Institute of Neurosciences, Mental Health and Addiction

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal “birthdating” confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.

BACKGROUND: It is important to evaluate the impact of cannabis use on onset and course of psychotic illness, as the increasing number of novice cannabis users may translate into a greater public health burden. This study aims to examine the relationship between adolescent onset of regular marijuana use and age of onset of prodromal symptoms, or first episode psychosis, and the manifestation of psychotic symptoms in those adolescents who use cannabis regularly. METHODS: A review was conducted of the current literature for youth who initiated cannabis use prior to the age of 18 and experienced psychotic symptoms at, or prior to, the age of 25. Seventeen studies met eligibility criteria and were included in this review. RESULTS: The current weight of evidence supports the hypothesis that early initiation of cannabis use increases the risk of early onset psychotic disorder, especially for those with a preexisting vulnerability and who have greater severity of use. There is also a dose-response association between cannabis use and symptoms, such that those who use more tend to experience greater number and severity of prodromal and diagnostic psychotic symptoms. Those with early-onset psychotic disorder and comorbid cannabis use show a poorer course of illness in regards to psychotic symptoms, treatment, and functional outcomes. However, those with early initiation of cannabis use appear to show a higher level of social functioning than non-cannabis users. CONCLUSIONS: Adolescent initiation of cannabis use is associated, in a dose-dependent fashion, with emergence and severity of psychotic symptoms and functional impairment such that those who initiate use earlier and use at higher frequencies demonstrate poorer illness and treatment outcomes. These associations appear more robust for adolescents at high risk for developing a psychotic disorder.

Neuropeptide Y (NPY) is considered to be an important neuromodulator in the regulation of emotional behavior. For example, NPY is consistently involved in anxiety-related behaviors and there is increasing support for a role of this peptide in mood disorders such as depression. Furthermore, recent evidence suggests that NPY has a significant role in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal. In addition, NPY is beginning to emerge as an important modulator in the etiology of alcoholism that is independent from the addictive and reinforcing properties of the traditional system commonly associated with dopamine and instead, is strongly associated with innate emotionality. The recent developments elucidating the role of NPY in emotion and alcohol dependence are reviewed and the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders is examined.

OBJECTIVE: This article describes the adoption of Individual Placement and Support (IPS) supported employment between 2013 and 2017 in Catalonia (Spain) in the context of high unemployment and a predominance of traditional preemployment training approaches. It reports the experience of implementing IPS to promote competitive job placement of people with mental disorders. METHOD: The Avedis Donabedian Research Institute (FAD) designed, trained, implemented, and evaluated the project. We used a longitudinal, mixed-methods approach. RESULTS: The demonstration project comprised 7 employment services and 12 ambulatory mental health centers. It followed up programs and participants from October 2013 to December 2017. The project added 1,188 new competitive jobs, increased the rate of competitive employment from 16% to 43%, and improved the fidelity of IPS by 44% on the organizational dimension and by 34% on services dimension. The quality of employment was similar to the overall employment market, with 94% of temporary jobs. The qualitative analysis confirmed several areas of improvement, including the vision of recovery, collaborations between vocational and mental health services, work patterns of practitioners, and views of work as an important treatment. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: A strong leadership team, consistent training, and commitment to model fidelity have established IPS in the pilot region as an important intervention to obtain and maintain competitive employment and recovery for people with a mental health condition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

AIM: Atypical antipsychotic treatment (e.g. risperidone) has been found to improve social functioning more than standard antipsychotic treatment. However, it is unclear which specific social behaviors are implicated in this improvement. The current study employed an interactive puzzle game to examine how social behaviors contribute to the improvement of social functioning by comparing patients receiving risperidone with those receiving trifluoperazine. METHODS: Scores on the Positive and Negative Syndrome Scale, executive functioning, and social functioning were obtained from 24 patients with schizophrenia receiving either risperidone (n = 12) or trifluoperazine (n = 12), before their social behavior was measured in the interactive Tangrams Game. Immediately after the Tangrams Game, participants filled in two questionnaires measuring their interpersonal trust and rejection toward their game partner. RESULTS: Patients receiving risperidone showed more social engagement, cooperative behavior and interpersonal trust toward their game partners than those receiving trifluoperazine. Additional multivariate analysis of variance revealed that lower affiliative behavior was a function of positive symptoms; interpersonal trust had an impact on social engagement but executive functioning did not explain lower interpersonal trust or social disengagement. CONCLUSION: Improvement of social competence by risperidone might be related to the enhancement of both social behaviors and interpersonal trust as well as better symptom resolution.

e've all heard stories about tea leaves having the power to forecast the future. But what if tea could actually help you remember the past?

Abstract Glioblastoma is the most common and aggressive primary adult brain tumor, remaining incurable despite current therapeutic strategies. Through a genome-wide essentiality screen, we previously identified disruptor of telomeric silencing-1-like (DOT1L) as one of the most important epigenetic regulators in glioblastoma stem cells (GSCs). Chemogenic inhibition of DOT1L epigenetic activity was found to increase the expression of neuronal markers while decreasing the expression of cancer stem cell markers at the transcriptional and protein level, suggesting GSC differentiation towards a neuronal lineage. Thus, we sought to investigate the mechanism of DOT1L in GSCs and whether disruption of DOT1L epigenetic activity promotes functional integration of GSCs into neural circuits. Here, we profiled the overall transcriptional and chromatin accessibility landscape of GSCs following DOT1L inhibition. Interestingly, we identified that DOT1L inhibition results in increased chromatin accessibility at key gene loci involved in neural differentiation, synaptic transmission, in addition to dopamine synthesis, packaging, and release, which correlated with upregulated gene expression. Furthermore, these gene loci exhibited alterations of the DOT1L epigenetic mark, H3K79me2. Transcriptional motif analysis of GSCs following DOT1L inhibition revealed dysregulated accessibility of transcription factor motifs known to be involved in regulating cellular response to neuronal signals. Cell viability assessment of GSCs treated with a DOT1L inhibitor and a panel of neurotransmitters further confirmed that DOT1L inhibition sensitizes GSCs to neuronal signals. These data suggest that disrupting the epigenetic activity of DOT1L reprograms the epigenetic landscape of GSCs to promote a functional, dopaminergic, neuronal-like state that exhibits enhanced responsiveness to neuronal signals. Future experiments aim to investigate the impact of disrupted DOT1L epigenetic activity on GSC-neuronal bidirectional communication and the mechanisms by which this influences the progression and aggressiveness of glioblastoma.

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor, with a median survival of 15 months despite current treatments. We recently established that the epigenetic regulator Disruptor of Telomeric Silencing-1-Like (DOT1L) was essential for the growth of brain tumor stem cells (BTSCs), which are thought to underlie GBM tumor initiation and treatment resistance. Given the previously recognized importance of DOT1L histone methylation for the regulation of the similarly rare and aggressive childhood cancer, Mixed Lineage Leukemia (MLL), we interrogated for common mechanisms in both BTSCs and MLL cells, that overlap due to the epigenetic role of DOT1L. To gain a more detailed perspective of the importance of the DOT1L epigenetic mark in BTSCs, we performed a chemogenomic screen using the DOT1L inhibitor, EPZ-5676. Results from this screen revealed genes from transcriptional and epigenetic complexes required for a therapeutic response to DOT1L inhibition in BTSCs. Gene targeting approaches and growth assays further identified the Polycomb Repressive Complex 2 (PRC2) as a common determining factor for the growth response of both BTSCs and MLL cells following DOT1L inhibition. Furthermore, analysis of the chromatin accessibility changes regulated by DOT1L and PRC2 histone methylation identified both shared and unique epigenetic characteristics of GBM and MLL. The extent to which these shared mechanisms underpin the pathogenic process in these distinct diseases is being further investigated by assessing the divergence in transcriptional responses that emerge from this common epigenetic phenomenon. The findings from this study will provide insight into the importance of shared epigenetic mechanisms that underlie the tumorigenesis of unique cancers affecting the brain and blood.

Abstract Glioblastoma (GBM) is a devastating brain cancer with a median overall survival of a mere 12-15 months. Patients receive the standard of care treatment, comprised of maximum surgical resection, ionizing radiation, and temozolomide chemotherapy, however the tumor inevitably recurs. Recurrent GBM is more invasive, difficult to resect, and treatment resistant. GBM brain tumor stem cells (BTSCs), a sub-population of stem-like tumor cells with the ability to self-renew and differentiate into a heterogeneous tumor, are thought to be at the root of recurrent disease. BTSCs isolated from primary and recurrent tumors from the same patient are rare due to fewer resections of recurrent tumors and reduced quality of recurrent tumor samples used to initiate cell lines. As a result, the process of tumor recurrence is vastly understudied in BTSCs. To further understand the process of recurrence and elucidate potential mechanisms of invasion and treatment resistance, we explored global transcriptomics in 40 primary versus 17 recurrent BTSC cultures. Additionally, we profiled changes at the chromatin level in a subset of primary versus recurrent BTSCs using ATAC sequencing. Several pathways were found to be upregulated in recurrent GBM BTSCs, including innate immune signaling at the mRNA and chromatin level, which may mediate the aggressive nature of recurrent BTSCs. Moreover, these signaling changes may be unique to the stem cell population within the tumor, as they are not observed when profiling primary versus recurrent bulk tumors. We are currently targeting these pathways genetically and pharmacologically in primary and recurrent GBM BTSCs established from the same patient and have uncovered mechanisms for treatment resistance, invasion, and recurrence. Our work investigating global signaling changes in primary versus recurrent BTSCs holds promise for uncovering new therapeutic targets or biomarkers for treatment of recurrent GBM.

Ethan Murphy,1 Chao Suo,1– 4 Govinda Poudel,5 Hannah Thomson,1 Valentina Lorenzetti1,6 1Neuroscience of Addiction and Mental Health Program, Australian Catholic University, Melbourne, VIC, Australia; 2Brain Park, Monash University, Melbourne, VIC, Australia; 3QIMR Berghofer, Brisbane, QLD, Australia; 4School of Psychology, University of Queensland, Brisbane, QLD, Australia; 5Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia; 6Clinical Psychopharmacology Unit, University College London, London, UKCorrespondence: Valentina Lorenzetti, Neuroscience of Addiction and Mental Health Program, Australian Catholic University, 115 Victoria Parade, Level 5 Daniel Mannix Building, Fitzroy, Melbourne, VIC, 3065, Australia, Email valentina.lorenzetti@gmail.comAbstract: The consumption of cannabinoids is highly prevalent and has been associated with altered structural, functional, and metabolic brain integrity, measured using PET and neuroimaging tools. However, the current neuroimaging evidence has been summarized by distinct modalities that measure different metrics of brain integrity, precluding a comprehensive understanding of the underlying neurobiology. A non-systematic narrative review method was used to summarize the multimodal neuroimaging evidence on brain integrity from experimental studies of cannabinoid intoxication and observational studies in non-intoxicated cannabis users. Consistent evidence showed that acute intoxication with delta-9-tetrahydrocannabinol (THC) was associated with greater brain activity in fronto-striatal pathways. For regular cannabis users compared to controls, there was consistent cross-sectional evidence of lower hippocampal volumetry and white matter microstructure of the superior longitudinal fasciculus, and of different fronto-striatal activity and connectivity during cue-reactivity tasks and resting-state. In cannabis users, there was emerging evidence from Positron Emission Tomography studies of altered neurochemistry in fronto-striatal pathways (eg, lower N-acetyl aspartate); lower glucose metabolism in the frontal cortex; and lower density of cannabinoid receptors, which may reverse with abstinence. Longitudinal multimodal neuroimaging studies are required to confirm if brain differences predate or follow the onset of cannabis use or cannabis use disorder, and whether changes in brain integrity in people who use cannabis dissipate with abstinence.Keywords: marijuana, MRS, fMRI, sMRI, PET, magnetic resonance imaging

Abstract Brain tumour stem cell population in glioblastoma (GBM) display key cancer stem cell characteristics of high self-renewal and drug resistance that are maintained by the coordinated functions of epigenetic and molecular regulators. Yet, specific epigenetic mechanisms that, in collaboration with relevant molecular pathways, help maintain a stem-like state in BTSCs remain poorly understood. Here, we identify HDAC2 as a foremost epigenetic regulator in BTSCs that specifically utilizes the transforming growth factor-β (TGF-β) pathway related proteins, SMAD3-SKI, for remodelling BTSC chromatin accessibility and transcriptional programs to facilitate their stemness and tumorigenic potentials. Our initial drug screening revealed that selective inhibition of HDAC1 and 2 with romidepsin was effective in targeting BTSC viability, cell proliferation and self-renewal in vitro. Using CRISPR-cas9 knockout and shRNA knockdown strategies, we further demonstrated that loss of HDAC2 disrupts an epigenetic and molecular coordination between HDAC2 and SMAD-SKI proteins, which negatively impacts BTSC survival, cell proliferation and self-renewal in vitro and improves median survival in orthotopic xenograft mouse models. Loss of HDAC2 showed reduction in the protein abundance of transcriptional regulator, SMAD3 and negative regulator protein, SKI. However, overexpression of SMAD3 in HDAC2 deficient BTSCs could partially rescues their cell functional deficits. These findings suggest that context-specific epigenetic regulations by HDAC2 and its interaction with the critical transcriptional regulators, SMAD3-SKI, maintains the stemness and growth characteristics of BTSCs. Further HDAC2 overexpression increases cell proliferation and self-renewal abilities in normal neural stem cells (NSCs). These findings thus support the role of HDAC2 as a key epigenetic determinant of stemness in normal NSCs and of cancer stem cell characteristics and tumorigenic potential in BTSCs. Collectively, our data raises the potential that disruption of the coordinated mechanisms regulated by HDAC2-SMAD3-SKI axis may be an effective therapeutic approach for targeting GBM BTSCs.

Abstract Glioblastoma (GBM) is the most common adult primary brain tumor plagued by inevitable recurrence and poor survival. We recently performed a genome wide CRISPR/Cas9 essentiality screen in GBM stem cells, revealing a plethora of potential targets for further exploration. The proteasome is a multimeric protein complex that degrades cellular proteins contributing to homeostatic proteostasis, stress response, and antigen presentation. Most proteasomal subunits are essential for GBM stem cell growth in vitro, however, they are also essential for non-malignant neural cells, suggesting that inhibition of those subunits may lead to toxicity. Indeed, adverse neurological symptoms were prevalent in phase III clinical trials for the brain penetrant proteasome inhibitor, Marizomib, which may be linked to the vital role of proteasome subunits in non-malignant neural counterparts. Proteasome inhibitors target the catalytic subunits of the proteasome, however the role of individual proteasome activators, most of which are non-essential for growth in vitro, have not been fully elucidated in GBM. Here, we examined the functionality of non-essential proteasome activator subunits in GBM stem cells in vitro and in vivo. Surprisingly, despite lack of growth changes in vitro, we observed abrogated stem-cell self-renewal in vitro and improved survival in vivo in orthotopic xenograft models following targeting of specific activator subunits. Molecular profiling of targeted cells revealed an upregulation of interferon-γ signaling and upregulation of antigen presentation machinery. Thus, targeting specific activator subunits may inhibit malignant growth in vivo while sparing normal neural counterparts from proteotoxic stress. We are further investigating enhanced antigen presentation by targeting these proteasome activator subunits and examining changes in the tumor microenvironment and survival in syngeneic immunocompetent models of GBM. Further understanding of this mechanism may provide novel targets for GBM treatment or improve immunotherapies in GBM.

Substance use is a primary risk factor for premature mortality and morbidity, and Burden of Disease (BoD) in the populations of high-income countries.1 The reduction of this substance use-related BoD requires effective public health intervention strategies. In Canada, a recent primary focus has been on responses to the ‘overdose death crisis’ which has claimed >52,000 lives since 2016, through acute drug toxicity fatalities—mostly from synthetic, toxic opioids.2 In 2023, this toll involved 8,623 fatalities (population rate: 21.5/100,000) of mostly young/middle-aged adults, making it the leading cause of unnatural deaths and a measurable driver of reduced life-expectancy in the Canadian population.

Measurement-based care using DSM-5 should be embedded in services now with scope for further development following efficacy and implementation trials. We are grateful to Kathy Bradley and her colleagues 1 and Dennis McCarty 2 for their helpful comments on our article on measurement-based care (MBC) 3. They draw on a wealth of applied experience in efficacy and implementation research in primary care (PC) and substance use disorder (SUD) treatment programmes. Their reflections emphasize the challenge of embedding sustainable clinical measurement of patient progress. Bradley and colleagues illustrate the way PC clinicians’ use of open-ended questions about SUD symptoms can facilitate discussions with patients, beginning with topics and experiences which are important to the person. This is an ideal way to help the patient feel understood, to build therapeutic alliance and review interventions offered. We had this in mind when envisaging DSM-5 criteria as the springboard to a collaborative discussion on the patient's specific SUD-related thoughts, emotions and behaviours. The aim is that treatment goals reflect personal priorities. We agree with Bradley's group that we must ensure the MBC administrative burden is minimized. This has been a priority for all contemporary developers of screening 4 and clinical instruments 5, reflecting a move away from unwieldy scale batteries and a focus on selecting items which provide the most useful information. As a minimum, we think drug craving and substance use should be monitored during the first 2 weeks after medication stabilization and regularly thereafter, to guide decisions as to whether treatment should be maintained, adjusted or switched. Brief items and scales are likely to correlate with DSM-5 SUD criteria but, importantly, they do not confirm remission. McCarty offers insight on his work with providers striving for process improvements in patient retention and engagement 6. He reports how managers stopped asking therapists to complete the brief Session Rating Scale and Outcome Rating Scale 7, 8 after inconsistent use and difficulties with data capture and feedback. This demonstrates how even a very brief measure can flounder in busy clinics. We agree that inconsistent completion confounds validity. Less frequent, consistent completion would be sufficient—and there are also other options. As we discussed, the PHQ-9 is commonly used to monitor symptoms for depression and inform treatment decisions. It is usually self-completed, so it does not compete with session time. Digitally enabled adjunctive psychological therapies can now be offered on-line or through mobile applications to help patients engage in self-monitoring of craving and self-study with discussion face-to-face with a therapist 9, 10. We appreciate that PC providers may query the cost of MBC, but in our view it is clearly warranted by the urgent need for improved treatment outcomes, especially in the context of the OUD epidemic. Clinical trials are needed to study MBC efficacy and implementation. Indicators that guide the way will emerge as a standard—but the objective must always be to help patients access and remain in effective, personalized treatment for as long as is needed. In our view, DSM-5 (or ICD-11) diagnosis and ongoing remission assessment, with interventions matched to symptoms, should be included as the standard of care in all out-patient and PC settings. J.M. declares research funding from Indivior to King's College London for a randomized controlled trial of injectable buprenorphine for the treatment of opioid use disorder.