Metabolic SystemWhite Paper Sourced from K. Re ssler Papers

28 th February

1: Cameron JL, Eagleson KL, Fox NA, Hensch TK, Levitt P. Social Origins of Developmental Risk for

Mental and Physical Illness. J Neurosci. 2017 Nov 8;37(45):10783-10791. doi:

10.1523/JNEUROSCI.1822-17.2017. Review. PubMed PMID:29118206; PubMed Central PMCID:

PMC5678010.

Pg 1

Abstract

Adversity in early childhood exerts an enduring impact on:

a. mental and physical health,

b. academic achievement,

c. lifetime productivity,

d. and the probability of interfacing with the criminal justice system.

More science is needed to understand how the brain is affected by early life stress (ELS), which produces

excessive activation of stress response systems broadly throughout the child's body (toxic stress).

Our research examines the importance of:

a. sex,

b. timing

c. and type of stress exposure,

d. and critical periods for intervention in various brain systems across species.

Neglect (the absence of sensitive and responsive caregiving) or disrupted interaction with offspring

induces robust, lasting consequences in mice, monkeys, and humans.

Complementary assessment of internalizing disorders and brain imaging in children suggests that early

adversity can interfere with white matter development in key brain regions, which may increase risk for

emotional difficulties in the long term.

Neural circuits that are most plastic during ELS exposure in monkeys sustain the greatest change in gene

expression, offering a mechanism whereby stress timing might lead to markedly different long-term

behaviors.

Rodent models reveal that disrupted maternal-infant interactions yield metabolic and behavioral outcomes

often differing by sex.

Moreover, ELS may further accelerate or delay critical periods of development, which reflect:

a. GABA circuit maturation,

b. BDNF,

c. and circadian Clock genes.

Such factors are associated with several mental disorders and may contribute to a premature closure of

plastic windows for intervention following ELS.

Together, complementary cross-species studies are elucidating principles of adaptation to adversity in

early childhood with molecular, cellular, and whole organism resolution.

Pgs 3/4 - 5

3. Initial results revealed significant impacts on all domains of functioning in young children who were

living in Bucharest institutions.

a. They were significantly:

i. delayed in intellect (IQ) (Smyke et al., 2007),

ii. had abnormal attachment-like behaviors toward caregivers (Zeanah et al., 2005)

iii. displayed significantly reduced EEG alpha power (Marshall et al., 2004) (Fig. 1A),

iv. and had multiple abnormal psychological behaviors,

v. including stereotypies

vi. and aggressive behaviors (Zeanah et al., 2009).

vii. EEG alpha power reflects synchronous neural activity that is associated with visual

attention and alertness.

viii. Low EEG power is consistent with dampened brain metabolism (Buzsaki et al., 2007).

4. This pattern of findings is consonant with a long history of reports regarding effects of

institutionalization on infant brain and behavioral development (Nelson et al., 2016).

Figure 1.Impact of early life stress across species. A, Analysis of EEG in children randomized for Foster Care, or Care as Usual in the Bucharest Early Intervention Study. There is significant reduction in alpha power in children randomized to Care as Usual in the institution, which reflects a disruption of normal developmental increases in information processing in frontal and central cortical regions (Marshall et al., 2004; Vanderwert et al., 2010). These effects are largely corrected only if foster care begins younger than 24 months of age. B, Limbic structures, which are particularly sensitive to ELS. C, 3D structure of GUCY1A3, and representative pseudocolored images depicting regional amygdala expression of GUCY1A3 mRNA in 3 animals: a control, maternally raised monkey, a week, 1 week separated monkey, and a month, 1 month separated monkey (Sabatini et al., 2007). D, Stress experienced at different developmental stages results in distinct changes in neuronal morphology. Depicted are dendritic arbors of neurons in prefrontal cortex. Early adversity in the form of disrupting infant-maternal interactions results in reduced arbors, whereas disruption later in development generates a paradoxical increase in dendritic growth (Bock et al., 2005; Xie et al., 2013). E, ELS in the first postnatal week results in an accelerated timing of a critical period for limbic circuit plasticity (Callaghan and Richardson, 2011; Bath et al., 2016). F, ELS in the first postnatal week in mice, followed by discovery-based comparative proteomics, yields both increased and decreased expression of specific mitochondrial proteins that are involved in respiration and cellular metabolism. These changes in the hippocampus differ by sex.

5. Post-randomization, children were followed up at 30, 42 and 54 months, as well as at 8 and 12 years of

age.

a. Regarding cognitive functioning, children randomized to Foster Care displayed higher IQ scores

compared with those remaining in Care as Usual at each of the assessment points.

b. Interestingly, at the early assessments (30, 42, and 54 months), there appeared to be a critical period

for the impact of the intervention.

c. Those children placed before 24 months were more likely to have higher scores compared with those

randomized thereafter (Nelson et al., 2007).

d. This pattern of intervention and timing effects held true not only for IQ but also for attachment

behavior (Smyke et al., 2010) and EEG alpha activity (Fig. 1A) (Vanderwert et al., 2010).

e. At age 12, intervention effects

i. for IQ

ii. and EEG alpha activity persisted,

iii. but the timing effects were lost (Almas et al., 2016; Vanderwert et al., 2016).

f. Some domains, such as:

i. white matter development,

ii. psychiatric status,

iii. and socio-emotional responding,

iv. exhibited intervention effects across assessment points without evidence of timing effects

(Humphreys et al., 2015; Bick et al., 2015).

g. Other domains, such as measures of:

i. gray matter volume (Sheridan et al., 2012),

ii. executive function (Bos et al., 2009),

iii. or attention deficit hyperactivity disorder symptoms (Humphreys et al., 2015),

iv. showed no signs of an intervention effect.

h. In these latter domains, all children with a history of institutionalization had:

i. less gray matter volume,

ii. poor executive skills,

iii. (and heightened symptoms of attention deficit hyperactivity disorder.

i. Attachment held particular importance for understanding psychiatric outcomes.

Pg 15

8. A key feature of fast-spiking PV+ cells is their high metabolic demand (Buzsaki et al., 2007),

a. which generates abundant reactive oxygen species.

b. The PNNs serve to protect PV+ cells

c. from this oxidative stress (Cabungcal et al., 2013).

9. But they can eventually succumb to the damage themselves, resulting:

a. in PNN loss

b. and transiently prolonged critical period plasticity (Morishita et al., 2015)

c. that may contribute to circuit instability in the etiology of mental illness (Do et al., 2015).

10. Maternal and perinatal immune challenge (Meyer et al., 2008; Jenkins et al., 2009), parental

separation (Brenhouse and Andersen, 2011), and social isolation (Harte et al., 2007; Schiavone et al.,

2009) have all been shown to lead to anomalies in hippocampal and/or prefrontal PV+circuits.

11. The impact of ELS on these critical period “triggers” and “brakes” is then of great interest.

a. Factors that may accelerate or delay GABA circuit maturation, such as BDNF (Huang et al., 1999; Bath et al., 2013),

b. Clock gene expression (Kobayashi et al., 2015; Marco et al., 2016),

c. Otx2 (Sugiyama et al., 2008; Pena et al., 2017),

d. or the GUCY1A3 mentioned above (Sabatini et al., 2007),

e. may be vulnerable to ELS,

f. predicting a shift in developmental timing.

Pgs 17/18-19

The application of discovery-based strategies, such as comparative genomic and proteomic profiling of

vulnerable circuits, also can guide investigations of mechanisms that underlie how ELS disrupts:

a. brain and

b. peripheral organ development and function.

1. Recent application of one such method,:

a. isobaric tag for relative and absolute quantitation,

b. on brain tissue isolated at various times in development,

c. inclusive of both sexes,

d. revealed that prominent among a disrupted developmental proteome are:

e. proteins involved in ATP production and

f. mitochondrial homeostasis.

2. Although requiring further investigation, the mitochondria-associated protein changes are:

a. consistent with temporal

b. and sex influences

c. on cellular responses to ELS during development (Fig. 1E) (K.L.E. and P.L., unpublished

observations).

3. The findings are aligned with those described by McEwen and colleagues (Picard and McEwen,

2014; Picard et al., 2014, 2015, 2017) following psychosocial stress.

4. Direct measures of mitochondria-associated phenotypes reveal that ELS using the limited bedding

paradigm results in:

a. sex-dependent adaptations

b. that likely reflect functional short- and longer-term functional changes (K.L.E. and P.L.,

unpublished observations).

5. Mitochondrial dysfunction has been associated with:

a. a variety of brain-based

b. and peripheral disorders c. that display a sex bias,

i. including affective disorders (Chang et al., 2015; Klinedinst and Regenold, 2015; Bansal

and Kuhad, 2016),

ii. diabetes (Koliaki and Roden, 2016; Wanagat and Hevener, 2016),

iii. liver disorders (Pessayre, 2007; Serviddio et al., 2008; Grattagliano et al., 2012),

iv. and neurodegenerative disorders (Wallace, 1999).

6. Sex differences in mitochondrial function have been reported and:

a. are typically associated with levels of circulating gonadal hormones following puberty (Gaignard

et al., 2015)

b. and the decline in estrogen and progesterone following menopause (Irwin et al., 2012; Rettberg et

al., 2014; Yin et al., 2015).

7. These may underlie, at least in part, the increased vulnerability of one sex to certain pathological

processes.

8. There remains, however, a limited understanding of:

a. the developmental origins of sex-dependent mitochondrial dysfunction,

b. which is particularly relevant in the context of neurodevelopmental disorders

c. that manifest before puberty.

3: Berens AE, Jensen SKG, Nelson CA 3rd. Biological embedding of childhood adversity: from

physiological mechanisms to clinical implications. BMC Med. 2017 Jul 20;15(1):135. doi:

10.1186/s12916-017-0895-4. Review. PubMed PMID: 28724431; PubMed Central PMCID:

PMC5518144.

Pg 1-3

Abstract

Background

Adverse psychosocial exposures in early life, namely experiences such as child maltreatment, caregiver stress or depression, and domestic or community violence, have been associated in epidemiological studies with increased lifetime risk of adverse outcomes, including:

a. diabetes,

b. heart disease,

c. cancers,

d. and psychiatric illnesses.

Additional work has shed light on the potential molecular mechanisms by which early adversity becomes “biologically embedded” in altered physiology across body systems.

This review surveys evidence on such mechanisms and calls on

a. researchers,

b. clinicians,

c. policymakers,

d. and other practitioners to act upon evidence.

Observations

Childhood psychosocial adversity has wide-ranging effects on:

a. neural, b. endocrine, c. immune,d. and metabolic physiology.

Molecular mechanisms broadly implicate disruption of:

a. central neural networks,

b. neuroendocrine stress dysregulation,

c. and chronic inflammation,

d. among other changes.

Physiological disruption predisposes individuals to common diseases across the life course.

Conclusions

Reviewed evidence has important implications for:

a. clinical practice,

b. biomedical research,

c. and work across other sectors relevant to public health

d. and child wellbeing.

Warranted changes include:

a. increased clinical screening for exposures among children and adults,

b. scale-up of effective interventions,

c. policy advocacy,

d. and ongoing research to develop new evidence-based response strategies.

Background

Epidemiological studies have demonstrated that adverse childhood experiences, namely exposures such as:

a. neglect,

b. abuse,

c. caregiver mental illness, and

d. family or community violence,

e. predict poorer long-term outcomes across health and social domains.

. Outcomes associated with early adversity include higher risk of:

a. type 2 diabetes,

b. obesity,

c. ischemic heart disease,

d. cancers,

e. depression,

f. addictions,

g. and premature mortality,

h. as well as social outcomes including:

i. unemployment and

ii. lower educational attainment [1, 2, 3, 4, 5, 6, 7, 8].

. Particularly convincing evidence comes from:

a. large birth cohorts and

b. prospective, longitudinal life-course studies exploring predictive relationships [3,5,6,7,8,9].

Pg 8

Pg 21

4. Differential patterns of dysregulation may reflect variation:

In factors including timing

and type of ELA [45],

genotype [46],

current age [29],

and concurrent psychopathology [47].

5. Importantly, HPA hyper- and hypo-reactivity both represent prototypical patterns associated with

excess allostatic load,

a. and both predict human stress-related chronic illnesses, including:

i. cardiovascular,

ii. metabolic, and

iii. psychiatric diseases

iv. linked epidemiologically to ELA [15, 29, 48].

6. Glucocorticoid dysregulation may also:

a. promote oncogenic tumor cell microenvironments

b. (in part via pro-inflammatory effects, as discussed below),

i. fostering growth,

ii. migration,

iii. invasiveness,

iv. and angiogenesis [49],

v. thus potentially contributing to observed links between ELA and cancers [7].

Pg 24

1. Imbalance in either sympathetic- or parasympathetic-dominant directions again represent:

a. manifestations of excess allostatic load

b. and predict stress-related diseases, including:

i. heart disease,

ii. obesity,

iii. type 2 diabetes,

iv. cancers,

v. and psychopathologies [55].

2. Pathology associations may differ by pattern of autonomic imbalance.

a. Several studies, for instance, found that attenuated sympathetic reactivity correlated with:

i. (i)  antisocial behavior

ii. (ii)  with callous-unemotional traits in ELA-exposed boys,

b. while heightened reactivity correlated with

i. (i)  antisocial behavior

ii. (ii)  without callous-unemotional traits [56].

3. Such findings remain exploratory, and the direction of causal links, if present, is unclear.

Pgs 27-34

8. Health implications of immunosuppression include:

a. compromised control of infection

b. and other threats.

c. Meanwhile, inflammatory mediators linked to ELA:

i. (e.g., IL-1,

ii. IL-6,

iii. TNF-alpha,

iv. CRP,

v. and fibrinogen)

d. are implicated in risk of:

i. cardiovascular

ii. and metabolic disease [17, 66, 67].

9. Inflammation is also a proposed mechanism mediating ELA effects on later:

a. depression,

b. age-related diseases [3],

c. neurodevelopmental changes [40],

d. cancers [49],

e. and other systemic effects discussed.

10. Considering cancer risk in particular,

a. immunosuppression impairs control of latent oncogenic viruses [68],

i. while inflammation further promotes oncogenic tumor microenvironments

ii. in conjunction with stress mediators, as discussed above [49].

Axis 4: Metabolic health

1. Interest in metabolic embedding of ELA stems from:

a. epidemiological [1, 69]

b. and clinical [70] studies linking ELA to:

i. obesity,

ii. dyslipidemia,

iii. and type 2 diabetes,

c. raising questions about possible causal pathways.

2. While research directly linking ELA to altered development of metabolic physiology remains emergent (versus clear indirect impacts via, e.g., chronic inflammation [3]),

a. potential loci of embedding are multiple.

i. Feeding-related regulation involves, among other networks,

ii. dopaminergic reward pathways under top-down control by the PFC,

iii. and hypothalamic nuclei integrating nutrient signals to induce hunger or satiety,

iv. and systemic shifts between catabolism and anabolism [71].

3. Peripheral energy homeostasis involves an interplay of:

a. anabolic (e.g., insulin)

b. and catabolic

i. (e.g., cortisol,

ii. glucagon,

iii. epinephrine/norepinephrine)

signals promoting:

i. increased glycemia

ii. and tissue insulin resistance.

4. Considering mechanisms of potential ELA effects,:

a. chronic inflammation,

b. as well as excess catabolic signaling in those with hypercortisolemia,

c. are proposed to drive metabolic dysfunction.

5. Preliminary models also posit that ELA may durably:

a. alter hepatic expression of:

i. cortisol-activating

ii. and -metabolizing enzymes,

iii. enhancing tissue-level insulin resistance

iv. even in those who later suppress hypercortisolemia [70].

6. Furthermore, a previous study linked ELA to altered central reward processing: a. promoting excess food intake in some individuals [72].

7. Additional work is needed to explore the hypothesized pathways.

Axis 5: The microbiome

1. The gut microbiome represents the collective genome of:

a. nearly 100 trillion commensal microorganisms,

b. including over 1000 bacterial species.

2. Dysbiosis, a pathogenic disruption of gut microbial composition or host-microbe interactions, is implicated in diseases including:

a. obesity,

b. type 2 diabetes,

c. and depression [73].

3. While genetically influenced, gut microbial composition responds to factors including:

a. stress,

b. diet,

c. infection,

d. drugs,

e. and toxins,

4. making the gut a potential mediator between environment and disease.

5. Various previous studies have suggested:

a. profound microbiome effects on:

i. neuroendocrine

ii. and immune function,

iii. such that dysbiosis could compound ELA-related changes including:

iv. cortisol dysregulation

v. and chronic inflammation [73, 74, 75, 76, 77].

6. Furthermore, growing literature on the “gut-brain axis” describes microbial influence on:

i. neural development

ii. and functioning [78].

7. Pathways of influence may include:

a. microbial vagus nerve activation,

b. neural signaling by microbial metabolites

c. or molecular patterns,

d. heightened inflammation with downstream neural effects,

e. and induction of epigenetic changes [77, 79, 80].

8. In animal experimentation and some small human studies, dysbiosis has also been shown:

a. to impact relevant brain

b. and behavioral parameters,

i. including cortisol regulation,

ii. depressive

iii. and anxious symptomatology,

iv. and social functioning [77, 79].

9. Whether ELA itself produces dysbiosis is a question of ongoing interest [74].

10. A study in rodents found that infant maternal separation durably:

a. altered fecal microbiota

b. and increased later inflammatory reactivity [81].

11. Work in monkeys, meanwhile, found that transient dysbiosis triggered by infant maternal separation predicted:

a. durable immune dysfunction,

b. supporting the possibility of early microbiome effects on development in other axes [82].

12. If human research replicates such findings, the health implications may be considerable.

Interactive effects across axes

1. The above evidence illustrates how ELA-related physiological changes generate feed- forward synergies;

a. for instance, if glucocorticoid toxicity compromises brain regions tasked with stress regulation [29],

b. or stress-related inflammation further disrupts: i. neural,

ii. gut microbial,

iii. and metabolic axes

iv. to compound HPA dysregulation

v. and further inflammation [83].

2. Meanwhile, brain functional changes

a. (e.g., altered executive functions

b. and reward processing)

c. may shape health-related behaviors

d. and ongoing social risk exposures [84].

3. Synergistic effects of ELA thus produce wide-ranging physiological changes marked by:

a. aberrant neural function,

b. endocrine activity,

c. chronic inflammation,

d. immunosuppression,

e. insulin resistance and,

f. potentially, dysbiosis.

4. These changes are substantially mediated by:

a. altered development of stress-response systems;

b. when acute, activation of these systems generates adaptive changes across body systems

i. (e.g., immune,

ii. metabolic,

iii. cardiovascular)

iv. to address threats.

5. However, chronic or excessive activation contributes to:

a. the pathogenic physiological “wear and tear”

b. described within the allostatic load paradigm [15, 29].

6. In full, ELA-induced changes may mediate:

a. epidemiological links to key diseases, including, among others,

i. obesity,

ii. dyslipidemia,

iii. type 2 diabetes,

iv. atherosclerosis,

v. asthma,

vi. thromboembolic events (myocardial infarction, stroke),

vii. cancer onset and progression, as well as

viii. addictions,

ix. psychopathology,

x. and adverse social outcomes [1, 2, 3, 4, 5, 6, 18].

Pg 37

1. We highlight four recommendations in particular.

2. First, we suggest that screening for ELA should become a routine part of clinical care for children and

adults.

a. This aspect of the “developmental history” can provide information about a patient’s risk of:

i. major pediatric

ii. and adult diseases,

iii. facilitating social support,

iv. protective intervention,

v. and/or decisions about disease screening

vi. and prevention.

4: McCrory EJ, Gerin MI, Viding E. Annual Research Review: Childhood maltreatment, latent

vulnerability and the shift to preventative psychiatry – the contribution of functional brain imaging. J

Child Psychol Psychiatry. 2017 Apr;58(4):338-357. doi: 10.1111/jcpp.12713. Epub 2017 Mar 13.

Review. PubMed PMID: 28295339.

The theory of latent vulnerability

1. The theory of latent vulnerability

a. reconceptualizes the link between

i. childhood maltreatment and the

ii. associated increased risk of

iii. psychiatric disorder across the life span (McCrory & Viding, 2015)

b. According to this theory,

i. maltreatment results in measurable alterations

ii. in a number of neurobiological systems that reflect calibration to

iii. neglectful and/or abusive early environments.

c. A general principle of the theory is that

i. these changes are often beneficial within the early maladaptive context

ii. (i.e. carry adaptive value within that particular setting)

iii. thus representing in part a functional response.

d. However, such adaptations are equally thought to

i. incur a longer term cost as they may mean that

ii. the individual is poorly optimized to negotiate the demands of

iii. other, more normative environments,

iv. thus increasing vulnerability to future stressors (McCrory & Viding, 2015).

e. Patterns of adaptation are likely to arise at multiple levels (see Cicchetti, 2016).

f. Recently, for example, we demonstrated that

i. young adults self-reporting childhood experiences of maltreatment

ii. displayed altered patterns of epigenetic modulation

iii. in genes implicated in a range of physical and psychiatric disorders (Cecil et al., 2016)

g. Geneontology analyses indicated that

i. individual maltreatment subtypes showed

ii. unique methylation patterns enriched for specific biological processes

h. (e.g.physicalabuse:

i. stress regulation,

ii. fear response,

iii. heart rate regulation;

i. physical neglect:

i. lipoprotein metabolism,

ii. polyamine metabolism,

iii. regulation of cholesterol efflux).

j. In addition, a ‘common’ epigenetic signature

i. across maltreatment subtypes was also observed,

ii. enriched for biological processes related to

iii. neural development and

iv. organismal growth (Cecil et al., 2016)

5: Calem M, Bromis K, McGuire P, Morgan C, Kempton MJ. Meta-analysis of association between

childhood adversity and hippocampus and amygdala volume in non-clinical and general population

samples. Neuroimage Clin. 2017 Feb 22;14:471-479. doi: 10.1016/j.nicl.2017.02.016. eCollection 2017.

Review. PubMed PMID: 28275547; PubMed Central PMCID: PMC5331153.

Pg 1

Childhood adversity, defined as difficult and unpleasant situations and experiences in childhood including

physical, sexual, or emotional abuse, neglect and poverty, is highly prevalent worldwide (Kessler et al.,

2010).

In a recent UK survey (Radford et al., 2013), 24.5% of young adults reported experiencing abuse or

neglect by a parent or caregiver during childhood.

Childhood abuse and neglect is associated with a range of negative physical and mental health outcomes

(see (Wilson, 2010) and (Norman et al., 2012) for reviews),

a. including posttraumatic stress disorder (Kessler et al., 1995),

b. psychosis (Varese et al., 2012),

c. depression and anxiety (Lindert et al., 2014),

d. diabetes (Huffhines et al., 2016) and

e. obesity (Danese and Tan, 2014).

f. Growing up in poverty, another highly prevalent form of childhood adversity,

i. is also related to a range of negative health consequences (Schickedanz et al., 2015).

These negative health outcomes may be due in part to the effects of childhood adversity on brain

development.

Childhood adversity can be a form of stress at a time where brains are especially sensitive to the

neurotoxic effects of excessive release of stress hormones and stress-related epigenetic changes (Lupien

et al., 2009).

Evidence for altered neurodevelopment comes from several studies that have now shown associations

between childhood adversity and neuroanatomical changes (for reviews, see (Hart and Rubia, 2012) and

(McLaughlin et al., 2014)).

The neurotoxic effect of stress has been demonstrated experimentally in animal studies and importantly,

the neuroanatomical effects of stress in these studies are similar to those found to be related to childhood

adversity in humans, particularly:

a. in the hippocampus

b. and corpus callosum (Teicher et al., 2006).

8. Thomason ME, Marusak, HA. Toward understanding the impact of trauma on the early developing

human brain. Neuroscience. 2017. Feb. 7; 342:55-67. doi: 10.101602.022.Epub Feb. 15. Review. PubMed

PMID 26892294; PubMed Central PMCID: PMC4985495.

Pg 12

Here, we provide a brief review of alterations in neural systems most frequently associated with traumatic

stress.

[slm: the stress response]

1. The stress pathway

a. is one of the most obvious candidates

b. when considering the impact of trauma on animal biology.

2. Although stress

a. induces responses across the entire body,

b. the brain is the central regulator of the stress response

c. through action of the hypothalamic–pituitary–adrenal (HPA) axis.

(slm: autonomic responses should be considered here; she may cover them further on) [slm: HPA Axis]

3. The HPA axis mobilizes

a. endocrine,

b. metabolic,

c. cardiovascular,

d. and immune system responses

i. (i)  by way of glucocorticoids, such as cortisol,

ii. (ii)  [which is ] the hormonal end product of the HPA axis in humans (Romeo and

McEwen, 2006).

[slm: the hippocampus]

4. The hippocampus,

a. situated bilaterally in medial temporal lobe,

b. is replete with glucocorticoid receptors

c. and is on the receiving end of the stress hormone cascade (McEwen and Milner, 2007; McEwen,

2012).

5. Repeat hits to this receptor system are associated with atrophy,:

a. reduced neurogenesis

b. and synaptogenesis,

c. and protein expression modification in animals (McEwen, 2012).

9. Teicher MH, Samson, JA. Annual Research Review: Enduring neurobiological effects of childhood

abuse and neglect. JChild Psychiatry. 2016 Mar: 57 (3) : 241-66. doi: 10.1111/jcpp.12507. Epub 2016

Feb 1. Review. PubMed PMID: 26831814; PubMed Central PMCID: PMC4760853.

1. The deleterious effects of

a. childhood maltreatment

b. and early deprivation

c. are widely reported and acknowledged.

2. Both

a. retrospective

b. and prospective

c. studies document associations between

d. exposure to early maltreatment and

i. poorer psychological

ii. and physical functioning

iii. in adulthood.

3. Survivors of childhood maltreatment show

a. higher prevalence of depression,

b. anxiety,

c. substance abuse,

d. eating disorders,

e. suicidal symptomatology,

f. psychosis and

g. personality disorder (see (2009; Bendall, Jackson, Hulbert, & McGorry, 2008; Norman, et al.,

2012; Teicher & Samson, 2013) for recent reviews)

h. as well as diminished cognitive functioning (de Bellis, Hooper, Spratt, & Woolley, 2009; Gould,

et al., 2012)

i. and poorer treatment response (Nanni, Uher, & Danese, 2012; Teicher & Samson, 2013).

4. Green and colleagues (2010)

a. estimated that maltreatment accounted

b. for 45% of the population attributable risk

c. for childhood onset psychiatric disorders.

5. In addition,

a. survivors of childhood maltreatment show

b. higher adult rates of inflammation (Danese, Pariante, Caspi, Taylor, & Poulton, 2007),

c. metabolic syndrome (Danese, et al., 2009),