Neurobiology of resilience

May combine two claims.

In the chronic social defeat stress paradigm, the firing rate of ventral tegmental area dopamine neurons is normal in resilient animals and increased in susceptible animals.

“Our initial analysis showed that the firing rate of VTA dopamine neurons was normal in resilient animals and increased in susceptible animals”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

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May combine two claims.

Sub-chronic unpredictable stress induces anhedonia, increased immobility on the forced swim test, and increased anxiety in rodents.

“sub–chronic unpredictable stress induces anhedonia (decreased sucrose preference), increased immobility on the forced swim test, and increased anxiety (greater latency to feed in a novel environment and decreased time grooming in the splash test).”

• cites [85] LaPlant, Q. et al. Role of nuclear factor κB in ovarian hormone-mediated stress hypersensitivity in female mice. Biol. Psychiatry 65, 874–880 (2009). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Elevated DHEA has been linked to increased suicidality in male veterans with PTSD.

“a contrary report linked elevated DHEA to increased suicidality in male veterans with PTSD11”

• cites [11] Butterfield, M.I. et al. Neuroactive steroids and suicidality in posttraumatic stress disorder. Am. J. Psychiatry 162, 380–382 (2005). sourceNot checked yet

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May combine two claims.

Stress exposure and adverse life events are important risk factors for both MDD and PTSD.

“stress exposure and adverse life events are important risk factors for both disorders.”

May combine two claims.

Stress resilience in animals is mediated both by the absence of molecular abnormalities found in susceptible animals and by novel molecular adaptations unique to resilient individuals.

“such resilience—the ability to avoid deleterious behavioral changes in response to chronic stress—is mediated not only by the absence of key molecular abnormalities which occur in susceptible animals to impair their coping ability, but also by the presence of novel molecular adaptations which occur uniquely in resilient individuals to help promote normal behavioral function.”

May combine two claims.

Elevated blood glucocorticoid levels are reported in roughly two-thirds of individuals with MDD, while a smaller subset shows reduced levels and less severe symptoms.

“Numerous studies have reported elevated blood glucocorticoid levels in roughly two–thirds of individuals with MDD, although a smaller subset of depressed individuals show reduced glucocorticoid levels and typically display less severe symptoms4.”

• cites [4] Stetler, C. & Miller, G.E. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom. Med. 73, 114–126 (2011). sourceNot checked yet

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Testosterone increases in winners after athletic competition in both men and women, and athletes with highest saliva testosterone have higher team rankings.

“In both men and woman, testosterone increases in “winners” following an athletic competition and, on average, athletes with the highest saliva testosterone levels have higher rankings within the team13.”

• cites [13] Oliveira, T., Gouveia, M.J. & Oliveira, R.F. Testosterone responsiveness to winning and losing experiences in female soccer players. Psychoneuroendocrinology 34, 1056–1064 (2009). sourceNot checked yet

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Testosterone levels are positively correlated with social connectedness with teammates and greater feelings of personal success and dominance.

“Testosterone levels are also positively correlated with the degree of social connectedness with teammates, greater feelings of personal success and dominance14.”

• cites [14] Edwards, D.A., Wetzel, K. & Wyner, D.R. Intercollegiate soccer: saliva cortisol and testosterone are elevated during competition, and testosterone is related to status and social connectedness with team mates. Physiol. Behav. 87, 135–143 (2006). sourceNot checked yet

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Blood DHEA increases under acute stress, and higher DHEA or DHEA-to-cortisol ratio is associated with less dissociative symptoms and superior performance in military survival training.

“Reports have shown that blood DHEA levels increase under acute stress and that a higher level of DHEA, or a higher DHEA to cortisol ratio, is associated with less dissociative symptoms and superior performance in healthy subjects undergoing military survival training9.”

• cites [9] Rasmusson, A.M., Vythilingam, M. & Morgan, C.A. III. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr. 8, 651–656, 665–667 (2003). sourceNot checked yet

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In PTSD, DHEA levels are elevated but higher levels correlate with symptom improvement and better coping, while lower DHEA-to-cortisol ratio correlates with greater PTSD symptom severity.

“a separate study found that DHEA levels were elevated in PTSD but that higher levels were correlated with symptom improvement and better coping while a lower DHEA to cortisol ratio was positively correlated with the severity of PTSD symptoms10.”

• cites [10] Yehuda, R., Brand, S.R., Golier, J.A. & Yang, R.K. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr. Scand. 114, 187–193 (2006). sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

DHEA responses to ACTH are elevated in PTSD and negatively correlated with symptom severity, suggesting DHEA release during stress may buffer PTSD severity.

“It has been reported that DHEA responses to adrenocorticotropic hormone (ACTH) were elevated in PTSD and negatively correlated with the severity of symptoms, suggesting that DHEA release during stress may buffer the severity of PTSD 9.”

• cites [9] Rasmusson, A.M., Vythilingam, M. & Morgan, C.A. III. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr. 8, 651–656, 665–667 (2003). sourceNot checked yet

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Hypocortisolemia has been widely reported in PTSD, but findings are mixed.

“Hypocortisolemia has also been reported widely in PTSD; however, here too the findings have been mixed5.”

• cites [5] Meewisse, M.L., Reitsma, J.B., de Vries, G.J., Gersons, B.P. & Olff, M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br. J. Psychiatry 191, 387–392 (2007). sourceNot checked yet

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Increased CSF CRH levels are documented in adults with a history of childhood abuse and do not always correlate with development of MDD or PTSD.

“Increased cerebrospinal fluid levels of corticotropin releasing hormone (CRH) have been documented more generally in adults who report a history of childhood abuse6, and thus does not always correlate with the development of MDD or PTSD7, 8.”

• cites [6] Heim, C., Newport, D.J., Mletzko, T., Miller, A.H. & Nemeroff, C.B. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33, 693–710 (2008). sourceNot checked yet

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• cites [7] Heim, C., Newport, D.J., Miller, A.H. & Nemeroff, C.B. Long-term neuroendocrine effects of childhood maltreatment. J. Am. Med. Assoc. 284, 2321 (2000). sourceNot checked yet

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• cites [8] Yehuda, R., Golier, J.A. & Kaufman, S. Circadian rhythm of salivary cortisol in Holocaust survivors with and without PTSD. Am. J. Psychiatry 162, 998–1000 (2005). sourceNot checked yet

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Classified as probably not a substantial claim.

The ability to avoid deleterious consequences of chronic stress depends on both passive and active resilience mechanisms.

“The ability to avoid such deleterious consequences of stress in turn depends on both passive and active resilience mechanisms.”

May combine two claims.

Cohen et al. used predator odor stress and classified rats into three equal groups: extremely, partially, or minimally disrupted, based on behavioral deficits and brain NPY changes.

“Cohen et al.23 recently utilized a predator odor to induce a stress response and then classified rats into 3 groups; one-third each that was extremely disrupted, partially disrupted, or minimally disrupted. The classifications were based largely on the number and type of behavioral deficits and the degree of change in brain NPY levels.”

• cites [23] Cohen, H. et al. The neuropeptide Y (NPY)-ergic system is associated with behavioral resilience to stress exposure in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 37, 350–363 (2012). sourceNot checked yet

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May combine two claims.

In learned helplessness models, depending on severity and duration of inescapable foot shock, about 30% of animals develop learned helplessness while another subset escapes with latencies seen in unstressed animals.

“Depending on the severity and duration of exposure to inescapable foot shock, a subset of animals, ~30% in some studies, develop learned helplessness—they fail to escape when escape becomes possible, while another subset (termed resilient) escapes with latencies seen in unstressed animals29.”

• cites [29] Berton, O. et al. Induction of deltaFosB in the periaqueductal gray by stress promotes active coping responses. Neuron 55, 289–300 (2007). sourceNot checked yet

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Resilient animals are not symptom-free; they show some maladaptive behavioral adaptations but resist many other maladaptive sequelae of chronic social stress.

“resilient animals are not devoid of symptoms and, in fact, exhibit some behavioral adaptations that appear maladaptive, but they exhibit clear resistance to many other maladaptive sequelae of the chronic social stress.”

May combine two claims.

Early studies in men suggest testosterone may be effective in treatment-resistant depression and as an adjunct to SSRI treatment.

“Early studies in men suggest that testosterone may be effective in treatment–resistant depression and as an adjunct to SSRI treatment17.”

• cites [17] Pope, H.G. Jr., Cohane, G.H., Kanayama, G., Siegel, A.J. & Hudson, J.I. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am. J. Psychiatry 160, 105–111 (2003). sourceNot checked yet

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May combine two claims.

The definition of resilience and the percentage of animals showing it vary across stress paradigms.

“the definition of resilience, and the percent of animals exhibiting resilience, varies across several stress paradigms.”

May combine two claims.

Higher blood NPY levels predict better performance under stress during military survival training and are found in Special Forces soldiers compared with non-Special Forces military counterparts.

“higher blood NPY levels were shown to predict better performance under stress during military survival training and were found in Special Forces soldiers, compared to their non–Special Forces military counterparts18.”

• cites [18] Morgan, C.A. III et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol. Psychiatry 47, 902–909 (2000). sourceNot checked yet

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NPY modulates stress responses in animals, and human studies support the possibility that NPY is protective under stress.

“Neuropeptide Y (NPY), a peptide neurotransmitter, modulates stress responses in animals, and studies in humans support the possibility that NPY may represent a protective factor in the face of stress18, 19.”

• cites [18] Morgan, C.A. III et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol. Psychiatry 47, 902–909 (2000). sourceNot checked yet

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• cites [19] Morgan, C.A. III et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol. Psychiatry 52, 136–142 (2002). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Maier and colleagues view learned helplessness risk as highly dependent on the animal's control over stress, with resilience promoted by control over stress cessation.

“Maier and colleagues view the risk of learned helplessness to be highly dependent upon the animal’s own control over the stress, with resilience promoted by control over cessation of the stress (For review see 30).”

• cites [30] Fleshner, M., Maier, S.F., Lyons, D.M. & Raskind, M.A. The neurobiology of the stress-resistant brain. Stress 14, 498–502 (2011). sourceNot checked yet

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The proportion of mice resilient to social defeat stress differs across strains; 10 days of social defeat yields about 35% resilience in C57BL6/J mice, while CD1 or FVB strains are closer to 100% resilient.

“10 days of social defeat in C57BL6/J mice results in ~35% resilient mice, while other strains such as CD1 or FVB are closer to 100% resilient 27.”

• cites [27] Golden, S.A., Covington, H.E. III, Berton, O. & Russo, S.J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183–1191 (2011). sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

Genetic factors are important determinants of risk or resilience to psychiatric disorders.

“Genetic factors are important determinants for the risk or resilience to psychiatric disorders.”

May combine two claims.

After chronic social defeat stress, all C57BL6/J male mice show heightened HPA reactivity, exploratory-based anxiety-like deficits, and stress-induced polydipsia.

“following chronic social defeat stress, all genetically inbred C57BL6/J male mice exhibit a constellation of symptoms including heightened reactivity of the HPA axis, deficits in exploratory–based behavior that are interpreted as increased anxiety, and stress–induced polydipsia24.”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

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May combine two claims.

Strain-dependent responses to restraint or chronic mild stress have been shown, indicating complex genetics regulate risk and resilience to chronic stress.

“Strain–dependent responses to other physical stressors such as restraint or CMS have been shown, underscoring the role of complex genetics in regulating risk and resilience to chronic stress32–34.”

• cites [32] Uchida, S. et al. Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron 69, 359–372 (2011). sourceNot checked yet

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• cites [33] Mozhui, K. et al. Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. J. Neurosci. 30, 5357–5367 (2010). sourceNot checked yet

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• cites [34] Andrus, B.M. et al. Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol. Psychiatry 17, 49–61 (2012). sourceNot checked yet

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May combine two claims.

Higher NPY levels in response to acute stress predict less psychological distress and fewer dissociative symptoms.

“higher levels of NPY in response to acute stress predicted less psychological distress and fewer symptoms of dissociation19.”

• cites [19] Morgan, C.A. III et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol. Psychiatry 52, 136–142 (2002). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Animals termed resilient usually show some deleterious symptoms after stress but do not exhibit deficits in key behavioral domains.

“The remaining animals, which have been termed resilient in some studies, usually exhibit some deleterious symptoms in response to the stress, but do not exhibit deficits in key behavioral domains.”

May combine two claims.

Extremely disrupted rats showed anxiety-like behaviors, increased acoustic startle, and large NPY reductions across multiple brain regions.

“The animals classified as extremely disrupted exhibited anxiety–like behaviors and increased acoustic startle responses, as well as large reductions in NPY across multiple brain regions.”

• cites [23] Cohen, H. et al. The neuropeptide Y (NPY)-ergic system is associated with behavioral resilience to stress exposure in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 37, 350–363 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In resilient mice, chronic mild stress did not reduce hippocampal volume or alter glutamate metabolism as it did in susceptible mice.

“CMS did not reduce hippocampal volume or alter glutamate metabolism in resilient mice as seen in susceptible mice.”

• cites [26] Delgado y Palacios, R. et al. Magnetic resonance imaging and spectroscopy reveal differential hippocampal changes in anhedonic and resilient subtypes of the chronic mild stress rat model. Biol. Psychiatry 70, 449–457 (2011). sourceNot checked yet

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May combine two claims.

The shape of the inverted U differs by sex, strain, and behavioral domain.

“The shape of the inverted U differs by many factors including sex, strain, and behavioral domain in question (Fig. 2).”

• cites [50] McEwen, B.S. & Gianaros, P.J. Stress- and allostasis-induced brain plasticity. Annu. Rev. Med. 62, 431–445 (2011). sourceNot checked yet

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Social avoidance in susceptible mice is likely maladaptive because it also occurs toward non-aggressive littermates and persists for more than six months despite housing with non-aggressive littermates.

“we have shown that susceptible mice also avoid non–aggressive C57BL6/J littermates, and that such social avoidance is essentially permanent—it persists for >6 months—despite housing with non–aggressive littermates, suggesting that it does reflect a maladaptive response36, 38.”

• cites [36] Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006). sourceNot checked yet

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• cites [38] Covington, H.E. III, Vialou, V.F., LaPlant, Q., Ohnishi, Y.N. & Nestler, E.J. Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neurosci. Lett. 493, 122–126 (2011). sourceNot checked yet

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Compared with non-separated monkeys, previously separated squirrel monkeys showed fewer anxiety signs, increased exploration, and diminished plasma cortisol and ACTH in a novel environment stress test.

“Compared to non–separated monkeys, previously separated monkeys showed fewer signs of anxiety and increased exploration of the environment coupled with diminished plasma levels of cortisol and ACTH44.”

• cites [44] Parker, K.J., Buckmaster, C.L., Schatzberg, A.F. & Lyons, D.M. Prospective investigation of stress inoculation in young monkeys. Arch. Gen. Psychiatry 61, 933–941 (2004). sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

The group defined resilience to chronic social defeat stress as absence of social avoidance, anhedonia, and metabolic syndrome, which are highly correlated.

“Our group has defined resilience to chronic social defeat stress as the absence of social avoidance, anhedonia, and metabolic syndrome, which are highly correlated with one another24, 27, 28, 36.”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

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• cites [27] Golden, S.A., Covington, H.E. III, Berton, O. & Russo, S.J. A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183–1191 (2011). sourceNot checked yet

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• cites [28] Lutter, M. et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat. Neurosci. 11, 752–753 (2008). sourceNot checked yet

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May combine two claims.

Female rodents tend to be more susceptible to stress-induced dysfunction in emotional domains but show greater stress resilience in cognitive domains.

“while female rodents tend to be more susceptible to stress–induced dysfunction in emotional domains (i.e., sucrose preference and forced swim test), they tend to show a greater degree of stress resilience in cognitive domains (i.e., object placement and recognition) (for review see51).”

• cites [51] Luine, V. Sex differences in chronic stress effects on memory in rats. Stress 5, 205–216 (2002). sourceNot checked yet

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Separated monkeys showed enhanced response inhibition to previously rewarding stimuli, suggesting improved cognitive control.

“Separated monkeys also demonstrated enhanced response inhibition to previously rewarding stimuli, suggesting improved cognitive control of behavior45.”

• cites [45] Parker, K.J., Buckmaster, C.L., Justus, K.R., Schatzberg, A.F. & Lyons, D.M. Mild early life stress enhances prefrontal-dependent response inhibition in monkeys. Biol. Psychiatry 57, 848–855 (2005). sourceNot checked yet

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May combine two claims.

During social defeat stress, animals that engage in less submissive posturing during attack show less social avoidance, suggesting this behavioral coping strategy may lessen stress effects.

“During social defeat stress, animals that engage in less submissive posturing during the attack show less social avoidance, suggesting that this behavioral coping strategy may affect the aggressive interaction and thereby lessen the effects of the stress55.”

• cites [55] Wood, S.K., Walker, H.E., Valentino, R.J. & Bhatnagar, S. Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. Endocrinology 151, 1795–1805 (2010). sourceNot checked yet

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McEwen and colleagues found that stress affects most rat behavioral domains with an inverted U-shaped curve, where low and high stress impair behavior and intermediate stress promotes positive coping.

“McEwen and colleagues systematically measured the type, length, and quality of stress experience on multiple rat behaviors and found that stress affects most behavioral domains with an inverted U–shape curve, where low and high levels of stress both impair behavior, while intermediate levels actually promote positive coping responses (for review see50).”

• cites [50] McEwen, B.S. & Gianaros, P.J. Stress- and allostasis-induced brain plasticity. Annu. Rev. Med. 62, 431–445 (2011). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Early intermittent separations enhance stress tolerance and promote resilience.

“These and related findings highlight the critical window of stress exposure and suggest that early intermittent separations enhance stress tolerance, i.e., promotes resilience.”

May combine two claims.

Coping with moderate stress can lead to a sense of mastery and promote future resilience.

“coping with moderate amounts of stress leads to an individual sense of mastery and promotes resilience in the future.”

May combine two claims.

Anhedonic and metabolic symptoms in susceptible mice are maladaptive and are reversed by chronic antidepressant administration.

“The anhedonic and metabolic symptoms are clearly maladaptive and indeed are reversed by chronic administration of antidepressants to susceptible mice36, 37.”

• cites [36] Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006). sourceNot checked yet

  Not checked in the free run.

• cites [37] Covington, H.E. III et al. Antidepressant actions of histone deacetylase inhibitors. J. Neurosci. 29, 11451–11460 (2009). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

An inverted U-shaped relationship between stress and coping exists across organisms and lifetimes, suggesting optimal stress exposure might prevent major psychiatric dysfunction.

“This inverted U shape relationship between stress and coping can be observed in all organisms throughout their lifetime and suggests that maintaining optimal stress exposure might prevent the development of major psychiatric dysfunction.”

May combine two claims.

Resilience in children and adults is a common outcome after adversity, representing successful adaptive coping.

“resilience in both children and adults is a common outcome following adversity – representing successful, adaptive coping in the face of stress39, 40.”

• cites [39] Masten, A.S. Ordinary magic. Resilience processes in development. Am. Psychol. 56, 227–238 (2001). sourceNot checked yet

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• cites [40] Bonanno, G.A. Loss, trauma, and human resilience: have we underestimated the human capacity to thrive after extremely aversive events? Am. Psychol. 59, 20–28 (2004). sourceNot checked yet

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May combine two claims.

More graded exposure of adults to stress might reduce vulnerabilities and promote resilience.

“there is some evidence that more graded exposure of adults to stress might reduce such vulnerabilities, that is, promote resilience.”

May combine two claims.

In the general population, 50-60% experience severe trauma, but estimated illness prevalence is only 7.8%.

“Within the general population, between 50–60% experience a severe trauma, yet the prevalence of illness is estimated to be only 7.8%41.”

• cites [41] Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C.B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995). sourceNot checked yet

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May combine two claims.

GluA2 is an AMPA glutamate receptor subunit that reduces calcium permeability and overall conductance of AMPA channels.

“an AMPA glutamate receptor subunit that reduces the Ca2+ permeability and overall conductance of AMPA channels71”

• cites [71] Vialou, V. et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat. Neurosci. 13, 745–752 (2010). sourceNot checked yet

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An independent active process in resilient mice normalizes ventral tegmental area firing to control levels and prevents social avoidance and sucrose preference deficits.

“there is an independent, active process occurring in resilient mice that normalizes VTA firing to control levels and thus prevents social avoidance and sucrose preference deficits”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Induction of K+ channels functionally occludes the increased Ih current and actively promotes behavioral resilience.

“such induction of K+ channels functionally occludes the increased Ih current and thereby actively promotes behavioral resilience24, 73”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

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• cites [73] Cao, J.L. et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010). sourceNot checked yet

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May combine two claims.

Early intermittent maternal separations that promote resilience increase cortical volume in the ventromedial prefrontal cortex, a change opposite in direction to that seen in depressed humans and stressed rodents.

“Early intermittent maternal separations that promote resilience increase cortical volume within ventromedial PFC (VMPFC)66, changes opposite in direction to those seen in depressed humans and stressed rodents.”

• cites [66] Katz, M. et al. Prefrontal plasticity and stress inoculation-induced resilience. Dev. Neurosci. 31, 293–299 (2009). sourceNot checked yet

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Environmental enrichment increases dendritic tree complexity, dendritic spine density, and synaptic protein levels of pyramidal neurons in the hippocampus and prefrontal cortex.

“environmental enrichment similarly increases the complexity of the dendritic tree, dendritic spine density, and synaptic protein levels of pyramidal neurons in hippocampus and PFC”

• cites [69] Kozorovitskiy, Y. et al. Experience induces structural and biochemical changes in the adult primate brain. Proc. Natl. Acad. Sci. USA 102, 17478–17482 (2005). sourceNot checked yet

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Most argue for hypoactivity of NAc in depression, supported by deep brain stimulation studies showing stimulation of the anterior limb of the internal capsule alleviates depression and anxiety symptoms.

“most would argue for hypoactivity of NAc in depression, which is supported by deep brain stimulation studies that show electrical stimulation of the anterior limb of the internal capsule (which includes NAc) alleviates symptoms of depression and anxiety.”

May combine two claims.

Chronic stress reduces dendritic arborization and glutamatergic dendritic spine density of pyramidal neurons in PFC and hippocampus, reduces hippocampal neurogenesis, and increases dendritic spine number or branching in amygdala and NAc.

“chronic stress reduces dendritic arborization and glutamatergic dendritic spine density of pyramidal neurons in PFC and hippocampus, and reduces hippocampus neurogenesis, while increasing dendritic spine number or branching in amygdala and NAc (for review see63).”

• cites [63] Christoffel, D.J., Golden, S.A. & Russo, S.J. Structural and synaptic plasticity in stress-related disorders. Rev. Neurosci. 22, 535–549 (2011). sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable).

Knowledge of resilience mechanisms can guide development of novel treatments for stress-related disorders by enhancing natural resilience mechanisms.

“The therapeutic implications of these findings are important and can pave the way for an innovative new approach to drug development for a range of stress–related syndromes.”

• Also stated in: § Introduction · plain

  “we conclude with a discussion of how this growing body of knowledge can guide the development of novel treatments for a range of stress–related disorders by enhancing such natural mechanisms of resilience.”

• AssumptionRests on an assumption: Enhancing natural resilience mechanisms will produce effective treatments for stress-related disorders.

May combine two claims.

Depression and anxiety in humans result in part from hypo-activation and reduced volume of frontal cortical and hippocampal regions that control subcortical structures such as NAc and amygdala, although hyper-activation of certain PFC regions is also involved.

“Numerous studies suggest that depression and anxiety in humans result in part from hypo–activation and reduced volume of frontal cortical and hipppocampal regions that control subcortical structures such as nucleus accumbens (NAc) and amygdala, although hyper–activation of certain PFC regions (e.g., subgenual area of anterior cingulate cortex) is also involved58–61.”

• cites [58] Price, J.L. & Drevets, W.C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010). sourceNot checked yet

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• cites [59] Murrough, J.W., Iacoviello, B., Neumeister, A., Charney, D.S. & Iosifescu, D.V. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol. Learn. Mem. 96, 553–563 (2011). sourceNot checked yet

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• cites [60] Mayberg, H.S. Targeted electrode-based modulation of neural circuits for depression. J. Clin. Invest. 119, 717–725 (2009). sourceNot checked yet

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• cites [61] van Tol, M.J. et al. Functional magnetic resonance imaging correlates of emotional word encoding and recognition in depression and anxiety disorders. Biol. Psychiatry 71, 593–602 (2012). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Hypoactive PFC and hippocampal inputs to subcortical neurons may mediate their activation and subsequent activity-dependent structural plasticity of dendrites.

“Hypoactive PFC and hippocampal inputs to neurons in these subcortical structures may mediate their activation and the subsequent activity–dependent structural plasticity of their dendrites, although further research is needed in this area.”

May combine two claims.

Increased immediate early gene expression in mPFC suggests increased neuronal activation that might be a pro-resilience adaptation.

“Increased expression of these immediate early genes would suggest increased neuronal activation within this brain region, which might represent a pro–resilience adaptation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

An epigenetic mechanism induced by chronic stress in resilient mice only controls HPA axis hyperactivity.

“One recent paper found an epigenetic mechanism, induced by chronic stress in resilient mice only, that controls HPA axis hyperactivity83”

• cites [83] Elliott, E., Ezra-Nevo, G., Regev, L., Neufeld-Cohen, A. & Chen, A. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nat. Neurosci. 13, 1351–1353 (2010). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Removal of ovarian hormones in rodents decreases the pro-depressant or anxiogenic effects of stress while simultaneously increasing the negative effects of stress on spatial and non-spatial memory.

“removal of ovarian hormones decreases the pro–depressant or anxiogenic effects of stress, while simultaneously increasing the negative effects of stress on spatial and non–spatial memory85, 91, 92”

• cites [85] LaPlant, Q. et al. Role of nuclear factor κB in ovarian hormone-mediated stress hypersensitivity in female mice. Biol. Psychiatry 65, 874–880 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [91] Autry, A.E., Adachi, M., Cheng, P. & Monteggia, L.M. Gender-specific impact of brain-derived neurotrophic factor signaling on stress-induced depression-like behavior. Biol. Psychiatry 66, 84–90 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [92] Bowman, R.E., Ferguson, D. & Luine, V.N. Effects of chronic restraint stress and estradiol on open field activity, spatial memory, and monoaminergic neurotransmitters in ovariectomized rats. Neuroscience 113, 401–410 (2002). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

On cognitive domains, females cope better with chronic forms of stress, whereas males tend to cope better with acute stress.

“the literature suggests that on cognitive domains females cope better with chronic forms of stress, whereas males tend to cope better with acute stress.”

May combine two claims.

Increased excitability of ventral tegmental area dopamine neurons mediates susceptibility, while normalization of their firing mediates resilience.

“increased excitability of VTA dopamine neurons mediates susceptibility, with normalization mediating resilience”

May combine two claims.

High levels of maternal care in rats are associated with decreased DNA methylation of the glucocorticoid receptor gene, higher glucocorticoid receptor expression, greater feedback inhibition of the HPA axis, and resilient stress responses in adulthood.

“high levels of maternal care are associated with decreased DNA methylation of the GR gene, higher levels of GR expression, greater feedback inhibition of the HPA axis, and resilient stress responses in adulthood (for review see 81)”

• cites [81] Weaver, I.C. et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci. 25, 11045–11054 (2005). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Stress enhances performance of female rodents on the radial arm maze, Morris water maze, Y-maze, non-associative learning, and object placement tasks, whereas stress impairs male performance in these assays.

“Stress enhances the performance of female rodents on the radial arm maze, Morris water maze, Y–maze, non–associative learning, and object placement tasks, whereas stress impairs male performance in these assays86–88.”

• cites [86] Conrad, C.D., Grote, K.A., Hobbs, R.J. & Ferayorni, A. Sex differences in spatial and non-spatial Y-maze performance after chronic stress. Neurobiol. Learn. Mem. 79, 32–40 (2003). sourceNot checked yet

  Not checked in the free run.

• cites [87] Galea, L.A. et al. Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience 81, 689–697 (1997). sourceNot checked yet

  Not checked in the free run.

• cites [88] Bowman, R.E., Beck, K.D. & Luine, V.N. Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm. Behav. 43, 48–59 (2003). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There is not a one-to-one correspondence between reward and resilience; not all molecular changes in the ventral tegmental area or nucleus accumbens that increase drug or natural reward promote resilience, and vice versa.

“there is not a one–to–one correspondence between reward and resilience. Not all molecular changes in the VTA or NAc that increase drug or natural reward promote resilience, and vice versa.”

May combine two claims.

Prenatal exposure to glucocorticoids increases CRH levels in the central nucleus of the amygdala and reduces volume of prefrontal cortex structures in adulthood.

“prenatal exposure to glucocorticoids increases CRH levels in the central nucleus of amygdala and reduces volume of PFC structures in adulthood70”

• cites [70] Lupien, S.J., McEwen, B.S., Gunnar, M.R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10, 434–445 (2009). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Increased firing of ventral tegmental area dopamine neurons has long been documented in response to rewards and aversive stimuli, and it has been suggested that they increase salience for both types of stimuli.

“increased firing of VTA dopamine neurons has long been documented in response to rewards as well as to aversive stimuli, and it has been suggested that they increase salience for both types of stimuli24, 73–76”

• cites [24] Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007). sourceNot checked yet

  Not checked in the free run.

• cites [73] Cao, J.L. et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010). sourceNot checked yet

  Not checked in the free run.

• cites [74] Goto, Y., Otani, S. & Grace, A.A. The Yin and Yang of dopamine release: a new perspective. Neuropharmacology 53, 583–587 (2007). sourceNot checked yet

  Not checked in the free run.

• cites [75] Grace, A.A., Floresco, S.B., Goto, Y. & Lodge, D.J. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 30, 220–227 (2007). sourceNot checked yet

  Not checked in the free run.

• cites [76] Brischoux, F., Chakraborty, S., Brierley, D.I. & Ungless, M.A. Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli. Proc. Natl. Acad. Sci. USA 106, 4894–4899 (2009). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Prolonged social isolation of adult mice or rats induces depression- and anxiety-like behavioral abnormalities and promotes susceptibility to chronic social defeat stress.

“which induces depression– and anxiety–like behavioral abnormalities49 and promotes susceptibility to chronic social defeat stress71”

• cites [49] Wallace, D.L. et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat. Neurosci. 12, 200–209 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [71] Vialou, V. et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat. Neurosci. 13, 745–752 (2010). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

After chronic social defeat stress, Crh gene expression is increased in the paraventricular nucleus of the hypothalamus of susceptible animals, and this adaptation is necessary for the development of social avoidance.

“after chronic social defeat stress, Crh gene expression is increased in the paraventricular nucleus (PVN) of hypothalamus of susceptible animals and that this adaptation is necessary for the development of social avoidance83”

• cites [83] Elliott, E., Ezra-Nevo, G., Regev, L., Neufeld-Cohen, A. & Chen, A. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nat. Neurosci. 13, 1351–1353 (2010). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In tests of acute stress or aversive conditioning, stress enhances learning in males and impairs it in females.

“in tests of acute stress or aversive conditioning, stress enhances learning in males and impairs it in females89, 90”

• cites [89] Wood, G.E. & Shors, T.J. Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc. Natl. Acad. Sci. USA 95, 4066–4071 (1998). sourceNot checked yet

  Not checked in the free run.

• cites [90] Wood, G.E., Beylin, A.V. & Shors, T.J. The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females. Behav. Neurosci. 115, 175–187 (2001). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

The observation that such approaches significantly reduce PTSD severity supports the view that targeting underlying biological mechanisms of stress inoculation may provide novel protein targets for new medications that further promote resilience in at-risk populations.

“The observation that such approaches significantly reduce PTSD severity supports the view that targeting underlying biological mechanisms of stress inoculation may provide us with novel protein targets for new medications that further promote resilience in at–risk populations.”

• AssumptionRests on an assumption: Such behavioral approaches significantly reduce PTSD severity.

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Such treatments might be understood as analogous to stress inoculation in that experiencing more moderate levels of stress, combined with techniques that reduce physiological and psychological perception of the trauma, can promote positive coping responses.

“Such treatments might be understood as being analogous to stress inoculation in that experiencing more moderate levels of stress, combined with techniques that reduce physiological and psychological perception of the trauma, can promote positive coping responses.”

• AssumptionRests on an assumption: Stress resilience is enhanced in specific populations, such as military personnel and rescue workers, through controlled exposure to stress-related stimuli.
• AssumptionRests on an assumption: Behavior therapy uses controlled stress exposure as one means to treat symptoms of mood and anxiety disorders.
• AssumptionRests on an assumption: Exposure therapy and cognitive behavioral therapy can aid individuals with PTSD through cognitive restructuring and relaxation techniques following a traumatic event to promote recovery.