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Pharmacological Reports Copyright © 2013 2013, 65, 14621470 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review Impact of early-life stress on the medial prefrontal cortex functions – a search for the pathomechanisms of anxiety and mood disorders Agnieszka Chocyk, Iwona Majcher-Maœlanka, Dorota Dudys, Aleksandra Przyborowska, Krzysztof Wêdzony Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland Correspondence: Agnieszka Chocyk, e-mail: [email protected] Abstract: Although anxiety and mood disorders (MDs) are the most common mental diseases, the etiologies and mechanisms of these psychopathologies are still a matter of debate. The medial prefrontal cortex (mPFC) is a brain structure that is strongly implicated in the pathophysiology of these disorders. A growing number of epidemiological and clinical studies show that early-life stress (ELS) during the critical period of brain development may increase the risk for anxiety and MDs. Neuroimaging analyses in humans and numerous reports from animal models clearly demonstrate that ELS affects behaviors that are dependent on the mPFC, as well as neuronal activity and synaptic plasticity within the mPFC. The mechanisms engaged in ELS-induced changes in mPFC function involve alterations in the developmental trajectory of the mPFC and may be responsible for the emergence of both early-onset (during childhood and adolescence) and adulthood-onset anxiety and MDs. ELS-evoked changes in mPFC synaptic plasticity may constitute an example of metaplasticity. ELS may program brain functions by affecting glucocorticoid levels. On the molecular level, ELS-induced programming is registered by epigenetic mechanisms, such as changes in DNA methylation pattern, histone acetylation and microRNA expression. Vulnerability and resilience to ELS-related anxiety and MDs depend on the interaction between individual genetic predispositions, early-life experiences and later-life environment. In conclusion, ELS may constitute a significant etiological factor for anxiety and MDs, whereas animal models of ELS are helpful tools for understanding the pathomechanisms of these disorders. Key words: early-life stress, maternal separation, prenatal stress, medial prefrontal cortex, synaptic plasticity, anxiety, mood disorders, epigenetics Abbreviations: 11B-HSD2 – 11b-hydroxysteroid dehydrogenase type 2, BDNF – brain-derived neurotrophic factor, ELS – early-life stress, GDNF – glial cell-derived neurotrophic factor, GFAP – glial fibrillary acidic protein, GR – glucocorticoid receptor, ILC – infralimbic cortex, LTD – long-term depression, LTP – long-term potentiation, MDs – mood disorders, miRNA – microRNA, mPFC – medial prefrontal cortex, MS – maternal separation, NCAM – neural cell adhesion molecules, PLC – prelimbic cortex, PTSD – post-traumatic stress disorder, SHRP – stress hyporesponsive period, vmPFC – ventromedial prefrontal cortex 1462 Pharmacological Reports, 2013, 65, 14621470 Introduction Anxiety and mood disorders (MDs) are the most prevalent mental disorders and the leading causes of years lived with disability all over the world [68]. They affect all age groups, from children and adolescents to adults [27]. Despite numerous research attempts and existing theories, the pathogenesis of anxiety and MDs is still poorly understood. Early-life stress, anxiety and mood disorders Agnieszka Chocyk et al. Clinical and epidemiological data from the past decade markedly point toward early-life stress (ELS) as a relevant risk factor for the development of anxiety and MDs. Early-life adversity in the maladaptive family functioning cluster (family violence, physical abuse, sexual abuse, neglect, parental mental illness and substance abuse) is most strongly correlated with mental disorder onset [30]. A recent World Mental Health Survey revealed that ELS is associated with 59.5% of childhood-onset MDs and 32.6% and 13.6% of adolescence- and later adulthood- (age 30+) onset MDs, respectively. In the case of anxiety disorders, ELS is generally responsible for approx. 30% of onsets, regardless of age group [30]. The neurobiological substratum for associations between ELS and the development of anxiety and MDs is widely studied with advanced in vivo neuroimaging technologies and preclinical studies, which apply various animal models [20, 56]. The medial prefrontal cortex as the key brain structure implicated in the pathophysiology of anxiety and mood disorders The medial prefrontal cortex (mPFC) is a forebrain structure known to regulate a variety of cognitive and emotional processes. Specifically, the ventral part of the mPFC (vmPFC) has been shown to be involved in such processes as (1) fear and anxiety, (2) risk taking, (3) decision making, and (4) attentional processes [25]. On the basis of evidence from neuroimaging, lesion analyses and post-mortem studies, the mPFC was recognized as a key brain structure, along with the amygdala, hippocampus and ventromedial parts of the basal ganglia, that is affected by anxiety and MDs [20, 44]. It was shown that patients suffering from MDs and anxiety disorder, e.g., post-traumatic stress disorder (PTSD), had reduced gray matter volume of the mPFC [20, 67]. Moreover, histopathological examinations showed several morphological abnormalities, such as reductions in synapses and synaptic proteins and elimination of glial cells in the mPFC of MD subjects [20]. Changes in neural and metabolic activities of the mPFC were also reported in patients with anxiety and MDs. In this respect, most neuroimaging studies demonstrated a decrease in neural activity of the vmPFC in PTSD patients [24]. In the case of MD patients, several reports showed elevated vmPFC activity and its modification during antidepressant medication [44]. As a frontal lobe structure, the mPFC exhibits a prolonged developmental trajectory. It is one of the last brain regions to mature during development [10]. Thus, it is not surprising that the mPFC is especially vulnerable to early-life insults (e.g., ELS). Several neuroimaging studies in humans revealed reduced mPFC volume in children, adolescents and adults with a history of ELS [23, 53, 63]. Moreover, a loss of sustained activity in the vmPFC in response to stress has recently been found in individuals who experienced early-life emotional abuse [65]. Therefore, it is postulated that adverse early-life experiences may constitute a significant etiological factor for anxiety and MDs. Despite the numerous advantages of advanced neuroimaging technologies applied to humans, the search for the specific pathomechanisms of the abovementioned disorders within the mPFC is possible only in preclinical studies that use (1) animal models of ELS, (2) behavioral tests reflecting some symptoms of anxiety and MDs and (3) a variety of biochemical and electrophysiological techniques [56]. ELS-induced dysfunction of the mPFC – implications from the behavioral studies in animal models There are many different experimental procedures that model ELS in animals (mostly in rodents). They can be divided simply into prenatal and early postnatal procedures, according to the developmental time when the stressful event is applied (for review, see: [38, 51]). Prenatal stress can be evoked in pregnant dams by various stressors, such as (1) lipopolysaccharide injection and viral infection (both cause maternal immune activation), (2) unpredictable psychological stress (restraint stress) or (3) malnutrition [38]. Early postnatal procedures are strongly represented by maternal separation (MS) paradigms, which are usually conducted during the first three weeks of rodent life. MS procedures are applied in many ways, such as a single 24-h-long MS or a prolonged repeated everyday MS (e.g., 3 h /day, on postnatal days 1–14) [51]. Pharmacological Reports, 2013, 65, 14621470 1463 As previously mentioned, the vmPFC is strongly engaged in fear and anxiety processes. It regulates both unconditioned (innate) fear responses and conditioned fear responses, based on associative learning (fear learning and memory, fear extinction) [25]. In general, neural circuits engaged in fear behaviors are evolutionarily conserved; therefore, the mechanisms underlining fear and anxiety can be successfully studied both in humans and laboratory animals. The vmPFC modulates fear behavior by its impact on the activity of the amygdala and periaqueductal gray [13]. The vmPFC is subdivided into distinct parts, including the ventral prelimbic cortex (PLC), infralimbic cortex (ILC) and medial orbital cortex [25]. The roles of specific parts of the vmPFC in the regulation of innate fear are still a matter of debate; both the PLC and ILC seem to exert a unique impact [13, 35]. However, the roles of the distinct parts of the vmPFC in the modulation of the different phases of fear memory consolidation are well established [37, 58]. The PLC is involved in the consolidation and recall of fear memory, whereas the ILC is required for the consolidation of extinction memory [37, 58]. Numerous animal studies consistently reveal that ELS enhances anxiety-like behaviors in tests that measure innate fear, such as the elevated plus maze or light/dark exploration test [15, 48, 62]. In contrast, when fear conditioning procedures are applied, earlylife-stressed animals display a reduction in fear expression [29, 61, 64]. Interestingly, both types of behavioral phenotypes present in animals with a history of ELS point toward a specific dysfunction of the vmPFC. A recent study supporting this idea showed that chemically induced synaptic inhibition of both the PLC and ILC produced similar changes in fear and anxiety responses, namely an increase in innate fear and a decrease in the expression of fear conditioning [35]. The reason for the different roles of the vmPFC in modulating innate and learned fear is still unknown. It is speculated that this phenomenon could be associated with differences in the vmPFC projection systems that regulate these distinct types of fear behavior and involve different neurotransmitters [35]. It is also unknown how ELS affects specific vmPFC functions to produce distinctive behavioral phenotypes in different fear-inducing paradigms. Resolving this complex problem may bring us closer to understanding the pathomechanisms of anxiety disorders. Another behavioral indication that ELS may affect the mPFC comes from studies showing that prenatally-stressed and MS animals display impairments in 1464 Pharmacological Reports, 2013, 65, 14621470 cognitive functions governed by the mPFC, measured by the temporal order memory task, the attentional set-shifting task and the delayed alternation task [3, 38]. It is worth mentioning that cognitive deficits are important hallmarks of MDs [12]. It should be stressed that animal models of ELS do not show consistent results concerning depressivelike symptoms, as measured by the forced swim test or sucrose preference test [38, 56, 62]. However, these tests are not specific for mPFC function [54]. The impact of ELS on structural and functional synaptic plasticity of the mPFC In addition to strong behavioral data implicating mPFC dysfunction in animals exposed to ELS, numerous biochemical, morphological and electrophysiological reports have shown that ELS affects neural activity and synaptic plasticity within the mPFC [3, 14–16, 60, 62]. Synaptic plasticity underlies the continuous ability of the brain to adapt to specific experiences in a changing environment. It can be divided into structural and functional plasticity [36]. Structural plasticity refers to the morphological remodeling of dendrites and synapses and synapse turnover, whereas functional synaptic plasticity is best characterized by the long-term potentiation (LTP) phenomenon [36]. An abundance of experimental data has accumulated concerning the effects of ELS on the structural plasticity of the mPFC [5, 15, 39, 40, 48]. ELS affects the morphology of the dendritic tree, the length of dendritic processes and spine/synapse density in pyramidal neurons of the mPFC [5, 15, 39, 40, 48]. Moreover, ELS influences the expression of neural cell adhesion molecules (NCAMs) in the mPFC [14, 16]. NCAM proteins belong to the immunoglobulin superfamily of cell adhesion molecules and are engaged in neural plasticity processes, such as (1) neurite outgrowth, (2) axon fasciculation and guidance, and (3) synapse stabilization [14, 16]. It is worth emphasizing that both impairments [5, 15, 39, 48] and intensifications [5, 40] in structural plasticity are observed in animals subjected to ELS. The direction and magnitude of ELS-induced morphological changes depend on several factors, such as the severity of ELS and the developmental stage of the brain Early-life stress, anxiety and mood disorders Agnieszka Chocyk et al. during the aversive experience and during the final morphological assessments [4]. In contrast, there are very few research reports concerning the impact of ELS on the neural activity and functional plasticity of the mPFC, especially on LTP processes. It was found that ELS decreased the metabolic activity of the mPFC in juveniles [6]. It was also shown that in adult rats, MS reduced basal unit activity and basal local field potential activity in the right and left mPFC cortex, respectively. Moreover, MS attenuated the hemispheric synchronization of the basal local field potential activity of the mPFC [60]. Recent data have shown that MS causes impairment of LTP processes in the mPFC of adolescent rats, which also displayed increased anxiety-like behavior [15]. These functional changes were accompanied by increased expression of the key proteins engaged in LTP (e.g., glutamate receptors 1 and 2, Ca2+/calmodulin-dependent protein kinase II, postsynaptic density protein 95) in the mPFC and by the atrophy of dendritic trees and reduced spine density in layer II/III pyramidal neurons of the mPFC [15]. Interestingly, in adult animals subjected to ELS, Baudin et al. (2012) revealed an upregulation of LTP processes in the mPFC and deficits in mPFC-dependent cognitive tasks [3]. The latest hypotheses and data suggest that glial cells play an important role in the process of synaptic plasticity [47]. It is well known that in addition to performing neural housekeeping functions, glial cells (mostly astrocytes) modulate synaptogenesis, synaptic efficacy and strength. These modulatory functions involve the release of specific neurotrophins, such as brain-derived and glia cell line-derived neurotrophic factors (BDNF and GDNF, respectively), as well as gliotransmitters (e.g., glutamate, ATP and D-serine) from astrocytes [47]. In experimental animals, glial ablation in the mPFC was able to induce depressivelike behaviors [2]. Moreover, numerous post-mortem studies revealed a clear reduction in glial cell number and density in the mPFC of depressive patients [20]. Interestingly, it was shown that ELS in animal models affected the number of S-100b- and GFAP-immunoreactive glial cells in the mPFC [8, 33, 41]. Additionally, functional genomic and proteomic analyses revealed strong effects of ELS on gene and protein markers related to oligodendrocyte maturation and myelination in the mPFC [7]. It is worth mentioning that ELS-induced changes in synaptic plasticity within the mPFC may be considered as the phenomenon of the brain plasticity per se. Moreover, ELS-induced plasticity interferes with nor- mal experience-induced plasticity throughout an individual’s life span. In other words, one experience alters the effect of others and induces “plasticity of synaptic plasticity” [1]. This vision of the effects of ELS is similar to the concept of the metaplasticity, originally proposed by Abraham and Bear [1]. This concept postulates that some conditions that occur, known as “priming” or “preconditioning”, may (after some period of time) modify the subsequent induction of synaptic plasticity [1]. The concept of metaplasticity initially referred to LTP and long-term depression (LTD) processes; however, it has recently been used to describe and understand stress-induced changes in synaptic plasticity [31, 55]. ELS-induced alterations in the developmental trajectory of the mPFC and emergence of early-onset mental disorders As previously mentioned, the mPFC is characterized by a prolonged maturation time and is one of the last brain structures to develop [10]. Within its developmental trajectory, adolescence is recognized as a time of a particularly intensive morphological and functional remodeling of the mPFC [10]. During adolescence, many relevant processes occur, including (1) a reduction in gray matter volume, (2) intensive myelination, (3) synapse pruning and (4) dynamic changes in receptor systems [10]. The processes of brain remodeling and maturation during adolescence may easily unmask malfunctions that originated earlier in life. Thus, it is not surprising that many early-onset psychopathologies emerge during this period [10]. Although the adolescent period has not been extensively studied in animal models of ELS, recent reports have revealed the effects of ELS on mPFC function and specific behaviors in adolescent animals [15, 32, 48, 71]. More importantly, some data show a correlation of depressive-like behavior and increased anxiety-like behavior with specific aberrations of the mPFC, such as impairments in structural and functional plasticity (as discussed previously) [15, 48], reduced GABA-ergic markers [32], and reduced glutamate metabolites [71] in adolescent rats subjected to ELS. Moreover, a few recent reports, both biochemical and behavioral, clearly documented that ELS alters the developmental trajectory of the mPFC [9, 11]. First, it was shown Pharmacological Reports, 2013, 65, 14621470 1465 that MS increases the specific adolescent peak in dopamine D1 receptor expression and blunts the adolescent peak in D2 receptor expression in projection neurons of the mPFC [9]. Second, another group of authors studying the fear extinction procedure linked specific behavioral phenotypes present in infant, juvenile and adolescent animals subjected to ELS to aberrations of mPFC development [11]. The abovementioned study was based on the fact that the effectiveness of fear extinction varies across development [49]. Less effective extinction is seen during adolescence, reflecting the specific stage of mPFC maturation [49]. It was revealed that MS leads to the emergence of a fear extinction phenotype typical for older animals. In other words, juvenile rats subjected to MS displayed an extinction phenotype usually observed in adolescents (poor extinction), whereas adolescent animals behaved like adults (good extinction retention) [11]. The functional role of the vmPFC (particularly the ILC) in fear extinction allows for the postulation that MS significantly interferes with mPFC maturation [11]. Taking into account the above cited data and the epidemiological estimation that early-life adversity is responsible for approx. 30% of adolescenceonset anxiety and MDs, 30% of childhood-onset anxiety disorders and 59.5% of childhood- onset MDs, ELS may constitute a very important etiological factor for early-onset psychopathology. The mechanisms mediating ELS-induced changes in brain function – a search for the epigenetic signature of early-life experiences The question then arises, how does ELS change/program brain functions and how is this programming registered? First, it should be noted that ELS acts during the critical period of brain development and maturation. In rodents, this period extends from gestation through the first three weeks of postnatal life [38, 51]. There are some specific mechanisms, both in humans and rodents, that protect the developing brain from harmful stress-induced elevation of glucocorticoid levels during this time period. For example, during gestation, placental 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) controls fetal glucocorticoid access. 11b-HSD2 is an enzyme that converts corti- 1466 Pharmacological Reports, 2013, 65, 14621470 sol/corticosterone to inactive metabolites and, in this way, constitutes a physiological barrier that protects the fetus from the detrimental effects of maternal glucocorticoids [26]. Moreover, during the early postnatal stage (on postnatal days 2–14 in rodents), the stress hyporesponsive period (SHRP) occurs. During the SHRP, mild stressors do not elicit an increase in corticosterone levels, and therefore, the maturating brain is protected [19]. A comparable SHRP is also found in humans during postnatal months 6–12 [22]. However, when confronted with severe and/or prolonged stress such as early-life adversity, the abovementioned protective mechanisms are not sufficient. Paradoxically, ELS specifically affects these processes and diminishes their effectiveness [26, 46, 59]. It was revealed that prenatal stress and anxiety downregulate placental 11b-HSD2 both in humans and laboratory animals [26, 46], whereas a MS procedure abolishes the SHRP [59]. As a consequence, animals subjected to ELS display persistent enhancement in hypothalamic-pituitary-adrenal (HPA) axis reactivity (for review, see [18]). The substantial role of glucocorticoids in brain development, maturation and everyday function is well known. During neurodevelopment, glucocorticoids regulate neurogenesis, differentiation, and migration [21, 28, 70]. Acting through their specific receptors, glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) affect transcription of specific genes or exert non-genomic effects by directed action on membrane lipids and proteins [52]. Thus, ELS-induced changes in glucocorticoid levels may permanently program brain functions [52]. A growing number of studies show that ELSinduced programming of brain functions is registered through epigenetic mechanisms [26, 42, 43, 50]. Epigenetic mechanisms regulate gene transcription without altering DNA sequence and involve (1) DNA methylations, (2) histone modifications, and (3) microRNAs (miRNAs). All of these processes are responsible for the normal pattern of expression typical of a specific cell and tissue. DNA methylation in the promoter region of a gene is usually associated with gene silencing. Histone modifications regulate the accessibility of chromatin to the transcription machinery, whereas miRNAs are ~22 nucleotide-long RNA molecules that can regulate gene expression at the post-transcriptional level, e.g., by repression of specific mRNA [17]. Early-life stress, anxiety and mood disorders Agnieszka Chocyk et al. The first clear evidence that early-life experiences program the brain by epigenetic mechanisms was shown by Weaver et al. in a model of the naturally occurring variation of maternal care [66]. The authors demonstrated that the quality of maternal care received by Long Evans rats in their first week of life regulates hippocampal GR expression through changes in DNA methylation levels in the GR promoter region [66]. Data showing the epigenetic signature of ELS are rapidly accumulating. It was revealed that prenatal stress downregulates placental 11b-HSD2 mRNA by increasing DNA methylation within the 11b-HSD2 gene promoter [26]. Other work has shown that prenatal stress increases global DNA methylation and changes the expression pattern of over 700 genes in the mPFC [42, 43]. In the case of postnatal ELS models, many studies showed changes in DNA methylation in the hippocampus (for review, see [18]). However, Provencal et al. [50] have recently demonstrated that different rearing methods (maternal vs. inanimate surrogate) produced different DNA methylation patterns in the mPFC of rhesus [50]. The epigenetic signature of ELS is also accomplished by histone modification. It was revealed that MS increases histone H4 acetylation at lysine K12 in the forebrain neocortex of adult Balb/c mice [34]. Additionally, Xie et al., showed an elegant correlation between MS-induced elevation in histone H4 acetylation and increased expression of two immediate early genes underlying experience-induced synaptic plasticity, Arc and Egr1, in the mouse hippocampus [69]. Moreover, these epigenetic changes were accompanied by increases in dendritic complexity and spine number in hippocampal CA3 pyramidal neurons [69]. To the best of our knowledge, this is the first report that links ELSinduced epigenetic changes with synaptic plasticity. Knowledge of miRNA functions is increasing rapidly. It is now known that miRNAs are enriched at synapses, where they quickly regulate the translation of specific proteins in response to synaptic activity [57]. Thus, miRNAs may be directly engaged in synaptic plasticity. Individual miRNAs are involved in the regulation of dendritic spine size and morphology, as well as in postsynaptic density protein 95 and NMDA receptor subunit NR2A mRNA expression [57]. Interestingly, a few reports have shown that prenatal [72] and early postnatal stress (MS) [62] change the expression profile of miRNAs in the whole brain and the mPFC, respectively [62]. Toward understanding vulnerability and resilience to ELS-related mental disorders – the main concepts Indisputably, ELS produces profound changes in brain function; however, not all subjects with a history of ELS develop psychopathologies. There are few promising concepts that try to explain this phenomenon. The more “classic” and traditional concept is the cumulative stress hypothesis [18, 45]. It postulates that the effects of stress are cumulative across an individual’s lifetime, and after passing a certain threshold, the probability of developing a psychopathology is increased. Thus, ELS may increase an individual’s vulnerability to aversive challenges in future life and may lead to a disease. The cumulative stress model assumes that the effects of cumulative adversity during development do not have advantageous aspects, such as providing a source of adaptation [18, 45]. In contrast, the match/mismatch hypothesis postulates that ELS may induce adaptation to certain (aversive) conditions and may prepare the individual for similar aversive events in the future (a match between early-life and late environments) [54]. In this way, ELS may induce specific coping mechanisms and promote resilience. However, if a mismatch occurs between early-life and later environments/experiences, coping strategies are compromised and vulnerability to psychopathology develops [54]. Therefore, in the match/mismatch model, the potential benefits or costs of adaptive plasticity depend on the environmental context. Both concepts (cumulative stress and match/mismatch hypotheses) are still being tested in animal models and in epidemiological studies; however, the results of these tests have so far been ambiguous. The main disadvantage of the above hypotheses is that they both say nothing about individual predispositions to aversive events [18, 45]. Attempts to integrate both hypotheses together with an individual/genetic background perspective were undertaken independently by Nederhof and Schmidt [45] and Daskalakis et al. [18], and a model of individual sensitivity to early programming in concurrence with the three-hit concept was proposed [18, 45]. The authors of the first concept used the term “a sensitivity to early programming”, defined as the ability of an individual to induce adaptive plasticity in response to aversive conditions that enhances fitness Pharmacological Reports, 2013, 65, 14621470 1467 under similar conditions in the future [45]. Subjects with high programming sensitivity will benefit from the match between early and late environments, and in this situation, the match/mismatch hypothesis will be applied and will promote resilience. On the other hand, a cumulative stress hypothesis will be applied to individuals who display low programming sensitivity and who are unable to induce adequate adaptation. They may accumulate the effects of stressful events during their lifetime and, in consequence, develop a disease [45]. The three-hit concept (i.e., hit-1: genetic predisposition, hit-2: early-life environment and hit-3: laterlife environment) adds the genetic background and completes the model of individual sensitivity to early programming described by Nederhof and Schmidt [18, 45]. The three-hit hypothesis of vulnerability and resilience proposes that during the critical time period of brain development, individual genetic factors interact with the early-life environment and experiencerelated factors. In consequence, these interactions (which constitute the genetic and epigenetic signatures of early-life experiences) program gene expression patterns and create specific phenotypes. Then, these “programmed phenotypes” meet specific laterlife environments/experiences, and depending on the interplay between them, vulnerability or resilience may occur [18]. The integrated models cited above need to be thoroughly tested; however, they definitely bring us closer to an understanding of the phenomenon of vulnerability and resilience, not only to ELS but also to stress events in general. Conclusions Altogether, clinical and epidemiological studies as well as advanced neuroimaging techniques and numerous preclinical studies in animal models strongly implicate that (1) early-life adversity is a relevant etiological factor for anxiety and MDs and (2) ELSinduced changes in synaptic plasticity within the mPFC may underlie the pathomechanisms of these psychopathologies. Given that early-life adversity has the potential to program brain function and behavior for the rest of an individual’s life, public awareness and sensitivity to child abuse and neglect should be increased. 1468 Pharmacological Reports, 2013, 65, 14621470 Acknowledgments: This work was supported by grant no. 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