Early Life Stress

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Xiaodong Wang - One of the best experts on this subject based on the ideXlab platform.

  • Molecular Mechanisms for Reprogramming Hippocampal Development and Function by Early-Life Stress - Editorial: Molecular Mechanisms for Reprogramming Hippocampal Development and Function by Early-Life Stress
    Frontiers in Molecular Neuroscience, 2016
    Co-Authors: Xiaodong Wang, Mathias V. Schmidt
    Abstract:

    The hippocampal formation is both a key component of the medial temporal lobe crucial for declarative memory and a main target of Stress mediators (e.g., glucocorticoids and neuropeptides) and Stress-related molecules (e.g., nutritional factors and cytokines). During the first weeks of Life, the hippocampus significantly increases in volume (Zhang et al., 2005) and several critical developmental processes coincide: generation of new neurons, outgrowth of neurites, formation of synaptic contacts, and establishment of neuronal circuits (Khalaf-Nazzal and Francis, 2013). Although the neonatal hypothalamic-pituitary-adrenal (HPA) axis is relatively hyporesponsive to environmental challenges, age-appropriate Stressors can activate Stress response, which in turn alters hippocampal development and increases the risk to develop neuropsychiatric disorders later in Life, dependent on adult Life conditions, and genetic predispositions (for recent reviews, see Lucassen et al., 2013; Tost et al., 2015; Bick and Nelson, 2016; Chen and Baram, 2016). As many neuropsychiatric disorders, such as schizophrenia and anxiety disorders, have developmental origins (Gross and Hen, 2004; Howes and Murray, 2014), dissecting the molecular mechanisms mediating the potentially detrimental consequences of Early-Life Stress will provide insight into the pathophysiology and intervention of these disorders. Most studies so far focus on the mechanisms of the long-term impact of Early-Life Stress on hippocampal plasticity in adolescence/adulthood, which are of clinical relevance. In comparison, molecular mechanisms on how Stress shapes the developing hippocampus have received attention only recently (Gross et al., 2012; Wei et al., 2012, 2015; Suri et al., 2013; Liao et al., 2014). We therefore initiated this research topic to sum up recent findings with an emphasis on both the dynamic effects of Early-Life Stress on hippocampal structure and function at different Life stages and the immediate effects of Stress on hippocampal development. Firstly, Huang provides an overview on the molecular and cellular alterations that modulate the effects of prenatal or postnatal Stress on hippocampal development, and discusses how epigenetic modifications underlie the programming effects of Early-Life Stress and contribute to the pathogenesis of epilepsy (Huang). In the dentate gyrus (DG) of the hippocampal formation, new neurons are continuously generated and selectively integrated to local circuits throughout the Lifespan. Unlike the adult DG where most granule cells are mature and settled in place, during the first postnatal week the infrapyramidal blade of DG is yet to be formed and a majority of neurons are still immature. Exposure to severe Stressors may thus perturb various aspects of neonatal and adult hippocampal neurogenesis and evoke lasting behavioral consequences. Lajud and Torner describe the key processes of neonatal DG development and review the short-term, intermediate and lasting effects of Early-Life Stress on hippocampal neurogenesis (Lajud and Torner). Koehl further discusses the interaction between environmental factors (including Early-Life Stress) and genetic background in shaping adult hippocampal neurogenesis and propose a conceptual framework for identifying genes that confer Stress resilience or vulnerability (Koehl). Early-Life adversities are also manifested by malnutrition or infection. The disruption of maternal care inevitably alters the levels of nutritional and inflammatory factors in the offspring, which may modulate the influences of Early Stress. Hoeijmakers and colleagues present a comprehensive update on the intricate interplay among these essential elements of Early-Life environment and discuss their synergistic effects in shaping hippocampal structure and cognition, with a specific focus on adult neurogenesis (Hoeijmakers et al.). Moreover, Lardner summarizes our current understanding on the involvement of vitamin D, a vital nutrient with pleiotropic effects that may be insufficiently available under Early-Life Stressful situations, in hippocampal development (Lardner). Neurotrophins, especially brain-derived neurotrophic factor (BDNF), regulate neural circuit formation and activity-dependent synaptic plasticity via Trk receptors. Daskalakis and colleagues address the cross-talk between glucocorticoids and BDNF-TrkB signaling in Early Stress-induced hippocampal maldevelopment and behavioral deficits (Daskalakis et al.). In the research report by Wang and colleagues, BDNF protein level is examined in the hippocampus, medial prefrontal cortex and nucleus accumbens at different time points after neonatal maternal separation, and sex difference is further compared and discussed (Wang et al.). These two articles highlight the modulatory role of BDNF in Early postnatal Stress-programmed hippocampal development. The serotonin (or 5-hydroxytriptamine, 5-HT) system is a main molecular target for the intervention of depression and anxiety and implicated in the acute Stress response. In another highlighted research article, Bravo and colleagues evaluate the mRNA levels of two key components of the serotonin system, 5-HT1A receptor and serotonin transporter (SERT), in adult rats with or without a history of neonatal maternal separation, and find that Early-Life Stress alters 5-HT1A and SERT mRNA levels in the amygdala and dorsal raphe nucleus, but not the hippocampus (Bravo et al.). These alterations may underlie the susceptibility of Early-Life Stressed individuals to affective or anxiety disorders. For altricial animals such as mice and rats, somatosensory input from the skin/whisker provides a major information source for representation of Early-Life environment. Erratic maternal care and/or peer interaction may thus result in abnormal experience-dependent synaptic plasticity and reshape the development of neocortex and hippocampus. Takatsuru and Koibuchi review how Early-Life Stress disrupts the structure and activity of the somatosensory cortex and suggest the involvement of glucocorticoids, glutamate, and microglia in Stress-induced somatosensory alterations (Takatsuru and Koibuchi). Taken together, this research topic summarizes recent progress on the mechanisms of the effects of Early postnatal Stress on hippocampal development, and underlines the interactions of various factors in programming hippocampal plasticity. Meanwhile, many more interesting questions and new challenges emerge, some of which are sketched below. Dynamics. Neural development and plasticity are highly dynamic, so are the influences of Early-Life Stress. It is important to explore how Stress dynamically modulates the levels and activity of Stress-related molecules, and how these molecular events affect the dynamics of neuronal structure (e.g., formation and elimination of dendritic spines) and activity at different Life stages. Interactions. Future studies need to balance between addressing the complex interactions (e.g., between the timing and features of the Stressor and concomitant critical developmental events; between genetic makeup and environmental elements; sex differences; etc.) and maintaining a manageable experimental design. Pathways. Our understanding on the mechanisms of Early-Life Stress may benefit from studies extending from dissecting the molecular pathways to mapping anatomical (i.e., neural circuits) and functional (i.e., network activity) pathways. Adaptation. While Early-Life adversity is undoubtedly a major risk factor for adult pathologies, not all alterations resulting from Early-Life Stress may be detrimental. Mounting evidence suggests that at least some of the molecular, structural or functional consequences of Early-Life Stress exposure are adaptive and may increase individual resilience to similar challenges later on. Future studies will therefore also address how the observed alterations affect vulnerability or resilience to additional challenges in adulthood. In short, we hope this collection will provide new perspectives and stimulate studies on the molecular mechanisms of Early-Life Stress and brain development.

  • editorial molecular mechanisms for reprogramming hippocampal development and function by Early Life Stress
    Frontiers in Molecular Neuroscience, 2016
    Co-Authors: Xiaodong Wang, Mathias V. Schmidt
    Abstract:

    The hippocampal formation is both a key component of the medial temporal lobe crucial for declarative memory and a main target of Stress mediators (e.g., glucocorticoids and neuropeptides) and Stress-related molecules (e.g., nutritional factors and cytokines). During the first weeks of Life, the hippocampus significantly increases in volume (Zhang et al., 2005) and several critical developmental processes coincide: generation of new neurons, outgrowth of neurites, formation of synaptic contacts, and establishment of neuronal circuits (Khalaf-Nazzal and Francis, 2013). Although the neonatal hypothalamic-pituitary-adrenal (HPA) axis is relatively hyporesponsive to environmental challenges, age-appropriate Stressors can activate Stress response, which in turn alters hippocampal development and increases the risk to develop neuropsychiatric disorders later in Life, dependent on adult Life conditions, and genetic predispositions (for recent reviews, see Lucassen et al., 2013; Tost et al., 2015; Bick and Nelson, 2016; Chen and Baram, 2016). As many neuropsychiatric disorders, such as schizophrenia and anxiety disorders, have developmental origins (Gross and Hen, 2004; Howes and Murray, 2014), dissecting the molecular mechanisms mediating the potentially detrimental consequences of Early-Life Stress will provide insight into the pathophysiology and intervention of these disorders. Most studies so far focus on the mechanisms of the long-term impact of Early-Life Stress on hippocampal plasticity in adolescence/adulthood, which are of clinical relevance. In comparison, molecular mechanisms on how Stress shapes the developing hippocampus have received attention only recently (Gross et al., 2012; Wei et al., 2012, 2015; Suri et al., 2013; Liao et al., 2014). We therefore initiated this research topic to sum up recent findings with an emphasis on both the dynamic effects of Early-Life Stress on hippocampal structure and function at different Life stages and the immediate effects of Stress on hippocampal development. Firstly, Huang provides an overview on the molecular and cellular alterations that modulate the effects of prenatal or postnatal Stress on hippocampal development, and discusses how epigenetic modifications underlie the programming effects of Early-Life Stress and contribute to the pathogenesis of epilepsy (Huang). In the dentate gyrus (DG) of the hippocampal formation, new neurons are continuously generated and selectively integrated to local circuits throughout the Lifespan. Unlike the adult DG where most granule cells are mature and settled in place, during the first postnatal week the infrapyramidal blade of DG is yet to be formed and a majority of neurons are still immature. Exposure to severe Stressors may thus perturb various aspects of neonatal and adult hippocampal neurogenesis and evoke lasting behavioral consequences. Lajud and Torner describe the key processes of neonatal DG development and review the short-term, intermediate and lasting effects of Early-Life Stress on hippocampal neurogenesis (Lajud and Torner). Koehl further discusses the interaction between environmental factors (including Early-Life Stress) and genetic background in shaping adult hippocampal neurogenesis and propose a conceptual framework for identifying genes that confer Stress resilience or vulnerability (Koehl). Early-Life adversities are also manifested by malnutrition or infection. The disruption of maternal care inevitably alters the levels of nutritional and inflammatory factors in the offspring, which may modulate the influences of Early Stress. Hoeijmakers and colleagues present a comprehensive update on the intricate interplay among these essential elements of Early-Life environment and discuss their synergistic effects in shaping hippocampal structure and cognition, with a specific focus on adult neurogenesis (Hoeijmakers et al.). Moreover, Lardner summarizes our current understanding on the involvement of vitamin D, a vital nutrient with pleiotropic effects that may be insufficiently available under Early-Life Stressful situations, in hippocampal development (Lardner). Neurotrophins, especially brain-derived neurotrophic factor (BDNF), regulate neural circuit formation and activity-dependent synaptic plasticity via Trk receptors. Daskalakis and colleagues address the cross-talk between glucocorticoids and BDNF-TrkB signaling in Early Stress-induced hippocampal maldevelopment and behavioral deficits (Daskalakis et al.). In the research report by Wang and colleagues, BDNF protein level is examined in the hippocampus, medial prefrontal cortex and nucleus accumbens at different time points after neonatal maternal separation, and sex difference is further compared and discussed (Wang et al.). These two articles highlight the modulatory role of BDNF in Early postnatal Stress-programmed hippocampal development. The serotonin (or 5-hydroxytriptamine, 5-HT) system is a main molecular target for the intervention of depression and anxiety and implicated in the acute Stress response. In another highlighted research article, Bravo and colleagues evaluate the mRNA levels of two key components of the serotonin system, 5-HT1A receptor and serotonin transporter (SERT), in adult rats with or without a history of neonatal maternal separation, and find that Early-Life Stress alters 5-HT1A and SERT mRNA levels in the amygdala and dorsal raphe nucleus, but not the hippocampus (Bravo et al.). These alterations may underlie the susceptibility of Early-Life Stressed individuals to affective or anxiety disorders. For altricial animals such as mice and rats, somatosensory input from the skin/whisker provides a major information source for representation of Early-Life environment. Erratic maternal care and/or peer interaction may thus result in abnormal experience-dependent synaptic plasticity and reshape the development of neocortex and hippocampus. Takatsuru and Koibuchi review how Early-Life Stress disrupts the structure and activity of the somatosensory cortex and suggest the involvement of glucocorticoids, glutamate, and microglia in Stress-induced somatosensory alterations (Takatsuru and Koibuchi). Taken together, this research topic summarizes recent progress on the mechanisms of the effects of Early postnatal Stress on hippocampal development, and underlines the interactions of various factors in programming hippocampal plasticity. Meanwhile, many more interesting questions and new challenges emerge, some of which are sketched below. Dynamics. Neural development and plasticity are highly dynamic, so are the influences of Early-Life Stress. It is important to explore how Stress dynamically modulates the levels and activity of Stress-related molecules, and how these molecular events affect the dynamics of neuronal structure (e.g., formation and elimination of dendritic spines) and activity at different Life stages. Interactions. Future studies need to balance between addressing the complex interactions (e.g., between the timing and features of the Stressor and concomitant critical developmental events; between genetic makeup and environmental elements; sex differences; etc.) and maintaining a manageable experimental design. Pathways. Our understanding on the mechanisms of Early-Life Stress may benefit from studies extending from dissecting the molecular pathways to mapping anatomical (i.e., neural circuits) and functional (i.e., network activity) pathways. Adaptation. While Early-Life adversity is undoubtedly a major risk factor for adult pathologies, not all alterations resulting from Early-Life Stress may be detrimental. Mounting evidence suggests that at least some of the molecular, structural or functional consequences of Early-Life Stress exposure are adaptive and may increase individual resilience to similar challenges later on. Future studies will therefore also address how the observed alterations affect vulnerability or resilience to additional challenges in adulthood. In short, we hope this collection will provide new perspectives and stimulate studies on the molecular mechanisms of Early-Life Stress and brain development.

  • Hippocampal neuroligin-2 links Early-Life Stress with impaired social recognition and increased aggression in adult mice
    Psychoneuroendocrinology, 2015
    Co-Authors: Christine Kohl, Xiaodong Wang, Jocelyn Grosse, Celine Fournier, D. Harbich, Sören Westerholz, Ji-tao Li, Alexandre Bacq, Claudia Sippel, Felix Hausch
    Abstract:

    Early-Life Stress is a key risk factor for the development of neuropsychiatric disorders later in Life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that Early-Life Stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics Early-Life Stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the Early-Life Stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating Early-Life Stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.

  • EarlyLife Stress‐induced anxiety‐related behavior in adult mice partially requires forebrain corticotropin‐releasing hormone receptor 1
    European Journal of Neuroscience, 2012
    Co-Authors: Xiaodong Wang, Wolfgang Wurst, Jan M Deussing, Christiana Labermaier, Florian Holsboer, Marianne B. Müller, Mathias V. Schmidt
    Abstract:

    Early-Life Stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in Early-Life Stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of Early-Life Stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in Stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but Early-Life Stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, Early-Life Stress had only subtle effects on anxiety-related behavior. Moreover, Early-Life Stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization Stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of Early-Life Stress, and suggest that other neural circuits are also involved in the programming effects of Early-Life Stress on anxiety-related behavior.

  • forebrain crf 1 modulates Early Life Stress programmed cognitive deficits
    The Journal of Neuroscience, 2011
    Co-Authors: Xiaodong Wang, Gerhard Rammes, Igor Kraev, Miriam Wolf, C Liebl, Sebastian H Scharf, Courtney J Rice, Wolfgang Wurst, F Holsboer, Jan M Deussing
    Abstract:

    Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of Early-Life Stress have suggested a role for this endogenous Stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1 knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1 in the long-lasting effects of Early-Life Stress on learning and memory. Early-Life Stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in Stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in Stressed mice. In addition, Early-Life Stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by Early-Life Stress are at least partly dependent on persistent forebrain CRF1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of Early-Life adversity.

Mathias V. Schmidt - One of the best experts on this subject based on the ideXlab platform.

  • Early Life Stress determines the effects of glucocorticoids and Stress on hippocampal function: Electrophysiological and behavioral evidence respectively
    Neuropharmacology, 2018
    Co-Authors: Anup G. Pillai, Mathias V. Schmidt, Marian Joëls, Florian Holsboer, Els H. Velzing, Sylvie L. Lesuis, Harm J. Krugers
    Abstract:

    Abstract Exposure to Early-Life adversity may program brain function to prepare individuals for adaptation to matching environmental contexts. In this study we tested this hypothesis in more detail by examining the effects of Early-Life Stress – induced by raising offspring with limited nesting and bedding material from postnatal days 2–9 – in various behavioral tasks and on synaptic function in adult mice. Early-Life Stress impaired adult performance in the hippocampal dependent low-arousing object-in-context recognition memory task. This effect was absent when animals were exposed to a single Stressor before training. Early-Life Stress did not alter high-arousing context and auditory fear conditioning. Early-Life Stress-induced behavioral modifications were not associated with alterations in the dendritic architecture of hippocampal CA1 pyramidal neurons or principal neurons of the basolateral amygdala. However, Early-Life Stress reduced the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and glutamate release probability specifically in hippocampal CA1 neurons, but not in the basolateral amygdala. These ex vivo effects in the hippocampus were abolished by acute glucocorticoid treatment. Our findings support that Early-Life Stress can hamper object-in-context learning via pre- and postsynaptic mechanisms that affect hippocampal function but these effects are counteracted by acute Stress or elevated glucocorticoid levels.

  • Molecular Mechanisms for Reprogramming Hippocampal Development and Function by Early-Life Stress - Editorial: Molecular Mechanisms for Reprogramming Hippocampal Development and Function by Early-Life Stress
    Frontiers in Molecular Neuroscience, 2016
    Co-Authors: Xiaodong Wang, Mathias V. Schmidt
    Abstract:

    The hippocampal formation is both a key component of the medial temporal lobe crucial for declarative memory and a main target of Stress mediators (e.g., glucocorticoids and neuropeptides) and Stress-related molecules (e.g., nutritional factors and cytokines). During the first weeks of Life, the hippocampus significantly increases in volume (Zhang et al., 2005) and several critical developmental processes coincide: generation of new neurons, outgrowth of neurites, formation of synaptic contacts, and establishment of neuronal circuits (Khalaf-Nazzal and Francis, 2013). Although the neonatal hypothalamic-pituitary-adrenal (HPA) axis is relatively hyporesponsive to environmental challenges, age-appropriate Stressors can activate Stress response, which in turn alters hippocampal development and increases the risk to develop neuropsychiatric disorders later in Life, dependent on adult Life conditions, and genetic predispositions (for recent reviews, see Lucassen et al., 2013; Tost et al., 2015; Bick and Nelson, 2016; Chen and Baram, 2016). As many neuropsychiatric disorders, such as schizophrenia and anxiety disorders, have developmental origins (Gross and Hen, 2004; Howes and Murray, 2014), dissecting the molecular mechanisms mediating the potentially detrimental consequences of Early-Life Stress will provide insight into the pathophysiology and intervention of these disorders. Most studies so far focus on the mechanisms of the long-term impact of Early-Life Stress on hippocampal plasticity in adolescence/adulthood, which are of clinical relevance. In comparison, molecular mechanisms on how Stress shapes the developing hippocampus have received attention only recently (Gross et al., 2012; Wei et al., 2012, 2015; Suri et al., 2013; Liao et al., 2014). We therefore initiated this research topic to sum up recent findings with an emphasis on both the dynamic effects of Early-Life Stress on hippocampal structure and function at different Life stages and the immediate effects of Stress on hippocampal development. Firstly, Huang provides an overview on the molecular and cellular alterations that modulate the effects of prenatal or postnatal Stress on hippocampal development, and discusses how epigenetic modifications underlie the programming effects of Early-Life Stress and contribute to the pathogenesis of epilepsy (Huang). In the dentate gyrus (DG) of the hippocampal formation, new neurons are continuously generated and selectively integrated to local circuits throughout the Lifespan. Unlike the adult DG where most granule cells are mature and settled in place, during the first postnatal week the infrapyramidal blade of DG is yet to be formed and a majority of neurons are still immature. Exposure to severe Stressors may thus perturb various aspects of neonatal and adult hippocampal neurogenesis and evoke lasting behavioral consequences. Lajud and Torner describe the key processes of neonatal DG development and review the short-term, intermediate and lasting effects of Early-Life Stress on hippocampal neurogenesis (Lajud and Torner). Koehl further discusses the interaction between environmental factors (including Early-Life Stress) and genetic background in shaping adult hippocampal neurogenesis and propose a conceptual framework for identifying genes that confer Stress resilience or vulnerability (Koehl). Early-Life adversities are also manifested by malnutrition or infection. The disruption of maternal care inevitably alters the levels of nutritional and inflammatory factors in the offspring, which may modulate the influences of Early Stress. Hoeijmakers and colleagues present a comprehensive update on the intricate interplay among these essential elements of Early-Life environment and discuss their synergistic effects in shaping hippocampal structure and cognition, with a specific focus on adult neurogenesis (Hoeijmakers et al.). Moreover, Lardner summarizes our current understanding on the involvement of vitamin D, a vital nutrient with pleiotropic effects that may be insufficiently available under Early-Life Stressful situations, in hippocampal development (Lardner). Neurotrophins, especially brain-derived neurotrophic factor (BDNF), regulate neural circuit formation and activity-dependent synaptic plasticity via Trk receptors. Daskalakis and colleagues address the cross-talk between glucocorticoids and BDNF-TrkB signaling in Early Stress-induced hippocampal maldevelopment and behavioral deficits (Daskalakis et al.). In the research report by Wang and colleagues, BDNF protein level is examined in the hippocampus, medial prefrontal cortex and nucleus accumbens at different time points after neonatal maternal separation, and sex difference is further compared and discussed (Wang et al.). These two articles highlight the modulatory role of BDNF in Early postnatal Stress-programmed hippocampal development. The serotonin (or 5-hydroxytriptamine, 5-HT) system is a main molecular target for the intervention of depression and anxiety and implicated in the acute Stress response. In another highlighted research article, Bravo and colleagues evaluate the mRNA levels of two key components of the serotonin system, 5-HT1A receptor and serotonin transporter (SERT), in adult rats with or without a history of neonatal maternal separation, and find that Early-Life Stress alters 5-HT1A and SERT mRNA levels in the amygdala and dorsal raphe nucleus, but not the hippocampus (Bravo et al.). These alterations may underlie the susceptibility of Early-Life Stressed individuals to affective or anxiety disorders. For altricial animals such as mice and rats, somatosensory input from the skin/whisker provides a major information source for representation of Early-Life environment. Erratic maternal care and/or peer interaction may thus result in abnormal experience-dependent synaptic plasticity and reshape the development of neocortex and hippocampus. Takatsuru and Koibuchi review how Early-Life Stress disrupts the structure and activity of the somatosensory cortex and suggest the involvement of glucocorticoids, glutamate, and microglia in Stress-induced somatosensory alterations (Takatsuru and Koibuchi). Taken together, this research topic summarizes recent progress on the mechanisms of the effects of Early postnatal Stress on hippocampal development, and underlines the interactions of various factors in programming hippocampal plasticity. Meanwhile, many more interesting questions and new challenges emerge, some of which are sketched below. Dynamics. Neural development and plasticity are highly dynamic, so are the influences of Early-Life Stress. It is important to explore how Stress dynamically modulates the levels and activity of Stress-related molecules, and how these molecular events affect the dynamics of neuronal structure (e.g., formation and elimination of dendritic spines) and activity at different Life stages. Interactions. Future studies need to balance between addressing the complex interactions (e.g., between the timing and features of the Stressor and concomitant critical developmental events; between genetic makeup and environmental elements; sex differences; etc.) and maintaining a manageable experimental design. Pathways. Our understanding on the mechanisms of Early-Life Stress may benefit from studies extending from dissecting the molecular pathways to mapping anatomical (i.e., neural circuits) and functional (i.e., network activity) pathways. Adaptation. While Early-Life adversity is undoubtedly a major risk factor for adult pathologies, not all alterations resulting from Early-Life Stress may be detrimental. Mounting evidence suggests that at least some of the molecular, structural or functional consequences of Early-Life Stress exposure are adaptive and may increase individual resilience to similar challenges later on. Future studies will therefore also address how the observed alterations affect vulnerability or resilience to additional challenges in adulthood. In short, we hope this collection will provide new perspectives and stimulate studies on the molecular mechanisms of Early-Life Stress and brain development.

  • editorial molecular mechanisms for reprogramming hippocampal development and function by Early Life Stress
    Frontiers in Molecular Neuroscience, 2016
    Co-Authors: Xiaodong Wang, Mathias V. Schmidt
    Abstract:

    The hippocampal formation is both a key component of the medial temporal lobe crucial for declarative memory and a main target of Stress mediators (e.g., glucocorticoids and neuropeptides) and Stress-related molecules (e.g., nutritional factors and cytokines). During the first weeks of Life, the hippocampus significantly increases in volume (Zhang et al., 2005) and several critical developmental processes coincide: generation of new neurons, outgrowth of neurites, formation of synaptic contacts, and establishment of neuronal circuits (Khalaf-Nazzal and Francis, 2013). Although the neonatal hypothalamic-pituitary-adrenal (HPA) axis is relatively hyporesponsive to environmental challenges, age-appropriate Stressors can activate Stress response, which in turn alters hippocampal development and increases the risk to develop neuropsychiatric disorders later in Life, dependent on adult Life conditions, and genetic predispositions (for recent reviews, see Lucassen et al., 2013; Tost et al., 2015; Bick and Nelson, 2016; Chen and Baram, 2016). As many neuropsychiatric disorders, such as schizophrenia and anxiety disorders, have developmental origins (Gross and Hen, 2004; Howes and Murray, 2014), dissecting the molecular mechanisms mediating the potentially detrimental consequences of Early-Life Stress will provide insight into the pathophysiology and intervention of these disorders. Most studies so far focus on the mechanisms of the long-term impact of Early-Life Stress on hippocampal plasticity in adolescence/adulthood, which are of clinical relevance. In comparison, molecular mechanisms on how Stress shapes the developing hippocampus have received attention only recently (Gross et al., 2012; Wei et al., 2012, 2015; Suri et al., 2013; Liao et al., 2014). We therefore initiated this research topic to sum up recent findings with an emphasis on both the dynamic effects of Early-Life Stress on hippocampal structure and function at different Life stages and the immediate effects of Stress on hippocampal development. Firstly, Huang provides an overview on the molecular and cellular alterations that modulate the effects of prenatal or postnatal Stress on hippocampal development, and discusses how epigenetic modifications underlie the programming effects of Early-Life Stress and contribute to the pathogenesis of epilepsy (Huang). In the dentate gyrus (DG) of the hippocampal formation, new neurons are continuously generated and selectively integrated to local circuits throughout the Lifespan. Unlike the adult DG where most granule cells are mature and settled in place, during the first postnatal week the infrapyramidal blade of DG is yet to be formed and a majority of neurons are still immature. Exposure to severe Stressors may thus perturb various aspects of neonatal and adult hippocampal neurogenesis and evoke lasting behavioral consequences. Lajud and Torner describe the key processes of neonatal DG development and review the short-term, intermediate and lasting effects of Early-Life Stress on hippocampal neurogenesis (Lajud and Torner). Koehl further discusses the interaction between environmental factors (including Early-Life Stress) and genetic background in shaping adult hippocampal neurogenesis and propose a conceptual framework for identifying genes that confer Stress resilience or vulnerability (Koehl). Early-Life adversities are also manifested by malnutrition or infection. The disruption of maternal care inevitably alters the levels of nutritional and inflammatory factors in the offspring, which may modulate the influences of Early Stress. Hoeijmakers and colleagues present a comprehensive update on the intricate interplay among these essential elements of Early-Life environment and discuss their synergistic effects in shaping hippocampal structure and cognition, with a specific focus on adult neurogenesis (Hoeijmakers et al.). Moreover, Lardner summarizes our current understanding on the involvement of vitamin D, a vital nutrient with pleiotropic effects that may be insufficiently available under Early-Life Stressful situations, in hippocampal development (Lardner). Neurotrophins, especially brain-derived neurotrophic factor (BDNF), regulate neural circuit formation and activity-dependent synaptic plasticity via Trk receptors. Daskalakis and colleagues address the cross-talk between glucocorticoids and BDNF-TrkB signaling in Early Stress-induced hippocampal maldevelopment and behavioral deficits (Daskalakis et al.). In the research report by Wang and colleagues, BDNF protein level is examined in the hippocampus, medial prefrontal cortex and nucleus accumbens at different time points after neonatal maternal separation, and sex difference is further compared and discussed (Wang et al.). These two articles highlight the modulatory role of BDNF in Early postnatal Stress-programmed hippocampal development. The serotonin (or 5-hydroxytriptamine, 5-HT) system is a main molecular target for the intervention of depression and anxiety and implicated in the acute Stress response. In another highlighted research article, Bravo and colleagues evaluate the mRNA levels of two key components of the serotonin system, 5-HT1A receptor and serotonin transporter (SERT), in adult rats with or without a history of neonatal maternal separation, and find that Early-Life Stress alters 5-HT1A and SERT mRNA levels in the amygdala and dorsal raphe nucleus, but not the hippocampus (Bravo et al.). These alterations may underlie the susceptibility of Early-Life Stressed individuals to affective or anxiety disorders. For altricial animals such as mice and rats, somatosensory input from the skin/whisker provides a major information source for representation of Early-Life environment. Erratic maternal care and/or peer interaction may thus result in abnormal experience-dependent synaptic plasticity and reshape the development of neocortex and hippocampus. Takatsuru and Koibuchi review how Early-Life Stress disrupts the structure and activity of the somatosensory cortex and suggest the involvement of glucocorticoids, glutamate, and microglia in Stress-induced somatosensory alterations (Takatsuru and Koibuchi). Taken together, this research topic summarizes recent progress on the mechanisms of the effects of Early postnatal Stress on hippocampal development, and underlines the interactions of various factors in programming hippocampal plasticity. Meanwhile, many more interesting questions and new challenges emerge, some of which are sketched below. Dynamics. Neural development and plasticity are highly dynamic, so are the influences of Early-Life Stress. It is important to explore how Stress dynamically modulates the levels and activity of Stress-related molecules, and how these molecular events affect the dynamics of neuronal structure (e.g., formation and elimination of dendritic spines) and activity at different Life stages. Interactions. Future studies need to balance between addressing the complex interactions (e.g., between the timing and features of the Stressor and concomitant critical developmental events; between genetic makeup and environmental elements; sex differences; etc.) and maintaining a manageable experimental design. Pathways. Our understanding on the mechanisms of Early-Life Stress may benefit from studies extending from dissecting the molecular pathways to mapping anatomical (i.e., neural circuits) and functional (i.e., network activity) pathways. Adaptation. While Early-Life adversity is undoubtedly a major risk factor for adult pathologies, not all alterations resulting from Early-Life Stress may be detrimental. Mounting evidence suggests that at least some of the molecular, structural or functional consequences of Early-Life Stress exposure are adaptive and may increase individual resilience to similar challenges later on. Future studies will therefore also address how the observed alterations affect vulnerability or resilience to additional challenges in adulthood. In short, we hope this collection will provide new perspectives and stimulate studies on the molecular mechanisms of Early-Life Stress and brain development.

  • EarlyLife Stress‐induced anxiety‐related behavior in adult mice partially requires forebrain corticotropin‐releasing hormone receptor 1
    European Journal of Neuroscience, 2012
    Co-Authors: Xiaodong Wang, Wolfgang Wurst, Jan M Deussing, Christiana Labermaier, Florian Holsboer, Marianne B. Müller, Mathias V. Schmidt
    Abstract:

    Early-Life Stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in Early-Life Stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of Early-Life Stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in Stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but Early-Life Stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, Early-Life Stress had only subtle effects on anxiety-related behavior. Moreover, Early-Life Stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization Stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of Early-Life Stress, and suggest that other neural circuits are also involved in the programming effects of Early-Life Stress on anxiety-related behavior.

  • Molecular mechanisms of Early Life Stress--lessons from mouse models.
    Neuroscience & Biobehavioral Reviews, 2009
    Co-Authors: Mathias V. Schmidt
    Abstract:

    Early Life Stress is one of the most explicit and undisputed environmental risk factors for disease later in Life, including metabolic and psychiatric diseases. The developmental timing and context of Stressful stimuli is thereby essential and determines the adaptive or maladaptive consequences. This review, which honors the invaluable accomplishments of one of the pioneers in the field, the late Seymour "Gig" Levine, focuses on the contribution of mouse models to the understanding of the molecular mechanisms that govern the acute and persistent effects of Early Life Stress. The importance of the postnatal period and the complex role of maternal care in regulating the offspring's Stress system activity are specifically addressed. Further, I discuss the possible molecular mechanisms that may be responsible for the persistent effects of Early Life Stress, including the important issue of resilience and susceptibility to adverse Life events.

Mario Francisco Juruena - One of the best experts on this subject based on the ideXlab platform.

  • Relationship Between Depression and Subtypes of Early Life Stress in Adult Psychiatric Patients
    Frontiers in Psychiatry, 2019
    Co-Authors: Camila Maria Severi Martins-monteverde, Sandra Marcia De Carvalho Tofoli, Cristiane Von Werne Baes, Emilene Reisdorfer, Thalita Padovan, Mario Francisco Juruena
    Abstract:

    Numerous studies have researched the aggravating and maintainer effect of Early Life Stress in patients adults with psychiatric disorders. This study examined the relationship between depression and subtypes of Early Life Stress among 81 psychiatric patients treated at the inpatient Day Hospital Unit of a University General Hospital. Psychiatric diagnosis was confirmed according to the MINI International Neuropsychiatric Interview (MINI). The Childhood Trauma Questionnaire (CTQ) was used for evaluating as retrospective assessment of the presence of ELS on these patients, and we also evaluated the severity of hopelessness with the Beck Hopelessness Scale (BHS). Our results suggested that the occurrence of depression in adulthood is related to situations of emotional abuse, sexual and physical neglect during childhood. The analysis between depression and childhood emotional abuse was significant after a multiple logistic regression analysis OR (IC 95%): 4.4 (1.7-11.2), even accounting for gender adjusted OR [AOR] 4.0; (IC 1.5-10.5); psychiatry family history AOR 3.8 (1.4-10.5); previous suicide attempted AOR 3.7; (1.4-10.5) and Hopelessness AOR 3.2 (1.11-9.4). Thus, these findings demonstrate emotional abuse as a significant risk factor to be part of the mechanism involved in the pathogenesis of depression related to Early Life Stress.

  • The Role of Early Life Stress in HPA Axis and Depression
    Understanding Depression, 2017
    Co-Authors: Mario Francisco Juruena, Anthony J. Cleare, Allan H. Young
    Abstract:

    Considerable evidence from various studies suggests a preeminent role for Early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that Early Life Stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between Stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of Early Life Stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression with Early Life Stress. Thus, more studies are needed to elucidate this issue.

  • 2204 – Differential diagnosis between bipolar disorder and borderline personality disorder based on Early Life Stress and psychoneuroendocrine assessment
    European Psychiatry, 2013
    Co-Authors: Angela Kaline Mazer, Mario Francisco Juruena
    Abstract:

    Introduction Bipolar Disorder (BD) and Borderline Personality Disorder (BPD) have common clinical features in the diagnosis. Factors included in the development and neurobiology of BD and BPD, as Early Stress and neuroendocrine markers, may represent indicators to difference them. Objective Assess Early Life Stress and HPA axis associated with diagnosis of BD and BPD. Methods Evaluation of 26 subjects, subdivided in groups of BD and BPD diagnosis, and health controls. Diagnostic was confirmed by Structured Clinical Interview for Axis I and II Disorders; Early Life Stress was investigated by Childhood Trauma Questionnaire and classified in subtypes physical abuse, sexual abuse, emotional abuse, physical neglect and emotional neglect. HPA axis was assessed by cortisol plasmatic levels. Results Early Life Stress is significantly higher in BD and, especially, BPD patients compared to controls, as well emotional abuse and neglect types; however, it didn’t differentiate the clinical groups. Cortisol levels was lower in BD group in relation of BPD, although without a significantly difference. In BPD group, cortisol levels was positively correlated to sexual abuse severity; in the same way, in BD group cortisol levels was correlated positively to emotional neglect. Conclusion Early Life Stress is more prevalent and severity in patients than in health controls, independently to diagnosis. BPD presents Early Life Stress more severity compared to BD group. Moreover, cortisol levels was lower in BD. Cortisol levels was positively correlated to subtypes of Early Life Stress and severity. This study indicates a promissory field to be better differentiate BD and BPD.

  • Early Life Stress, HPA axis, and depression
    Psychology and Neuroscience, 2011
    Co-Authors: Sandra Marcia De Carvalho Tofoli, Cristiane Von Werne Baes, Camila Martins, Mario Francisco Juruena
    Abstract:

    evidence from various studies suggests a preeminent role for Early adverse experiences in the development of psychopathology, especially depression. The most recent studies reviewed herein suggest that Early Life Stressors are associated with an increased risk for mood disorders in adulthood. This review examines the emerging literature on the relationship between Stress, hypothalamic-pituitary-adrenal (HPA) axis function, and depression and the role of Early Life Stress as an important risk factor for HPA axis dysregulation. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. Moreover, HPA axis changes appear to be state- dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during antidepressant treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in major depression, but few studies have assessed the activity of mineralocorticoid receptors in depression. Thus, more studies are needed to elucidate this issue. Keywords: Early Life Stress, childhood trauma, depression, treatment-resistant depression, hypothalamic-pituitary-adrenal axis.

  • Analysis of the occurrence of Early Life Stress in adult psychiatric patients: a systematic review
    Psychology and Neuroscience, 2011
    Co-Authors: Camila Martins, Sandra Marcia De Carvalho Tofoli, Cristiane Von Werne Baes, Mario Francisco Juruena
    Abstract:

    The purpose of the paper was to conduct a systematic review of Early Life Stress and its association with psychiatric disorders in adulthood. The occurrence of Early Stress has lasting negative consequences on the individual, with psychopathology onset one of the most important consequences. The degree of Early Life Stress is associated with the severity of psychiatric disorders and disability in adulthood. Methodology: We conducted a search of two databases (PubMed and SciELO), limited to the time span 1990-2010, using the following keywords: child abuse, maltreatment, Early Stress, and psychiatric disorders. Thirty-one papers were selected for this review. Results: We found that the subtypes of Early Life Stress such as emotional and physical neglect and sexual, emotional, and physical abuse have associations with several psychiatric disorders, but the Borderline Personality Disorder and Mood Disorders are more associated with the categories listed. Conclusions: Exposure to adversities in childhood and adolescence is predictive of psychiatric disorders in adulthood. More studies are needed to understand the mechanisms by which Early Life Stress is a risk factor for future psychopathology.

Tallie Z Baram - One of the best experts on this subject based on the ideXlab platform.

  • new insights into Early Life Stress and behavioral outcomes
    Current opinion in behavioral sciences, 2017
    Co-Authors: Jessica L Bolton, Jenny Molet, Tallie Z Baram
    Abstract:

    Adverse Early-Life experiences, including various forms of Early-Life Stress, have consistently been linked with vulnerability to cognitive and emotional disorders later in Life. Understanding the mechanisms underlying the enduring consequences of Early-Life Stress is an active area of research, because this knowledge is critical for developing potential interventions. Animal models of Early-Life Stress typically rely on manipulating maternal/parental presence and care, because these are the major sources of Early-Life experiences in humans. Diverse models have been created, and have resulted in a wealth of behavioral outcomes. Here we focus on recent findings highlighting Early-Life Stress-induced behavioral disturbances, ranging from hippocampus-dependent memory deficits to problems with experiencing pleasure (anhedonia). The use of naturalistic animal models of chronic Early-Life Stress provides insight into the spectrum of cognitive and emotional outcomes and enables probing the underlying mechanisms using molecular-, cellular-, and network-level approaches.

  • toward understanding how Early Life Stress reprograms cognitive and emotional brain networks
    Neuropsychopharmacology, 2016
    Co-Authors: Yuncai Chen, Tallie Z Baram
    Abstract:

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

  • naturalistic rodent models of chronic Early Life Stress
    Developmental Psychobiology, 2014
    Co-Authors: Jenny Molet, Pamela M Maras, Sarit Avishaieliner, Tallie Z Baram
    Abstract:

    A close association between Early-Life experience and cognitive and emotional outcomes is found in humans. In experimental models, Early-Life experience can directly influence a number of brain functions long-term. Specifically, and often in concert with genetic background, experience regulates structural and functional maturation of brain circuits and alters individual neuronal function via large-scale changes in gene expression. Because adverse experience during sensitive developmental periods is often associated with neuropsychiatric disease, there is an impetus to create realistic models of distinct Early-Life experiences. These can then be used to study causality between Early-Life experiential factors and cognitive and emotional outcomes, and to probe the underlying mechanisms. Although chronic Early-Life Stress has been linked to the emergence of emotional and cognitive disorders later in Life, most commonly used rodent models of involve daily maternal separation and hence intermittent Early-Life Stress. We describe here a naturalistic and robust chronic Early-Life Stress model that potently influences cognitive and emotional outcomes. Mice and rats undergoing this Stress develop structural and functional deficits in a number of limbic-cortical circuits. Whereas overt pathological memory impairments appear during adulthood, emotional and cognitive vulnerabilities emerge already during adolescence. This naturalistic paradigm, widely adopted around the world, significantly enriches the repertoire of experimental tools available for the study of normal brain maturation and of cognitive and Stress-related disorders including depression, autism, post-traumatic Stress disorder, and dementia.

Margaret J Morris - One of the best experts on this subject based on the ideXlab platform.

  • The impact of poor diet and Early Life Stress on memory status
    Current opinion in behavioral sciences, 2016
    Co-Authors: Margaret J Morris, Vivian Le, Jayanthi Maniam
    Abstract:

    In this review we summarise the implications of consuming a diet high in fat and sugar and experience of Early adversity, also known as Early Life Stress, on memory and their impacts on brain inflammatory and neurogenesis processes. Research shows that both such high energy diets and Early Life Stress can produce similar, direct effects on memory performance; however the underpinning mechanism(s) are still unclear. There is strong clinical evidence showing that both insults are associated with increased peripheral inflammation. Hence, here, we propose a mechanism that links peripheral and brain inflammation induced defects in hippocampal neurogenesis in mediating the memory impairment following Early Life Stress. Limited work has examined the consequences of combining a poor diet with Early Life Stress, and here we propose an exacerbation of the effects on the brain when these factors are combined. Given that Early Life Stressors such as childhood maltreatment, poverty and war are inevitable on a global scale, and that there is a rising obesity epidemic, driven by an increased intake of high energy food, research on the short and long-term effects of these factors and subsequently proper management approaches are of increasing importance.

  • Early Life Stress hpa axis adaptation and mechanisms contributing to later health outcomes
    Frontiers in Endocrinology, 2014
    Co-Authors: Jayanthi Maniam, Christopher P Antoniadis, Margaret J Morris
    Abstract:

    Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which then modulates the degree of adaptation and response to a later Stressor. It is known that Early Life Stress can impact on later health but less is known about how Early Life Stress impairs HPA axis activity, contributing to maladaptation of the Stress response system. Early Life Stress exposure (either prenatally or in the Early postnatal period) can impact developmental pathways resulting in lasting structural and regulatory changes that predispose to adulthood disease. Epidemiological, clinical and experimental studies have demonstrated that Early Life Stress produces long-term hyper responsiveness to Stress with exaggerated circulating glucocorticoids, and enhanced anxiety and depression-like behaviours. Recently, evidence has emerged on Early Life Stress induced metabolic derangements, for example hyperinsulinemia and altered insulin sensitivity on exposure to a high energy diet later in Life. This draws our attention to the contribution of later environment to disease vulnerability. Early Life Stress can alter the expression of genes in peripheral tissues, such as the glucocorticoid receptor and 11-beta hydroxysteroid dehydrogenase (11β-HSD1). We propose that interactions between altered HPA axis activity and liver 11β-HSD1 modulates both tissue and circulating glucocorticoid availability, with adverse metabolic consequences. This review discusses the potential mechanisms underlying Early Life Stress induced maladaptation of the HPA axis, and its subsequent effects on energy utilisation and expenditure. The effects of positive later environments as a means of ameliorating Early Life Stress induced health deficits, and proposed mechanisms underpinning the interaction between Early Life Stress and subsequent detrimental environmental exposures on metabolic risk will be outlined. Limitations in current methodology linking Early Life Stress and later health outcomes will also be addressed.