Background . Current lipid-lowering drugs often leave significant residual risk for adverse outcomes. Identification of previously approved drugs for new indications, drug repurposing, may provide a cost effective alternative to de novo drug developing. Objectives . We combined clinical, transcriptomic, computational, and experimental strategies to explore lipid-lowering and plaque-stabilizing effects of atypical antidepressant trazodone. Methods . First, a connectivity mapping strategy was used to match rosuvastatin gene expression signature derived from a clinical trial of 85 patients with to the expression patterns of 1,309 different small molecules to discover a similarity between the rosuvastatin and trazodone gene expression signatures. Then, we assessed the lipid-lowering ability of trazodone in vitro using HepG2 cells and in vivo using molecular imaging of rabbit atherosclerotic lesions. In addition, we analyzed electronic medical records of patients from three large medical centers who had a prescription for trazodone and lipid laboratory measurements available. Results . Trazodone significantly reduced cholesterol levels in the HepG2 human hepatocyte model, decreased atherosclerotic plaque burden in a rabbit model and lowered low-density lipoprotein (LDL) cholesterol levels in patients. Conclusion . Our results indicate that trazodone may be a promising candidate for adjunctive lipid lowering therapy. It may provide significant benefits to patients with hyperlipidemia, including lipid level reduction and formation of a more favorable atherosclerotic plaque morphology. Patients diagnosed with major depressive disorder requiring better lipid control would benefit the most from the for adjunctive lipid lowering therapy.

Cognitive function depends on frontal cortex development; however, the mechanisms driving this process are poorly understood. Here, we identify that dynamic regulation of the nicotinic cholinergic system is a key driver of attentional circuit maturation associated with top-down frontal neurons projecting to visual cortex. The top-down neurons receive robust cholinergic inputs, but their nicotinic tone decreases following adolescence by increasing expression of a nicotinic brake, Lynx1 Lynx1 shifts a balance between local and long-range inputs onto top-down frontal neurons following adolescence and promotes the establishment of attentional behavior in adulthood. This key maturational process is disrupted in a mouse model of fragile X syndrome but was rescued by a suppression of nicotinic tone through the introduction of Lynx1 in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinformatics approach, we systematically scanned 2001 environmental chemicals and identified 50 chemicals that consistently dysregulate two transcriptional signatures of critical period plasticity. These chemicals included pesticides (e.g., pyridaben), antimicrobials (e.g., bacitracin), metals (e.g., mercury), anesthetics (e.g., halothane), and other chemicals and mixtures (e.g., vehicle emissions). Application of a chemogenomic enrichment analysis and hierarchical clustering across these diverse chemicals identified two clusters of chemicals with one that mimicked an immune response to pathogen, implicating inflammatory pathways and microglia as a common chemically induced neuropathological process. Thus, we established an integrative bioinformatics approach to systematically scan thousands of environmental chemicals for their ability to dysregulate molecular signatures relevant to critical periods of development.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior.

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brain's transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

Childhood critical periods of experience-dependent plasticity are essential for the development of environmentally appropriate behavior and cognition. Disruption of critical periods can alter development of normal function and confer risk for neurodevelopmental disorders. While genes and their expression relevant to neurodevelopment are associated with schizophrenia, the molecular relationship between schizophrenia and critical periods has not been assessed systematically. Here, we apply a transcriptome-based bioinformatics approach to assess whether genes associated with the human critical period for visual cortex plasticity, a well-studied model of cortical critical periods, are aberrantly expressed in schizophrenia and bipolar disorder. Across two dozen datasets encompassing 522 cases and 374 controls, we find that the majority show aberrations in expression of genes associated with the critical period. We observed both hyper- and hypo-critical period plasticity phenotypes at the transcriptome level, which partially mapped to drug candidates that reverse the disorder signatures in silico. Our findings indicate plasticity aberrations in schizophrenia and their treatment may need to be considered in the context of subpopulations with elevated and others reduced plasticity. Future work should leverage ongoing consortia RNA-sequencing efforts to tease out the sources of plasticity-related transcriptional aberrations seen in schizophrenia, including true biological heterogeneity, interaction between normal development/aging and the disorder, and medication history. Our study also urges innovation towards direct assessment of visual cortex plasticity in humans with schizophrenia to precisely deconstruct the role of plasticity in this disorder.

High and increasing prevalence of neurodevelopmental disorders place enormous personal and economic burdens on society. Given the growing realization that the roots of neurodevelopmental disorders often lie in early childhood, there is an urgent need to identify childhood risk factors. Neurodevelopment is marked by periods of heightened experience-dependent neuroplasticity wherein neural circuitry is optimized by the environment. If these critical periods are disrupted, development of normal brain function can be permanently altered, leading to neurodevelopmental disorders. Here, we aim to systematically identify human variants in neuroplasticity-related genes that confer risk for neurodevelopmental disorders. Historically, this knowledge has been limited by a lack of techniques to identify genes related to neurodevelopmental plasticity in a high-throughput manner and a lack of methods to systematically identify mutations in these genes that confer risk for neurodevelopmental disorders. Using an integrative genomics approach, we determined loss-of-function (LOF) variants in putative plasticity genes, identified from transcriptional profiles of brain from mice with elevated plasticity, that were associated with neurodevelopmental disorders. From five shared differentially expressed genes found in two mouse models of juvenile-like elevated plasticity (juvenile wild-type or adult Lynx1-/- relative to adult wild-type) that were also genotyped in the Mount Sinai BioMe Biobank we identified multiple associations between LOF genes and increased risk for neurodevelopmental disorders across 10,510 patients linked to the Mount Sinai Electronic Medical Records (EMR), including epilepsy and schizophrenia. This work demonstrates a novel approach to identify neurodevelopmental risk genes and points toward a promising avenue to discover new drug targets to address the unmet therapeutic needs of neurodevelopmental disease.

Background Worldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e., a treatment failure) that affects the quality of life of patient. To implement individualized interventions, it is necessary to predict those individuals at highest risk for 30-day readmission. In this study, our aim was to conduct a data-driven investigation to find the pharmacological factors influencing 30-day all-cause, intra- and interdepartmental readmissions after an index psychiatric admission, using the compendium of prescription data (prescriptome) from electronic medical records (EMR). Methods The data scientists in the project received a deidentified database from the Mount Sinai Data Warehouse, which was used to perform all analyses. Data was stored in a secured MySQL database, normalized and indexed using a unique hexadecimal identifier associated with the data for psychiatric illness visits. We used Bayesian logistic regression models to evaluate the association of prescription data with 30-day readmission risk. We constructed individual models and compiled results after adjusting for covariates, including drug exposure, age, and gender. We also performed digital comorbidity survey using EMR data combined with the estimation of shared genetic architecture using genomic annotations to disease phenotypes. Results Using an automated, data-driven approach, we identified prescription medications, side effects (primary side effects), and drug-drug interaction-induced side effects (secondary side effects) associated with readmission risk in a cohort of 1275 patients using prescriptome analytics. In our study, we identified 28 drugs associated with risk for readmission among psychiatric patients. Based on prescription data, Pravastatin had the highest risk of readmission (OR = 13.10; 95% CI (2.82, 60.8)). We also identified enrichment of primary side effects ( n = 4006) and secondary side effects ( n = 36) induced by prescription drugs in the subset of readmitted patients ( n = 89) compared to the non-readmitted subgroup ( n = 1186). Digital comorbidity analyses and shared genetic analyses further reveals that cardiovascular disease and psychiatric conditions are comorbid and share functional gene modules (cardiomyopathy and anxiety disorder: shared genes ( n = 37; P = 1.06815E-06)). Conclusions Large scale prescriptome data is now available from EMRs and accessible for analytics that could improve healthcare outcomes. Such analyses could also drive hypothesis and data-driven research. In this study, we explored the utility of prescriptome data to identify factors driving readmission in a psychiatric cohort. Converging digital health data from EMRs and systems biology investigations reveal a subset of patient populations that have significant comorbidities with cardiovascular diseases are more likely to be readmitted. Further, the genetic architecture of psychiatric illness also suggests overlap with cardiovascular diseases. In summary, assessment of medications, side effects, and drug-drug interactions in a clinical setting as well as genomic information using a data mining approach could help to find factors that could help to lower readmission rates in patients with mental illness.

Given that thousands of chemicals released into the environment have the potential capacity to harm neurodevelopment, there is an urgent need to systematically evaluate their toxicity. Neurodevelopment is marked by critical periods of plasticity wherein neural circuits are refined by the environment to optimize behavior and function. If chemicals perturb these critical periods, neurodevelopment can be permanently altered. Focusing on 214 human neurotoxicants, we applied an integrative bioinformatics approach using publically available data to identify dozens of neurotoxicant signatures that disrupt a transcriptional signature of a critical period for brain plasticity. This identified lead (Pb) as a critical period neurotoxicant and we confirmed in vivo that Pb partially suppresses critical period plasticity at a time point analogous to exposure associated with autism. This work demonstrates the utility of a novel informatics approach to systematically identify neurotoxicants that disrupt childhood neurodevelopment and can be extended to assess other environmental chemicals.

Introduction: Statins not infrequently fall short of target reduction in hyperlipidemia. Recently approved anti-lipid drugs are prohibitively expensive. Repurposing previously-approved drugs for ne...

Heightened juvenile cortical plasticity declines into adulthood, posing a challenge for functional recovery following brain injury or disease. A network of inhibition is critical for regulating plasticity in adulthood, yet contributions of interneuron types other than parvalbumin (PV) interneurons have been underexplored. Here we show Lypd6, an endogenous positive modulator of nicotinic acetylcholine receptors (nAChRs), as a specific molecular target in somatostatin (SST) interneurons for reactivating cortical plasticity in adulthood. Selective overexpression of Lypd6 in adult SST interneurons reactivates plasticity through the α2 subtype of nAChR by rapidly activating SST interneurons and in turn inhibiting sub-population of PV interneurons, a key early trigger of the juvenile form of plasticity. Chemogenetic activation of SST interneurons confirms the causal role of SST interneuron activity in reactivating plasticity. Collectively, we identify the Lypd6-nAChRα2 system and associated SST-PV disinhibitory microcircuit as the novel SST interneuron-specific targets for reactivating plasticity in adulthood. This provides potential insights into therapeutic strategies against disorders where recovery is limited due to diminished plasticity in adulthood, such as amblyopia and psychiatric disorders characterized by deficits in SST interneurons.

Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found that the administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest that inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicate that treating inflammation may reduce the burden of neurodevelopmental disorders.

Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.