Stress and the social brain: behavioural effects and neurobiological mechanisms

Sandi, Carmen; Haller, József

doi:10.1038/nrn3918

Cited by 494 publications

(420 citation statements)

References 218 publications

(165 reference statements)

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“…These correlations corroborate studies that show that HPA-axis disturbances can cause deficits in social behavior later in life (reviewed in ref. 57) and that social behavior is (co)regulated by the hippocampus (58).…”

Section: Resultsmentioning

confidence: 99%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/ stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.maternal immune activation | prenatal stress | sex differences | Cntnap2 | autism A utism spectrum disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders. The core symptoms of ASD are deficits in social communication and social interactions (Diagnostic and Statistical Manual of Mental Disorders V) and one of the most noticeable biological constants in this group of disorders is the sex difference: ∼80% of the children diagnosed with an ASD are boys (1). Many genes have been implicated in the etiologies underlying ASD in humans and ASD-like behavior in animal models. Some of these genes are located on the sex chromosomes and many of these genes may be able to affect other sex-chromosomal genes or may otherwise indirectly lead to sex-specific effects (reviewed in ref.2). However, it seems unlikely that these genes can account for the full sex bias in incidence and it is becoming increasingly clear that environmental factors play a very important role as well (3), and that these factors can interact with one another (2, 4). Moreover, prenatal testosterone (an indirect genetic factor) affects human behavior (5, 6) and may increase the risk to develop an ASD (7).Although today it is commonly proposed that many neurodevelopmental disorders result from interactions between "nature" and "nurture," studies investigating the gene-environment interaction in the development of ASD are scarce.In this study we tested whether an interaction between an ASD-related genetic mutation and an environmental factor may be a...

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Section: Resultsmentioning

confidence: 99%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Pathological changes in monoamine synapses, hypothalamus‐pituitary‐adrenal axis, and brain‐derived neurotrophic factor are believed to cause neuronal atrophy in the ventral tegmental area, nucleus accumbens, and prefrontal cortex from depressive patients and depression‐like animals (Banasr, Dwyer, & Duman, 2011; Bennett et al, 2008; Duman, 2010; Elizalde et al, 2008; Ma, Xu, et al, 2016; Pittenger & Duman, 2008; Sandi & Haller, 2015; Xu, Cui, & Wang, 2016). In addition, major depression may be caused by a lack of reward in life to lower the use in the function of brain reward circuits including the ventral tegmental area, nucleus accumbens, and prefrontal cortex (Wang & Cui, 2015; Zhu, Wang, Ma, Cui, & Wang, 2017).…”

Section: Introductionmentioning

confidence: 99%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

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Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

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“…A variety of prenatal and postnatal stressors have been used in these studies, with a preponderance of studies finding emotional consequences including behaviors that typically signify depression, anxiety, and social isolation. The consequences of early-life (prenatal as well as postnatal) stress on emotional and social behaviors have been a subject of several recent reviews (eg, Sandi and Haller, 2015;Nishi et al, 2014). Here, we summarize in Table form the consequences of chronic early-life adversity provoked by abnormal maternal care in the limited bedding-nesting environment (Gilles et al, 1996;Molet et al, 2014), a model recently adopted and adapted by over 50 laboratories around the world (eg, Raineki et al, 2010;Wang et al, 2011;Bolton et al, 2013;Machado et al, 2013;Maniam et al, 2014;Kohl et al, 2015;Naninck et al, 2015; Table 1).…”

Section: Emotional and Social Consequences Of Early-life Experience Vmentioning

confidence: 99%

“…Accordingly, the central nervous system is equipped with several sensing mechanisms to identify stress, as well as processes to respond to stressful signals and be modified by them. Cognitive brain networks, including those centered on the hippocampus and prefrontal cortex regions involved in emotional processes, such as amygdala and the nucleus accumbens, as well as network involved in social behaviors, appear to be particularly vulnerable to the effects of stress (Kim and Diamond, 2002;Joëls and Baram, 2009;Lupien et al, 2009;Malter Cohen et al, 2013;Sandi and Haller, 2015). Important parameters that govern the effects of stress on brain functions include the context and nature of the stress (Zoladz and Diamond, 2008;Joëls and Baram, 2009;McEwen and Gianaros, 2011;Schwabe et al, 2011).…”

mentioning

confidence: 99%

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

Chen

Baram

2015

Neuropsychopharmacol

394

327

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Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Adverse early-life experiences provoke the release and modify the expression of several stress mediators and neurotransmitters within specific brain regions. The interaction of these mediators with developing neurons and neuronal networks may lead to long-lasting structural and functional alterations associated with cognitive and emotional consequences. Although a vast body of work has linked quantitative and qualitative aspects of stress to adolescent and adult outcomes, a number of questions are unclear. What distinguishes 'normal' from pathologic or toxic stress? How are the effects of stress transformed into structural and functional changes in individual neurons and neuronal networks? Which ones are affected? We review these questions in the context of established and emerging studies. We introduce a novel concept regarding the origin of toxic early-life stress, stating that it may derive from specific patterns of environmental signals, especially those derived from the mother or caretaker. Fragmented and unpredictable patterns of maternal care behaviors induce a profound chronic stress. The aberrant patterns and rhythms of early-life sensory input might also directly and adversely influence the maturation of cognitive and emotional brain circuits, in analogy to visual and auditory brain systems. Thus, unpredictable, stress-provoking early-life experiences may influence adolescent cognitive and emotional outcomes by disrupting the maturation of the underlying brain networks. Comprehensive approaches and multiple levels of analysis are required to probe the protean consequences of early-life adversity on the developing brain. These involve integrated human and animal-model studies, and approaches ranging from in vivo imaging to novel neuroanatomical, molecular, epigenomic, and computational methodologies. Because early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies, understanding the underlying processes will have profound implications for the world's current and future children.

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Stress and the social brain: behavioural effects and neurobiological mechanisms

Cited by 494 publications

References 218 publications

Sex-specific gene–environment interactions underlying ASD-like behaviors

Sex-specific gene–environment interactions underlying ASD-like behaviors

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

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