A single dose of cocaine rewires the 3D genome structure of midbrain dopamine neurons.

Midbrain dopamine neurons (DNs) respond to a first exposure to addictive drugs and play key roles in chronic drug usage1-3. As the synaptic and transcriptional changes that follow an acute cocaine exposure are mostly resolved within a few days4,5, the molecular changes that encode the long-term cellular memory of the exposure within DNs remain unknown. To investigate whether a single cocaine exposure induces long-term changes in the 3D genome structure of DNs, we applied Genome Architecture Mapping and single nucleus transcriptomic analyses in the mouse midbrain. We found extensive rewiring of 3D genome architecture at 24 hours past exposure which remains or worsens by 14 days, outlasting transcriptional responses. The cocaine-induced chromatin rewiring occurs at all genomic scales and affects genes with major roles in cocaine-induced synaptic changes. A single cocaine exposure triggers extensive long-lasting changes in chromatin condensation in post-synaptic and post-transcriptional regulatory genes, for example the unfolding of Rbfox1 which becomes most prominent 14 days post exposure. Finally, structurally remodeled genes are most expressed in a specific DN sub-type characterized by low expression of the dopamine auto-receptor Drd2, a key feature of highly cocaine-sensitive cells. These results reveal an important role for long-lasting 3D genome remodelling in the cellular memory of a single cocaine exposure, providing new hypotheses for understanding the inception of drug addiction and 3D genome plasticity.

Epigenetic regulatory layers in the 3D nucleus.

Nearly 7 decades have elapsed since Francis Crick introduced the central dogma of molecular biology, as part of his ideas on protein synthesis, setting the fundamental rules of sequence information transfer from DNA to RNAs and proteins. We have since learned that gene expression is finely tuned in time and space, due to the activities of RNAs and proteins on regulatory DNA elements, and through cell-type-specific three-dimensional conformations of the genome. Here, we review major advances in genome biology and discuss a set of ideas on gene regulation and highlight how various biomolecular assemblies lead to the formation of structural and regulatory features within the nucleus, with roles in transcriptional control. We conclude by suggesting further developments that will help capture the complex, dynamic, and often spatially restricted events that govern gene expression in mammalian cells.

Disturbed body schema, perceptual body image, and attitudinal body image in patients with borderline personality disorder.

Background: Borderline personality disorder (BPD) is a severe mental disorder that affects attitudes toward the body. However, whether this condition also affects body schema and perceptual body image remains unclear. Previous questionnaire-based studies found dissatisfaction with one's body in patients with BPD. In addition to attitudinal body image, our study investigates whether body schema and perceptual body image are disturbed in patients with BPD. Method: Our study included 31 patients diagnosed with BPD (25 women) and 30 healthy individuals (19 women) (Mage = 29 for both groups). The SCID-5-PD interview was used to determine personality disorder. Attitudinal body image was measured using the Body Attitude Test (BAT) factors. Body schema and perceptual body image were measured by two conditions of a body representation task, the body portraying method (BPM). Results: BPD patients achieved higher scores in all three BAT factors and were more susceptible to misinformation in both conditions of BPM. Based on the results, BPD patients appear to have more negative attitudes toward their bodies and worse perceptual body image and body schema. Conclusion: The novel finding of our study is that, besides the previously found attitudinal dissatisfaction with the body, individuals with BPD also show disturbances at the levels of body schema and perceptual body image. Our findings concerning disturbances in body schema and perceptual body need further research into their etiological factors and provide new therapeutic targets for the treatment of BPD.

Moral Injury and Shame Mediate the Relationship Between Childhood Trauma and Borderline Personality Disorder, PTSD, and Complex PTSD Symptoms in Psychiatric Inpatients.

Moral injury (MI) has received increased research attention in the past decades. However, despite its detrimental mental health consequences, MI has not been studied in psychiatric patients. We aimed to establish the relationship between childhood trauma, MI, and borderline personality disorder (BPD), posttraumatic stress disorder (PTSD), and disturbances in self-organization symptoms (DSO), a core diagnostic criterion of complex PTSD besides PTSD symptoms, and shame as a moral emotion in an inpatient psychiatric sample (N = 240). We found that the impact of childhood trauma on present BPD, PTSD, and DSO symptoms was mediated by MI and shame; the models accounted for up to 31% of variance in symptomatology. To our knowledge, this study is the first to investigate MI in a psychiatric sample, and our results highlight the importance of considering MI as a critical factor of patient experiences in relation to childhood trauma that potentially contributes to the development of psychiatric symptoms.

Moral injury in psychiatric patients with personality and other clinical disorders: development, psychometric properties, and validity of the Moral Injury Events Scale-Civilian Version.

Background: Moral injury emerges when someone perpetrates, fails to prevent, or witnesses acts that violate their own moral or ethical code. Nash et al. [(2013). Psychometric evaluation of the moral injury events scale. Military Medicine, 178(6), 646-652] developed a short measure, the Moral Injury Events Scale (MIES) to facilitate the empirical study of moral injury in the military. Our study aimed to develop a civilian version of the measure (MIES-CV) and examine its psychometric properties in a sample of psychiatric inpatients .Methods: In this cross-sectional study, the sample comprised 240 adult patients (71.7% female) with a mean age of 31.57 (SD = 11.69). The most common diagnoses in the sample were anxiety disorders (58.3%), depressive disorders (53.8%), and borderline personality disorder (39.6%). Participants were diagnosed using structured clinical interviews and filled out psychological questionnaires.Results: Exploratory factor analysis suggested that Nash et al.'s model (Perceived Transgressions, Perceived Betrayals) represents the data well. This two-factor solution showed an excellent fit in the confirmatory factor analysis, as well. Meaningful associations were observed between moral injury and psychopathology dimensions, shame, reflective functioning, well-being, and resilience. The Perceived Betrayals factor was a significant predictor of bipolar disorders, PTSD, paranoid personality disorder, borderline personality disorder, and avoidant personality disorder.Conclusions: Our study demonstrated that this broad version of the MIES is a valid measure of moral injury that can be applied to psychiatric patients.

The Moral Injury Events Scale­Civilian Version is a reliable and valid instrument.The original 2-factor solution (Perceived Transgressions, Perceived Betrayals) yielded a good fit to the data.Moral injury's Perceived Betrayals factor predicted bipolar disorders, PTSD, and three personality disorders (paranoid PD, borderline PD, avoidant PD).

Cell-type specialization is encoded by specific chromatin topologies.

The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1-3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4-6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive 'melting' of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.