Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to ...depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.
•A large-scale multi-brain region transcriptomic cohort to probe stress susceptibility•Reveals susceptible and resilient transcriptional networks across brain regions•Identifies many novel hub genes that emerge in susceptible mice•In vivo validation of key regulators at molecular, synaptic, and behavioral levels
Molecular mechanisms of dysregulated circuit function in depression are poorly understood. Employing integrative network analysis of large-scale RNA sequencing data, Bagot et al. identify distinct inter-regional transcriptional networks regulating depression susceptibility versus resilience. In vivo validation of networks suggests novel antidepressant targets.
In most animals, the majority of the nervous system is generated and assembled into neuronal circuits during embryonic development
. However, during juvenile stages, nervous systems still undergo ...extensive anatomical and functional changes to eventually form a fully mature nervous system by the adult stage
. The molecular changes in post-mitotic neurons across post-embryonic development and the genetic programs that control these temporal transitions are not well understood
. Here, using the model system Caenorhabditis elegans, we comprehensively characterized the distinct functional states (locomotor behaviour) and the corresponding distinct molecular states (transcriptome) of the post-mitotic nervous system across temporal transitions during post-embryonic development. We observed pervasive, neuron-type-specific changes in gene expression, many of which are controlled by the developmental upregulation of the conserved heterochronic microRNA LIN-4 and the subsequent promotion of a mature neuronal transcriptional program through the repression of its target, the transcription factor lin-14. The functional relevance of these molecular transitions are exemplified by a temporally regulated target gene of the LIN-14 transcription factor, nlp-45, a neuropeptide-encoding gene, which we find is required for several distinct temporal transitions in exploratory activity during post-embryonic development. Our study provides insights into regulatory strategies that control neuron-type-specific gene batteries to modulate distinct behavioural states across temporal, sexual and environmental dimensions of post-embryonic development.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The postnatal brain undergoes chromatin and transcriptional changes that underlie functional maturation (e.g., electrophysiological properties, morphology, connectivity, network activity) across the ...lifespan. While these changes are observed across the animal kingdom, changes associated with maturation, including timing, are often neuron-type, brain-region, and species specific.Sensory stimulus coordination of neuronal activity and cross-modal neurotransmission is one mechanism by which the external environment regulates neuronal maturation.Neuronal activity controls the molecular changes underlying neuronal maturation by regulating transcriptional and chromatin factors.Aspects of postnatal neuronal maturation are regulated by cell-intrinsic sensory stimulus-independent genetic timer cascades. These mechanisms are intertwined with cell-extrinsic mechanisms to control maturation.
Embryonic neurodevelopment, particularly neural progenitor differentiation into post-mitotic neurons, has been extensively studied. While the number and composition of post-mitotic neurons remain relatively constant from birth to adulthood, the brain undergoes significant postnatal maturation marked by major property changes frequently disrupted in neural diseases. This review first summarizes recent characterizations of the functional and molecular maturation of the postnatal nervous system. We then review regulatory mechanisms controlling the precise gene expression changes crucial for the intricate sequence of maturation events, highlighting experience-dependent versus cell-intrinsic genetic timer mechanisms. Despite significant advances in understanding of the gene-environmental regulation of postnatal neuronal maturation, many aspects remain unknown. The review concludes with our perspective on exciting future research directions in the next decade.
Embryonic neurodevelopment, particularly neural progenitor differentiation into post-mitotic neurons, has been extensively studied. While the number and composition of post-mitotic neurons remain relatively constant from birth to adulthood, the brain undergoes significant postnatal maturation marked by major property changes frequently disrupted in neural diseases. This review first summarizes recent characterizations of the functional and molecular maturation of the postnatal nervous system. We then review regulatory mechanisms controlling the precise gene expression changes crucial for the intricate sequence of maturation events, highlighting experience-dependent versus cell-intrinsic genetic timer mechanisms. Despite significant advances in understanding of the gene-environmental regulation of postnatal neuronal maturation, many aspects remain unknown. The review concludes with our perspective on exciting future research directions in the next decade.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heterochrony is a foundational concept in animal development and evolution, first introduced by Ernst Haeckel in 1875 and later popularized by Stephen J. Gould1. A molecular understanding of ...heterochrony was first established by genetic mutant analysis in the nematode C. elegans, revealing a genetic pathway that controls the proper timing of cellular patterning events executed during distinct postembryonic juvenile and adult stages2. This genetic pathway is composed of a complex temporal cascade of multiple regulatory factors, including the first-ever discovered miRNA, lin-4, and its target gene, lin-14, which encodes a nuclear, DNA-binding protein2,3,4. While all core members of the pathway have homologs based on primary sequences in other organisms, homologs for LIN-14 have never been identified by sequence homology. We report that the AlphaFold-predicted structure of the LIN-14 DNA binding domain is homologous to the BEN domain, found in a family of DNA binding proteins previously thought to have no nematode homologs5. We confirmed this prediction through targeted mutations of predicted DNA-contacting residues, which disrupt in vitro DNA binding and in vivo function. Our findings shed new light on potential mechanisms of LIN-14 function and suggest that BEN domain-containing proteins may have a conserved role in developmental timing.
Greene et al. show that the DNA-binding domain of Lin-14, a protein required for normal developmental timing in Caenorhabditis elegans, is homologous to the BEN domain, suggesting the possibility that proteins containing the BEN domain may have a general role in developmental timing in animals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that the precisely timed
regulatory circuit triggers an ...initial dendritic growth activity, whereas the precisely timed
regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a set time frame. Loss-of-function mutations in the
microRNA gene cause limited dendritic outgrowth, whereas loss-of-function mutations in its direct target, the
transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the
microRNA gene prevent a developmental decline in dendritic growth ability, whereas loss-of-function mutations in its direct target, the
tripartite motif protein gene, cause further decline.
and
regulatory circuits are expressed in the right place at the right time to set start and end times for dendritic arborization. Replacing the
upstream cis-regulatory sequence at the
locus with a late-onset
upstream cis-regulatory sequence delays dendrite arborization, whereas replacing the
upstream cis-regulatory sequence at the
locus with an early-onset
upstream cis-regulatory sequence causes a precocious decline in dendritic growth ability. Our results indicate that the
and the
regulatory circuits control the timing of dendrite arborization through antagonistic regulation of the DMA-1 receptor level on dendrites. The LIN-14 transcription factor likely directly represses
gene expression through a transcriptional means, whereas the LIN-41 tripartite motif protein likely indirectly promotes
gene expression through a posttranscriptional means.
Efforts are ongoing to map synaptic wiring diagrams, or connectomes, to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important ...neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene-expression datasets with biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This network is characterized by high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several key network hubs are little-studied neurons that appear specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand how networks of neuromodulatory signaling are organized.
Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's ...reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Furthermore, we demonstrate that repeated cocaine exposure causes persistent decreases in heterochromatization in this brain region, suggesting a potential role for heterochromatic regulation in the long-term actions of cocaine. To identify precise genomic loci affected by these alterations, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence of the H3K9me3 mark mainly within intergenic regions of the genome and identified specific patterns of cocaine-induced H3K9me3 regulation at repetitive genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats e.g., long interspersed nuclear element (LINE)-1 repeats were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, ...are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Over the past decade, rapid advances in epigenomics research have extensively characterized critical roles for chromatin regulatory events during normal periods of eukaryotic cell development and ...plasticity, as well as part of aberrant processes implicated in human disease. Application of such approaches to studies of the CNS, however, is more recent. Here we provide a comprehensive overview of available tools for analyzing neuroepigenomics data, as well as a discussion of pending challenges specific to the field of neuroscience. Integration of numerous unbiased genome-wide and proteomic approaches will be necessary to fully understand the neuroepigenome and the extraordinarily complex nature of the human brain. This will be critical to the development of future diagnostic and therapeutic strategies aimed at alleviating the vast array of heterogeneous and genetically distinct disorders of the CNS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic ...dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise.
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