Background Telomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure. Methods Two-hundred and ninety healthy adults provided information on childhood parental loss and maltreatment and completed diagnostic interviews. Participants were categorized into four groups based upon the presence or absence of childhood adversity and the presence or absence of lifetime psychopathology (depressive, anxiety, and substance use disorders). Telomere length and mtDNA copy number were measured from leukocyte DNA by qPCR. Results Childhood adversity and lifetime psychopathology were each associated with shorter telomeres (p < .01) and higher mtDNA copy numbers (p < .001). Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment. A history of substance disorders was also associated with significantly higher mtDNA copy numbers. Conclusion This study provides the first evidence of an alteration of mitochondrial biogenesis with early life stress and with anxiety and substance use disorders. We replicate prior work on telomere length and psychopathology, and show that this effect is not secondary to medication use or comorbid medical illness. Finally, we show that early life stress and psychopathology are each associated with these markers of cellular aging.

These results highlight the central role of the sgACC, default mode network, and salience network as predictors of TMS response and suggest their involvement in mechanisms of action. Furthermore, this work indicates that there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders.

Early life stress (ELS), in the form of childhood maltreatment, abuse, or neglect, increases the risk for psychiatric sequelae later in life. The neurobiology of response to early stress and of reward processing overlap substantially, leading to the prediction that reward processing may be a primary mediator of the effects of early life stress. We describe a growing body of literature investigating the effects of early life stressors on reward processing in animals and humans. Despite variation in the reviewed studies, an emerging pattern of results indicates that ELS results in deficits of ventral striatum-related functions of reward responsiveness and approach motivation, especially when the stressor is experienced in early in development. For stressors experienced later in the juvenile period and adolescence, the animal literature suggests an opposite effect, in which ELS results in increased hedonic drive. Future research in this area will help elucidate the transdiagnostic impact of early life stress, and therefore potentially identify and intervene with at-risk youth, prior to the emergence of clinical psychopathology.

Many patients with depression fail to derive sufficient benefit from available treatment options, with up to a third never reaching remission despite multiple trials of appropriate treatment. Novel antidepressant agents are needed, and drugs targeting nicotinic acetylcholine receptors (nAChRs) appear to hold promise in this regard. nAChRs are involved in a variety of neurobiological systems implicated in the pathophysiology of depression. In addition to their role in cholinergic neurotransmission, they modulate dopamine function and influence inflammation and hypothalamic–pituitary–adrenal axis activity. Pre-clinical studies have suggested antidepressant-like effects of drugs targeting nAChRs, with the most consistent results observed with α4β2 nAChR modulators such as vareni-cline and nonspecific nAChR antagonists such as mecamylamine. These agents appear to offer the most potential antidepressant-like efficacy when used in conjunction with other established antidepressant treatments. nAChR modulators also influence neural processes that appear to mediate the behavioral effects of antidepressants, such as hippocampal cell proliferation. Clinical evidence, while limited, shows preliminary efficacy for mecamylamine and vareni-cline. Taken together, the preclinical and clinical evidence suggests that drugs targeting nAChRs may represent an important new approach to the treatment of depression.

Early life stress (ELS) is a significant risk factor for psychopathology, although there are few functional imaging studies investigating its effects. Previous literature suggests that ELS is associated with changes in structure and function in the medial prefrontal cortex (MPFC), which forms the main anterior node of the default network (DN). This study investigated the impact of ELS history on resting state DN connectivity, using seed-based correlation analyses (SCA) involving the posterior cingulate cortex (PCC). Data were analyzed from 22 adult subjects without psychiatric or medical illness (13 with and 9 without ELS); none were taking psychotropic medication. Relative to controls, the ELS group had significant decreases in DN connectivity, observed between the PCC seed and the MPFC and inferior temporal cortex. Further analyses revealed a trend-level increase in connectivity between the amygdala and MPFC associated with ELS history. In conclusion, this study found that subjects with ELS, in the absence of psychiatric illness and medication exposure, demonstrated decreased DN connectivity, and trend-level increases in connectivity between the amygdala and MPFC. These findings suggest that altered resting state connectivity is a correlate of stress exposure, rather than a product of medication or psychiatric morbidity.

Early adversity increases risk for developing psychopathology. Epigenetic modification of stress reactivity genes is a likely mechanism contributing to this risk. The glucocorticoid receptor (GR) gene is of particular interest because of the regulatory role of the GR in hypothalamic–pituitary–adrenal (HPA) axis function. Mounting evidence suggests that early adversity is associated with GR promoter methylation and gene expression. Few studies have examined links between GR promoter methylation and psychopathology, and findings to date have been mixed. Healthy adult participants (N=340) who were free of psychotropic medications reported on their childhood experiences of maltreatment and parental death and desertion. Lifetime depressive and anxiety disorders and past substance-use disorders were assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Methylation of exon 1F of the GR gene (NR3C1) was examined in leukocyte DNA via pyrosequencing. On a separate day, a subset of the participants (n=231) completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Childhood adversity and a history of past substance-use disorder and current or past depressive or anxiety disorders were associated with lower levels of NR3C1 promoter methylation across the region as a whole and at individual CpG sites (P<0.05). The number of adversities was negatively associated with NR3C1 methylation in participants with no lifetime disorder (P=0.018), but not in those with a lifetime disorder. GR promoter methylation was linked to altered cortisol responses to the Dex/CRH test (P<0.05). This study presents evidence of reduced methylation of NR3C1 in association with childhood maltreatment and depressive, anxiety and substance-use disorders in adults. This finding stands in contrast to our prior work, but is consistent with emerging findings, suggesting complexity in the regulation of this gene.

Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were divided into 4 groups based on presence or absence of early life adversity and lifetime psychopathology: No Adversity/ No Disorder, n=136; Adversity/ No Disorder, n=91; No Adversity/ Disorder, n=46; Adversity/ Disorder, n=119). Telomere length and mtDNA copy number were measured using quantitative polymerase chain reaction. There was a positive correlation between mtDNA and telomere length in the entire sample (r=0.120, p<0.001) and in each of the four groups of participants (No Adversity/ No Disorder, r=0.291, p=0.001; Adversity/ No Disorder r=0.279, p=0.007; No Adversity/ Disorder r=0.449, p=0.002; Adversity/ Disorder, r=0.558, p<0.001). These correlations remained significant when controlling for age, smoking, and body mass index and establish an association between mtDNA and telomere length in a large group of women and men both with and without early adversity and psychopathology, suggesting co-regulation of telomeres and mitochondrial function. The mechanisms underlying this association may be important in the pathophysiology of age-related medical conditions, such as heart disease and cancer, as well as for stress-associated psychiatric disorders.

Mutations in the MTR gene, which encodes methionine synthase on human chromosome 1p43, result in the methylcobalamin deficiency G (cblG) disorder, which is characterized by homocystinuria, hyperhomocysteinemia, and hypomethioninemia. To investigate the molecular basis of the disorder, we have characterized the structure of the MTR gene, thereby identifying exon-intron boundaries. This enabled amplification of each of the 33 exons of the gene, from genomic DNA from a panel of 21 patients with cblG. Thirteen novel mutations were identified. These included five deletions (c.12-13delGC, c.381delA, c.2101delT, c.2669-2670delTG, and c.2796-2800delAAGTC) and two nonsense mutations (R585X and E1204X) that would result in synthesis of truncated proteins that lack portions critical for enzyme function. One mutation was identified that resulted in conversion of A to C of the invariant A of the 3' splice site of intron 9. Five missense mutations (A410P, S437Y, S450H, H595P, and I804T) were identified. The latter mutations, as well as the splice-site mutation, were not detected in a panel of 50 anonymous DNA samples, suggesting that these sequence changes are not polymorphisms present in the general population. In addition, a previously described missense mutation, P1173L, was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-->T transition in a CpG island, has occurred on at least two separate genetic backgrounds.