Biology subjects

Trevisan, A. J.

Publications and source records attributed to Trevisan, A. J..

4 recordsLinked to original sources

bioRxiv2024

Spinal neuron diversity scales exponentially with swim-to-limb transformation during frog metamorphosis

Vertebrates exhibit a wide range of motor behaviors, ranging from swimming to complex limb-based movements. Here we take advantage of frog metamorphosis, which captures a swim-to-limb-based movement transformation during the development of a single organism, to explore changes in the underlying spinal circuits. We find that the tadpole spinal cord contains small and largely homogeneous populations of motor neurons (MNs) and V1 interneurons (V1s) at early escape swimming stages. These neuronal populations only modestly increase in number and subtype heterogeneity with the emergence of free swimming. In contrast, during frog metamorphosis and the emergence of limb movement, there is a dramatic expansion of MN and V1 interneuron number and transcriptional heterogeneity, culminating in cohorts of neurons that exhibit striking molecular similarity to mammalian motor circuits. CRISPR/Cas9-mediated gene disruption of the limb MN and V1 determinants FoxP1 and Engrailed-1, respectively, results in severe but selective deficits in tail and limb function. Our work thus demonstrates that neural diversity scales exponentially with increasing behavioral complexity and illustrates striking evolutionary conservation in the molecular organization and function of motor circuits across species.

neuroscience↗

bioRxiv2024

The transcriptomic landscape of spinal V1 interneurons reveals a role for En1 in specific elements of motor output

Neural circuits in the spinal cord are composed of diverse sets of interneurons that play crucial roles in shaping motor output. Despite progress in revealing the cellular architecture of the spinal cord, the extent of cell type heterogeneity within interneuron populations remains unclear. Here, we present a single-nucleus transcriptomic atlas of spinal V1 interneurons across postnatal development. We find that the core molecular taxonomy distinguishing neonatal V1 interneurons perdures into adulthood, suggesting conservation of function across development. Moreover, we identify a key role for En1, a transcription factor that marks the V1 population, in specifying one unique subset of V1Pou6f2 interneurons. Loss of En1 selectively disrupts the frequency of rhythmic locomotor output but does not disrupt flexion/extension limb movement. Beyond serving as a molecular resource for this neuronal population, our study highlights how deep neuronal profiling provides an entry point for functional studies of specialized cell types in motor output.

neuroscience↗

bioRxiv2024

Synaptic plasticity in human thalamocortical assembloids

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA-sequencing revealed that most cells in mature thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits. HighlightsO_LIHuman thalamic organoids consist of mostly glutamatergic projection neurons. C_LIO_LIThalamocortical assembloids form reciprocal glutamatergic synapses. C_LIO_LISynapses are functional and undergo short-term plasticity resembling animal models. C_LIO_LILong-term potentiation and depression reveal mechanisms distinct from rodents. C_LI eTOCHuman organoids are often used to model diseases with synaptic pathology; however, few studies have examined synaptic function via single-cell or single-synapse recordings. Patton et al. fused human thalamic and cortical organoids into assembloids to examine synaptic transmission and short- and long-term synaptic plasticity in human thalamocortical and corticothalamic circuits. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/578421v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@21546org.highwire.dtl.DTLVardef@c2ba28org.highwire.dtl.DTLVardef@4bc28aorg.highwire.dtl.DTLVardef@1d12a98_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone

Microglia are the primary phagocytes in the central nervous system and are responsible for clearing dead cells generated during development or disease. The phagocytic process shapes the phenotype of the microglia, which affects the local environment. A unique population of microglia reside in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence this neurogenic niche is not well-understood. Here, we demonstrate that phagocytosis creates a pro-neurogenic microglial phenotype in the V-SVZ and that these microglia phagocytose apoptotic cells via the engulfment receptor Jedi-1. Deletion of Jedi-1 decreases apoptotic cell clearance, triggering the development of a neuroinflammatory phenotype, reminiscent of neurodegenerative and-age-associated microglia, that reduces neural precursor proliferation via elevated interleukin (IL)-1{beta} signaling; inhibition of IL-1 receptor rescues precursor proliferation in vivo. Together, these results reveal a critical role for Jedi-1 in connecting microglial phagocytic activity to a phenotype that promotes neurogenesis in the developing V-SVZ. Graphical Abstract. Jedi-1-dependent phagocytosis supports neurogenesis via suppression of microglial inflammatory pathway activationTop: Wild-type Proliferative-zone-Associated Microglia (PAMs) (cyan) use the engulfment receptor Jedi-1 ( Jedi) to engulf apoptotic cells (yellow) in the neurogenic ventricular-subventricular zone (V-SVZ) of the early postnatal brain. Jedi activation supports neural precursor cell (NPC) proliferation and the generation of new neurons. Bottom: Deletion of Jedi reduces microglial phagocytosis and transforms PAMs into Disease-associated Inflammatory Microglia (DIMs) characterized by the upregulation of canonical inflammatory genes and core DIM markers iden ified in the aging and neurodegenerative brain (Nlrp3, NLR family pyrin domain-containing 3; Tnf, tumor necrosis factor; Ccl4, C-C chemokine ligand 4 (also called macrophage inflammatory protein 1{beta}); Ccr5, C-C chemokine receptor type 5). Increased interleukin-1{beta} (IL-1{beta}) synthesis, release, and signaling in the Jedi-null V-SVZ reduces NPC proliferation and newborn neuron number. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/531012v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@16b9785org.highwire.dtl.DTLVardef@a8be50org.highwire.dtl.DTLVardef@66b726org.highwire.dtl.DTLVardef@1825d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe engulfment receptor Jedi-1 is expressed by microglia in the neonatal ventricular-subventricular zone (V-SVZ) neurogenic niche. C_LIO_LIJedi-1 knockout microglia have decreased engulfment ability, resulting in accumulation of dead cells in the V-SVZ. C_LIO_LILoss of Jedi-1 leads to a neuroinflammatory phenotype in microglia that is characteristic of neurodegenerative and age-associated microglia. C_LIO_LIMicroglial-specific loss of Jedi-1 reduces neurogenesis, which is rescued in vivo by inhibition of interleukin-1{beta} signaling. C_LI

neuroscience↗