Biological Psychiatry

OBJECTIVE: Familial, obstetric, and early-life environmental risks for schizophrenia spectrum disorder (SSD) alter normal cerebral development leading to formation of characteristic brain deficit patterns prior to onset of symptoms. We hypothesized that the insidious effects of these risks may increase brain similarity to adult SSD deficit patterns in prepubescent children. METHODS: We used data collected by the Adolescent Brain and Cognitive Development study (ABCD; N=8,940, age=9...

BACKGROUND: Second generation antipsychotics (SGAs) are front-line treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the D3 dopamine receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling. METHODS: Here, we use a combination of two photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at the D3R...

BACKGROUND: Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted or repetitive behaviors. Due to the extremely high genetic and phenotypic heterogeneity, it is critical to pinpoint the genetic factors for the understanding of the pathology of these disorders. METHODS: We analyzed the exomes generated by the SPARK project and performed a meta-analysis with previous data. We then generated a zebrafish knockout model and three mouse Gigyf1 knockout models to examine the function of GIGYF1 in neurodevelopment and behavior...

BACKGROUND: Elucidating the neural basis of infant positive emotionality (PE) and negative emotionality (NE) can identify biomarkers of pathophysiological risk. Our goal was to determine how functional interactions among large-scale networks supporting emotional regulation influence WM microstructural-emotional behavior relationships in 3-month-old infants. We hypothesized that microstructural-emotional behavior relationships would be differentially mediated or suppressed by underlying resting-state functional connectivity (rsFC), particularly between Default Mode Network (DMN) and Central Executive Network (CEN) structures...

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BACKGROUND: Variability exists in trajectories of Alzheimer's disease (AD). We aimed to identify genetic modulators of clinical progression in AD. METHODS: We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1,158 and 211,817 non-demented individuals from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the UK Biobank (UKB) (325 and 1,103 progressed in average follow-up of 4...

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BACKGROUND: The ventromedial prefrontal cortex (vmPFC) has been viewed as a locus to store and recall extinction memory. However, the synaptic and cellular mechanisms underlying this process remain elusive. METHODS: We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the vmPFC for fear extinction retrieval. RESULTS: We found that both constitutive and conditional APPL1 knockout decreases NMDA receptor (NMDAR) function in the vmPFC and impairs fear extinction retrieval...

BACKGROUND: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 dopamine receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal D2R, a typical feature of addiction, over-eating and other psychiatric pathologies...

BACKGROUND: Genome-wide association studies have discovered blocks of common variants-likely transcriptional-regulatory-associated with major depressive disorder (MDD), though the functional subset and their biological impacts remain unknown. Likewise, why depression occurs in females more frequently than males is unclear. We therefore tested the hypothesis that risk-associated functional variants interact with sex and produce greater impact in female brains. METHODS: We developed techniques to directly measure regulatory variant activity and sex interactions using massively parallel reporter assays (MPRAs) in the mouse brain in vivo, in a cell type-specific manner, and applied these approaches to measure activity of >1,000 variants from >30 MDD loci...

BACKGROUND: Emotion regulation has been linked to specific brain networks based on functional neuroimaging, but networks causally involved in emotion regulation remain unknown. METHODS: We studied patients with focal brain damage (n=167) who completed the "managing emotion" subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), a measure of emotion regulation. First, we tested whether patients with lesions to an a priori network derived from functional neuroimaging showed impaired emotion regulation...

BACKGROUND: Memory deficits are central to many neuropsychiatric diseases. During acquisition of new information memories can become vulnerable to interference, yet mechanisms that underlie interference are unknown. METHODS: We describe a novel transduction pathway that links NMDAR to AKT signaling via the IEG Arc, and evaluate its role in memory. The signaling pathway is validated using biochemical tools and genetic animals, and function is evaluated in assays of synaptic plasticity and behavior...

A central goal of computational psychiatry is to identify systematic relations between transdiagnostic dimensions of psychiatric symptomatology and the latent learning and decision-making computations that inform individuals' thoughts, feelings, and choices. The vast majority of psychiatric disorders emerge prior to adulthood, yet little work has extended these computational approaches to study the development of psychopathology. Here, we lay out a roadmap for future studies implementing this approach by developing empirically and theoretically informed hypotheses about how developmental changes in model-based control of action and Pavlovian learning processes may modulate vulnerability to anxiety and addiction...

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Individuals with psychiatric disorders are at increased risk of age-related diseases and early mortality. Recent studies demonstrate that this link between mental health and aging is reflected in epigenetic clocks, aging biomarkers based on DNA methylation. The reported relationships between epigenetic clocks and mental health are mostly correlational, and the mechanisms are poorly understood. Here, we review recent progress concerning the molecular and cellular processes underlying epigenetic clocks, as well as novel technologies enabling further studies of the causes and consequences of epigenetic aging...

BACKGROUND: Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRS) remains limited. METHODS: The UK Biobank recruited 502,534 individuals aged 37 to 73 living in the UK between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion or duplication)...

BACKGROUND: Metabolic differences have been reported between individuals with and without Major Depressive Disorder (MDD), but their consistency and causal relevance has been unclear. METHODS: We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in UK Biobank (N = 29, 757). We then applied 2-sample bidirectional Mendelian Randomisation (MR) and colocalization analysis to identify potentially causal relationships between each metabolite and MDD...