The long-lasting effects of early life adversities are sex dependent: The signature of miR-34a.

BACKGROUND: Exposure to early life adversities (ELA) can influence a plethora of biological mechanisms leading to stress-related disorders later in life through epigenetic mechanisms, such as microRNAs (miRs). MiR-34 is a critical modulator of stress response and stress-induced pathologies and a link between ELA and miR-34a has been reported. METHODS: Here using our well-established model of ELA (Repeated Cross Fostering) we investigate the behavioral long-term effects of ELA in male and female mice. We also assess basal and ELA-induced miR-34a expression in adult mice and investigate whether ELA affects the later miR-34a response to adult acute stress exposure across brain areas (medial preFrontal Cortex, Dorsal Raphe Nuclei) and peripheral organs (heart, plasma) in animals from both sexes. Finally, based on our previous data demonstrating the critical role of Dorsal Raphe Nuclei miR-34a expression in serotonin (5-HT) transmission, we also investigated prefrontal-accumbal 5-HT outflow induced by acute stress exposure in ELA and Control females by in vivo intracerebral microdialysis. RESULTS: ELA not just induces a depressive-like state as well as enduring changes in miR-34a expression, but also alters miR-34a expression in response to adult acute stress exclusively in females. Finally, altered DRN miR-34a expression is associated with prefrontal-accumbal 5-HT release under acute stress exposure in females. LIMITATIONS: Translational study on humans is necessary to verify the results obtained in our animal models of ELA-induced depression. CONCLUSIONS: This is the first evidence showing long-lasting sex related effects of ELA on brain and peripheral miR-34a expression levels in an animal model of depression-like phenotype.

Early-life social stress induces permanent alterations in plasticity and perineuronal nets in the mouse anterior cingulate cortex.

Child maltreatment disrupts trajectories of brain development, but the underlying pathways are unclear. Stressful stimuli in early life interfere with maturation of local inhibitory circuitry and deposition of perineuronal nets (PNNs), specialized extracellular matrix structures involved in the closure of critical periods of development. Alterations in cortical PNN and parvalbumin (PV) following early-life stress (ELS) have been detected in human and animal studies. Aberrations in the anterior cingulate cortex (ACC) are the most consistent neuroimaging findings in maltreated people, but the molecular mechanisms linking ELS with ACC dysfunctions are unknown. Here, we employed a mouse model of early social threat to test whether ELS experienced in a sensitive period for ACC maturation could induce long-term aberrations of PNN and PV development in the ACC, with consequences on plasticity and ACC-dependent behavior. We found that ELS increased PNN but not PV expression in the ACC of young adult mice. This was associated with reduced frequency of inhibitory postsynaptic currents and long-term potentiation impairments and expression of intense object phobia. Our findings provide information on the long-term effects of ELS on ACC functionality and PNN formation and present evidence for a novel neurobiological pathway underlying the impact of early adversity on the brain.

The "systems approach" to treating the brain: opportunities in developmental psychopharmacology
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The significance of early life for the long-term programming of mental health is increasingly being recognized. However, most psychotropic medications are currently intended for adult patients, and early psychopharmacological approaches aimed at reverting aberrant neurodevelopmental trajectories are missing. Psychopharmacologic intervention at an early age faces the challenge of operating in a highly plastic system and requires a comprehensive knowledge of neurodevelopmental mechanisms. Recently the systems biology approach has contributed to the understanding of neuroplasticity mechanisms from a new perspective that interprets them as the result of complex and dynamic networks of signals from different systems. This approach is creating opportunities for developmental psychopharmacology, suggesting novel targets that can modulate the course of development by interfering with neuroplasticity at an early age. We will discuss two interconnected systems-the immune and gut microbiota-that regulate neurodevelopment and that have been implicated in preclinical research as new targets in the prevention of aberrant brain development.
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Cada vez se reconoce más la importancia de la vida temprana para la programación a largo plazo de la salud mental. Sin embargo, la mayoría de los medicamentos psicotrópicos está destinada actualmente a pacientes adultos, y faltan enfoques psicofarmacológicos en niños, orientados a revertir trayectorias del neurodesarrollo aberrantes. La intervención psicofarmacológica a una edad temprana enfrenta el desafío de operar en un sistema altamente plástico y requiere de un conocimiento completo de los mecanismos del neurodesarrollo. Recientemente, el enfoque de la biología de sistemas ha contribuido a la comprensión de los mecanismos de neuroplasticidad desde una nueva perspectiva que los interpreta como el resultado de redes complejas y dinámicas de señales de diferentes sistemas. Este enfoque está creando oportunidades para la psicofarmacología del desarrollo, sugiriendo nuevos objetivos que pueden modular el curso del desarrollo al interferir con la neuroplasticidad a una edad temprana. Discutiremos dos sistemas interconectados, el inmunológico y la microbiota intestinal, que regulan el neurodesarrollo y que han sido implicados en la investigación preclínica como nuevos objetivos en la prevención del desarrollo cerebral aberrante.

L'importance des premières années pour la programmation à long terme de la santé mentale est de plus en plus reconnue. Cependant, la plupart des médicaments psychotropes sont à destination des patients adultes, et des approches psychopharmacologiques précoces ayant pour but de corriger des neurodévelopements aberrants font défaut. Une intervention psychopharmacologique à un âge précoce doit faire face au défi d'agir dans un système hautement plastique et requiert une connaissance exhaustive des mécanismes du neurodévelopement. Récemment l'approche par la biologie des systèmes a participé à la compréhension des mécanismes de la neuroplasticité dans une nouvelle perspective qui les interprète comme le résultat des signaux de réseaux complexes et dynamiques provenant de différents systèmes. Cette approche crée des opportunités pour la psychopharmacologie pédiatrique, suggérant de nouvelles cibles qui pourraient moduler le cours du développement en interférant avec la neuroplasticité à un âge précoce. Nous discuterons deux systèmes interconnectés ­ le système immunitaire et le microbiote intestinal ­ qui régulent le neurodévelopement et qui ont été étudiés dans des recherches précliniques en tant que nouvelles cibles dans la prévention du développement aberrant du cerveau.

Serotonin receptor 1A modulates actin dynamics and restricts dendritic growth in hippocampal neurons.

Mice lacking serotonin receptor 1A (Htr1a) display increased anxiety behavior that depends on the expression of the receptor in the forebrain during the third to fifth postnatal weeks. Within the forebrain, Htr1a is prominently expressed in the soma and dendrites of CA1 pyramidal neurons of the hippocampus and these cells undergo rapid dendritic growth and synapse formation during this period. Consistent with a possible role of Htr1a in synaptic maturation, CA1 pyramidal neurons in the knockout mice show increased ramification of oblique dendrites. These findings suggest that Htr1a may shape hippocampal circuits by directly modulating dendritic growth. Here we show that pharmacological blockade of the receptor during the third to fifth postnatal weeks is sufficient to reproduce the increased branching of oblique dendrites seen in knockout mice. Using dissociated hippocampal cultures we demonstrate that serotonin functions through Htr1a to attenuate the motility of dendritic growth cones, reduce their content of filamentous actin and alter their morphology. These findings suggest that serotonin modulates actin cytoskeletal dynamics in hippocampal neurons during a limited developmental period to restrict dendritic growth and achieve a long-term adjustment of neural connectivity.