Anthony Christopher Vernon

Antenatal depression affects up to 20% of pregnancies worldwide and is associated with increased neuropsychiatric vulnerability in offspring, yet the enduring behavioural, neuroanatomical, and molecular features associated with maternal mood disturbance remain incompletely characterized. T o model depression that begins before conception, female mice were subjected to social-isolation rearing (SIR) from weaning through gestation and lactation, and behavioural, neuroanatomical, and molecular outcomes were assessed in adult offspring of both sexes. Offspring of SIR dams exhibited robust anxiety-like behaviours across multiple paradigms. High-resolution ex vivo structural magnetic resonance imaging revealed reduced relative volumes of the thalamus and striatum, together with relative expansion of gustatory/visceral and visual cortices. Multivariate analyses identified a pattern of thalamostriatal and other regional volume differences that covaried with behavioural impairment. Diffusion tensor imaging further identified region-specific elevations in fractional anisotropy, consistent with persistent differences in brain microstructure. Transcriptomic profiling of the thalamus revealed widespread, sex-dependent differences in gene expression, implicating pathways related to synaptic organization, protein synthesis, neuronal plasticity, and myelination. Exploratory DNA-methylation analyses identified nominal, sex-dependent pathway enrichments that did not survive false-discovery-rate correction. Together, these findings show that maternal stress beginning before pregnancy leaves a persistent imprint on offspring brain structure, microstructure, and epigenetic regulation, converging on the thalamus as a central hub of intergenerational vulnerability. This work establishes SIR as a translationally relevant model of depression that predates conception and provides integrated MRI- and molecular-level biomarkers for dissecting mechanisms and informing early preventive strategies.

ZNF804A was among the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A in the regulation of gene expression and synaptic function, but the role of this gene in neurodevelopment and in schizophrenia pathogenesis remains unclear. To study its function during neurodevelopment, we generated isogenic human induced pluripotent stem cells with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons, and studied their transcriptomic, synaptic, and protein signatures. Mutant neurons showed modest evidence for changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell compartment–specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal and translational proteins within neurites, and high-content imaging confirmed increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation.

Human brain function is dependent on synaptic architecture and function between a range of different cell types. Glutamatergic and GABAergic neurons provide the basis by which the excitatory and inhibitory balance is achieved in cortical networks, and microglia interact with them to shape synaptic architecture and neural networks. Understanding the interactions between these cell types is crucial to elucidating mechanisms relevant to brain physiology and, potentially, to neurodevelopmental and neurological disorders. Here, we establish a rapid and reproducible human tri-culture platform comprising deterministically-programmed glutamatergic neurons, GABAergic neurons, and microglia to facilitate cell-cell interaction studies during human cortical development. Using these deterministically-programmed ioCells, we systematically optimised neuronal ratios, culture conditions, and the timing of microglial integration to generate a stable neuronal network prior to microglia incorporation. Multi-electrode arrays (MEAs) recordings identified an 80:20 glutamatergic-to-GABAergic ratio as the most robust configuration for sustained and reproducible network activity in this context. Structural characterisation using automated high-content imaging confirmed the formation of both excitatory and inhibitory synapses, while longitudinal MEA recordings demonstrated stable network maturation following microglial incorporation. Microglia incorporation influenced neuronal firing dynamics, increasing burst activity without disrupting early synapse formation. As a proof of concept for disease modelling, we incorporated microglia carrying the Alzheimer’s disease-associated TREM2 R47H mutation and detected subtle but reproducible alterations in neuronal burst dynamics. Together, this work establishes a defined human neuron-microglia triculture platform that enables scalable investigation of neuroimmune interactions and genetic variants, laying the foundations for more complex future models.

Antenatal depression, affecting 10–20% of pregnancies worldwide, represents a major public health concern due to its association with maternal suicide, obstetric complications, and long-term neurodevelopmental and psychiatric vulnerability in offspring. Despite its prevalence and impact, the neurobiological mechanisms by which maternal mood disturbance shapes offspring brain development remain poorly understood. To address this, we employed a social-isolation rearing (SIR) paradigm in female C57BL/6N mice spanning preconception, gestation, and lactation. Adult offspring were evaluated using established assays of anxiety-like behavior, high-resolution ex vivo structural magnetic resonance imaging, and thalamic bulk RNA sequencing. Offspring of SIR dams exhibited consistent anxiety phenotypes across multiple behavioral tests. Neuroimaging revealed thalamic and striatal hypotrophy together with expansion of gustatory/visceral and visual cortices. Multivariate partial least-squares modelling identified thalamostriatal reductions as the principal latent factor associated with behavioral variance, whereas cortical hypertrophy covaried with exploratory drive. Transcriptomic analysis demonstrated extensive, sex-divergent reprogramming: males showed enrichment of pathways regulating protein synthesis and synaptic organization, while females exhibited alterations related to neuronal plasticity and myelin development. These findings establish preconceptional SIR as a translational model of maternal depression, identify the thalamus as a key locus of intergenerational vulnerability, and provide integrated imaging and molecular markers that may inform mechanistic studies and preventive interventions for offspring exposed to maternal mood disorders.

Social deficits are a hallmark of schizophrenia, often characterized by impairments in processing and integrating socially transmitted information. However, translational models that accurately capture these deficits remain scarce. The Disrupted-in-Schizophrenia 1 gene ( DISC1 ), a key susceptibility factor implicated in the etiology of psychiatric disorders, has been shown to cause DISC1 protein aggregation and dysfunctional signaling when modestly overexpressed, ultimately resulting in aberrant dopamine homeostasis. In this study, we employed a transgenic rat model overexpressing human DISC1 (tgDISC1 rats) to investigate social reward learning and microstructural integrity in the brain. Using a modified Social Transmission of Food Preference (STFP) task, we report that male tgDISC1 rats failed to update reward preferences based on social information, despite intact nonsocial reward learning—suggesting a specific deficit in social reward learning. Diffusion tensor imaging (DTI) in a behaviorally naive cohort revealed reduced fractional anisotropy (FA) in key subcortical regions, including the nucleus accumbens, amygdala, and substantia nigra, as well as areas mediating cortical-subcortical communication as the thalamus. Structural alterations in corresponding neuroanatomical areas have also been described in DTI of schizophrenia patients. Our findings link aberrant DISC1 signaling with impaired connectivity in parts of the mesolimbic system, critical for integrating social information into decision-making. This model recapitulates both behavioral and structural endophenotypes of schizophrenia and suggests that social impairments may stem from a fine-grained circuit-selective dysfunction rather than a generalized reward processing deficit. The tgDISC1 rat thus offers a translational platform for probing the neural substrates of social dysfunction in psychiatric disorders.

Modern neuroscience understands the brain as a complex system whose functional properties are determined by the myriads of interactions of its cellular components. In the difficult route to obtain better understanding of this organ, mathematical tools have become ever more effective, and we are now able to simulate the dynamics of brain signals from digital representations that have high fidelity to experimental data. However, these simulations are generated by inherently simple neuronal models that contain assumptions that, by necessity, can be at times far removed from the underlying neurobiology. Here we develop an integrated view of brain dynamics that describes how the neurovascular units — made of neurons, capillaries and glia — collectively determine the development of the functional properties of brain neuronal populations and maintain their homeostatic control. These interactions are instructed by genetic programmes modulated by local environmental conditions. These complexities can be integrated into generative models and supply helpful analytics able to link the observable data to neurobiological entities if detailed brain mappings of molecular and cellular components are available. We further highlight how the development of these generative models could be relevant to the understanding of psychiatric conditions.