows. Abbreviations: CMV = cytomegalovirus; MCS = multiple cloning site; IRES = internal ribosomal entry site; eGFP = enhanced green fluorescent protein; LTR = long terminal repeat; amp R = ampicillin resistance gene; pUC = origin of replicatio...

Immunofluorescent staining of GFP-positive cells at the tMCAO lesion site. (A) Confocal fluorescent micrographs of anti-GFP staining in the ischemic hemisphere 6 h post-tMCAO and 3 h post-DC infusion. (B) GFP-positive cells at the lesion site 3 h post-cell infusion co-labeled and overlayed with CD11c or MHC class II (OX6). Nuclei are counterstained...

Identification of in vitro and in vivo parameters found to influence the injury-homing capacity of cultured DCs. (A) Schematic indicating the brain regions shown in (B) and (C). (B) Representative fluorescent micrograph showing low injury-homing capacity to the tMCAO-lesioned cortex at 6 h post-injury, 3 h post-cell infusion. (C) Representative flu...

Flow cytometric analysis of bone marrow-derived DC cultures treated with LPS. Representative histograms showing mean fluorescent intensity (x-axis) vs. percentage of gated cells (y-axis) for OX42, CD11c, MHC class II (OX6), CD80, CCR2, and VLA-4 for 7-day-old DC cultures. Black lines correspond to fluorescent signal from isotype controls. Blue line...

In vivo bioluminescent tracking of luciferase-transduced DCs. Representative images of 2 rats infused with luciferase-DCs 3 h post-tMCAO and imaged at 3 h and again at 24 h post-DC infusion. For each rat/imaging time point, adjacent dorsal and ventral views are displayed. Rat number and imaging time post-DC infusion is indicated in the top of each...

Relative neurotoxicity of transduced DCs in vitro. Quantification of rat primary cortical neuron survival 24 h after exposure to increasing doses of (A) DCs transduced with LV-GFP or (B) DCs transduced with LV-hBDNF. *** P<0.001; * P<0.05 by one-way ANOVA and Tukey post-hoc analysis. n = 48 wells for 0 and 1000; n = 6 wells for 500; n = 18 wells fo...

Supporting Materials and Methods. (DOC)

Have humans always waged war? Is warring an ancient evolutionary adaptation or a relatively recent behavior—and what does that tell us about human nature? This book brings together experts in evolutionary biology, archaeology, anthropology, and primatology to answer fundamental questions about peace, conflict, and human nature in an evolutionary co...

Toxoplasma gondii (T. gondii) is one of the world’s most successful brain parasites. T. gondii engages in parasite manipulation of host behavior and infection has been epidemiologically linked to numerous psychiatric disorders. Mechanisms by which T. gondii alters host behavior are not well understood, but neuroanatomical cyst presence and the loca...

It has been known for decades that wild baboons are naturally infected with Treponema pallidum, the bacterium that causes the diseases syphilis (subsp. pallidum), yaws (subsp. pertenue), and bejel (subsp. endemicum) in humans. Recently, a form of T. pallidum infection associated with severe genital lesions has been described in wild baboons at Lake...

Treponema paraluiscuniculi is identical to Treponema denticola ATCC 35405 at five informative genetic sites, while T. pallidum subsp. pallidum is identical to T. denticola at none. (DOCX)

Pathological anxiety is thought to reflect a maladaptive state characterized by exaggerated fear. Naturally occurring perturbations that reduce fear can be crucial in the search for new treatments. The protozoan parasite Toxoplasma gondii invades rat brain and removes fear of rats for cat odors, a change believed to be parasitic manipulation of hos...

Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum...

I write amid the frenzy of the September campaign season, when the airways are filled with politicians saying the same thing: They are willing to sacrifice themselves, to take on the terrible burdens of power and privilege, just to help us all. Alas, these individuals seem to have a certain outdated view about the physiological correlates of leader...

Our drive to exceed our evolutionary limits sets us apart from other beasts

Innate behaviors are shaped by contingencies built during evolutionary history. On the other hand, environmental stimuli play a significant role in shaping behavior. In particular, a short period of environmental enrichment can enhance cognitive behavior, modify effects of stress on learned behaviors and induce brain plasticity. It is unclear if mo...

Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have be...

Background and Objective: Akt is a serine-threonine kinase that plays critical role in promoting cell survival. Akt consists of three isoforms (Akt1, 2, 3), with Akt3 predominantly expressed in the brain. Although Akt pathway has been shown to mediate neuronal survival in cerebral ischemic injury, it is unclear how these Akt isoforms contribute to...

Females in various species typically avoid males infected with parasites, while parasite-free males advertise their status through conspicuous phenotypic traits. This process selects for heritable resistance and reduces direct exposure of the female to parasites. Coevolving parasites are likely to attempt to circumvent this obstacle. In this paper,...

Linear dominance hierarchies are thought to form within groups of social animals to minimize conflict over access to resources. Dominance in both male and female African elephants (Loxodonta africana) is based mostly on intrinsic factors relating to age, and dominance hierarchies have been described within and between family groups of females. Very...

(DOC)

Toxoplasma Alters Volumes and c-Fos Expression of Limbic Regions Involved in Processing Cat Odor. (A) Schematic diagram (adapted from Paxinos and Watson 2007) of coronal slices of rat brain showing areas of c-Fos and volume quantification. (B) Volumes of amygdalar and hypothalamic regions of interest in uninfected and Toxoplasma-infected animals. C...

Density of c-Fos positive cells (mean ± SEM). (PDF)

Cat odors induce rapid, innate and stereotyped defensive behaviors in rats at first exposure, a presumed response to the evolutionary pressures of predation. Bizarrely, rats infected with the brain parasite Toxoplasma gondii approach the cat odors they typically avoid. Since the protozoan Toxoplasma requires the cat to sexually reproduce, this chan...

Are alpha male baboons more stressed than other high-ranking males?

Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contr...

A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causi...

Hormones seem to play important roles in the regulation of human aggression. Multiple studies have confirmed that testosterone (T) levels exhibit complex relationships with aggression, dominance, and/or risk-taking behavior. Some evidence suggests that cortisol (CORT) interacts with T and may also be associated with aspects of mood and aggression....

Gene therapy has demonstrated the protective potential of a variety of genes against stroke. However, conventional gene therapy vectors are limited due to the inability to temporally control their expression, which can sometimes lead to deleterious side effects. Thus, an inducible vector that can be temporally controlled and activated by the insult...

The sections in this article are:

Although the anti-inflammatory actions of glucocorticoids (GCs) are well established, evidence has accumulated showing that proinflammatory GC effects can occur in the brain, in a poorly understood manner. Using electrophoretic mobility shift assay, real-time PCR, and immunoblotting, we investigated the ability of varying concentrations of corticos...

Successful treatment of fear and anxiety disorders is presently a difficult task. A major limitation is the fact that underlying physiological mechanisms of fear and anxiety are only now beginning to be understood. As we obtain more information about mechanisms and brain circuits involved, treatment of these conditions will become increasingly real...

Politically aggressive militant groups usually rely on support from a larger community, although evidence suggests that only some members of that larger community support that aggression. A major subtype of political aggression is that associated with religious differences--or Religio-Political Aggression (RPA). Little previous research has explore...

Viral vectors bearing protective transgenes can decrease neurotoxicity after varied necrotic insults. A neuron that dies necrotically releases glutamate, calcium and reactive oxygen species, thereby potentially damaging neighboring neurons. This raises the possibility that preventing such neuron death via gene therapy can secondarily protect neighb...

The behavioural manipulation hypothesis posits that parasites can change the behaviour of hosts to increase the reproductive fitness of the parasite. The protozoan parasite Toxoplasma gondii fits this description well. Sexual reproduction occurs in the cat intestine, from which highly stable oocysts are excreted in faeces. Grazing animals, includin...

The basolateral amygdala is critical for generating anxiety, and exposure to glucocorticoids induces anxiety. The demonstrated ability of glucocorticoids to cause dendritic expansion and increase excitability in the amygdala could help mediate the behavioral effects of glucocorticoids, and thus may be important therapeutic target for anxiety. In co...

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading en...

Increasingly, it has become the case that the leading diseases of westernized life are ones that can be worsened by stress, particularly psychosocial stress. As such, an understanding of individual differences in vulnerability to stress-related disease is critical. This article explores the fact that it is not only essential to understand stress-re...

Stress, particularly in the form of chronic psychosocial stressors, can have pathogenic effects throughout the body. As a facet of this, stress, via excessive release of the adrenal steroid hormone glucocorticoids (GCs), can have adverse neurobiological effects. These are centered in the hippocampus, a primary GC target in the brain, and include di...

During early development, rats show the unlikely behavior of becoming attracted to the very stimulus that they should avoid. A new study shows that this occurs as a result of a complex interplay of glucocorticoid secretion and dopaminergic tone in the amygdala.

Neuronal apoptosis following ischemia can be mediated by a caspase-dependent pathway, which involves the mitochondrial release of cytochrome c that initiates a cascade of caspase activation. In addition, there is a caspase-independent pathway, which is mediated by the release of apoptosis-inducing factor (AIF). Using caspase inhibitor gene therapy,...

NAP (NAPVSIPQ, generic name, davunetide), a neuroprotective peptide in clinical development for neuroprotection against Alzheimer's disease and other neurodegenerative indications, has been recently shown to provide protection against kainic acid excitotoxicity in hippocampal neuronal cultures. In vivo, kainic acid toxicity models status epilepticu...

Glucocorticoids (GCs) are hormones released during the stress response that are well known for their immunosuppressive and anti-inflammatory properties; however, recent advances have uncovered situations wherein they have effects in the opposite direction. The CNS is a particularly interesting example, both because of its unique immune environment,...

Individual differences in coping response lie at the core of vulnerability to conditions like post-traumatic stress disorder (PTSD). Like humans, not all animals exposed to severe stress show lasting change in affect. Predator stress is a traumatic experience inducing long-lasting fear, but not in all rodents. Thus, individual variation may be a cr...

Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the ex...

NAPVSIPQ (NAP), an 8 amino acid peptide derived from activity-dependent neuroprotective protein (ADNP), provides neuroprotection through interaction with microtubules. Previous results have demonstrated NAP protection against oxygen-glucose deprivation in hippocampal cells in culture. Furthermore, in vivo studies have shown that NAP reduces caspase...

The ability to discriminate between spatial contexts is crucial for survival. This ability can be succinctly tested in the paradigm of fear renewal. In this paradigm, a change of spatial context results in robust renewal of conditioned fear, even if the conditioned fear has been previously extinguished. Chronic stress and environmental enrichment a...

The amygdala plays a critical role in the development of anxiety and the regulation of stress hormone secretion. Reciprocally, stress and stress hormones can induce amygdala hypertrophy, a phenomenon related to enhanced anxiety. As such, modulating amygdaloid function can potentially reduce maladaptive features of the stress response. The amygdala...

The peptide NAP (NAPVSIPQ) was shown to protect neurons against a wide variety of insults. Particularly, NAP was shown to be neuroprotective in vitro against cyanide in hippocampal cultures and against oxygen-glucose deprivation in hippocampal and cortical neuronal cultures. Cyanide causes energy depletion in the cell and destroys the cytoskeleton,...

Apoptosis arises from neuronal damage following an ischemic insult. Apoptosis-inducing factor (AIF) is a protein released from mitochondria in response to pro-apoptotic signals which then translocates to the nucleus and triggers DNA fragmentation. In parallel with this, pro-apoptotic signals cause the release of cytochrome c from mitochondria, acti...

Fear arousal, initiated by an environmental threat, leads to activation of the stress response, a state of alarm that promotes an array of autonomic and endocrine changes designed to aid self-preservation. The stress response includes the release of glucocorticoids from the adrenal cortex and catecholamines from the adrenal medulla and sympathetic...

The basolateral amygdala is critical for generation of anxiety. In addition, exposure to both stress and glucocorticoids induces anxiety. Demonstrated ability of the amygdala to change in response to stress and glucocorticoids could thus be important therapeutic target for anxiety management. Several studies have reported a relationship between anx...

Decades of studies have shown that eliminating circadian rhythms of mammals does not compromise their health or longevity in the laboratory in any obvious way. These observations have raised questions about the functional significance of the mammalian circadian system, but have been difficult to address for lack of an appropriate animal model. Surg...

The basolateral complex of the amygdala (BLA) is uniquely affected by steroid hormones. Whereas glucocorticoids (GCs)--the adrenal hormones released during stress--increase the excitability of BLA neurons, estrogen decreases it. In this study, we used a vector designed to express a chimeric gene that contains the GC-binding domain of the GC recepto...

It is well established that mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) influence hippocampal-dependent spatial memory. MRs are saturated in the presence of low corticosterone (CORT) levels; consequently receptor protein levels play a rate-limiting role in regulating the positive effects of MR-mediated gene transcription. I...