Biology subjects

Tremblay, M.-E.

Publications and source records attributed to Tremblay, M.-E..

24 records · Page 2Linked to original sources

bioRxiv2021

Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

neuroscience↗

bioRxiv2021

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized, however, less is known about the effects of MIA-exposure on embryo development. To address this gap, we performed high-resolution ex vivo magnetic resonance imaging (MRI) to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA-exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late exposed offspring. We further examined hippocampal neuroanatomy using electron microscopy and identified differential effects due to MIA-timing. An increase in apoptotic cell density was observed in the GD9 exposed offspring, while an increase in the density of dark neurons and glia, putative markers for increased neuroinflammation and oxidative stress, was observed in GD17 exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA-timing on the earliest stages of neurodevelopment.

neuroscience↗

bioRxiv2021

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

neuroscience↗

bioRxiv2019

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.\n\nOne Sentence SummaryLow maternal omega-3 fatty acids intake impairs microglia-mediated synaptic refinement via 12-HETE pathway in the developing brain.

neuroscience↗

bioRxiv2019

Stress-induced neuronal hypertrophy decreases the intrinsic excitability in stress habituation

A rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark stress response to an imminent threat, but its chronic activation can be detrimental. Thus, the long-term survival of animals requires experience-dependent fine-tuning of the stress response. However, the cellular mechanisms underlying the ability to decrease the stress responsiveness of the HPA axis remain largely unsolved. Using a stress habituation model in male mice and slice patch-clamp electrophysiology, we studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis. We found that the intrinsic excitability of these neurons substantially decreased after daily repeated restraint stress in a time course that coincided with their loss of stress responsiveness in vivo. This plasticity of intrinsic excitability co-developed with an expansion of surface membrane area, resulting in an increase in input conductance with minimal changes in conductance density. Moreover, multi-photon and electron microcopy data found that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that efficiently accommodates membrane area expansion with proportionally less expansion of gross cell volume. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.\n\nSignificance statementThe long-term survival of animals requires experience-dependent fine-tuning of stress response. Using a mouse model of repeated stress that develops habituation of the hypothalamic-pituitary-adrenal (HPA) axis, our study demonstrates a robust decrease in the intrinsic excitability of the output neuroendocrine neurons of the HPA axis. Mechanistically, we show that repeated stress increases the cell size of these neurons (i.e. surface membrane area). This cell-size change increases input conductance, and hence decreases excitability. Our findings challenge a conventional view that plasticity of intrinsic excitability relies on changes on membrane excitability resulting from up- and down-regulation of various voltage-gated ion channels. Our study reports a novel structure-function relationship for intrinsic excitability plasticity that correlates with habituation of the neuroendocrine stress response.

neuroscience↗

bioRxiv2018

Cell-lineage specificity of primary cilia during epididymis post-natal development

Primary cilia are sensory organelles that orchestrate major signaling pathways during organ development and homeostasis. By using a double Arl13b/mCherry-Cetn2/GFP transgenic mouse model, we characterized the spatio-temporal localization of primary cilia in the epididymis, from birth to adulthood. We report here a constitutive localisation of primary cilia in peritubular myoid cells and a dynamic profiling in differentiated epithelial cells throughout post-natal development. While primary cilia are present at the apical pole of the undifferentiated epithelial cells from birth to puberty, they are absent from the apical pole of the epithelium in adults, where they appear exclusively associated with cytokeratin 5-positive basal cells. Exogenous labeling of primary cilia marker Arl13b and IFT88 confirmed the cell lineage specific localization of primary cilia in basal cells and myoid cells in human epididymides. From whole epididymis tissues and serum-free cultures of DC2 murine epididymal principal cell lines we determined that primary cilia from the epididymis are associated with the polycystic kidney disease-related proteins polycystin 1 (PC1) and polycystin 2 (PC2), and Gli3 Hedgehog signaling transcription factor. Thus, our findings unveil the existence of primary cilia sensory organelles, which have the potential to mediate mechano/ chemo-signaling events in the epididymis.

developmental biology↗