Biology subjects

Vrudhula, U.

Publications and source records attributed to Vrudhula, U..

4 recordsLinked to original sources

bioRxiv2024

Disruption of Cholinergic Retinal Waves Alters Visual Cortex Development and Function

Retinal waves represent an early form of patterned spontaneous neural activity in the visual system. These waves originate in the retina before eye-opening and propagate throughout the visual system, influencing the assembly and maturation of subcortical visual brain regions. However, because it is technically challenging to ablate retina-derived cortical waves without inducing compensatory activity, the role these waves play in the development of the visual cortex remains unclear. To address this question, we used targeted conditional genetics to disrupt cholinergic retinal waves and their propagation to select regions of primary visual cortex, which largely prevented compensatory patterned activity. We find that loss of cholinergic retinal waves without compensation impaired the molecular and synaptic maturation of excitatory neurons located in the input layers of visual cortex, as well as layer 1 interneurons. These perinatal molecular and synaptic deficits also relate to functional changes observed at later ages. We find that the loss of perinatal cholinergic retinal waves causes abnormal visual cortex retinotopy, mirroring changes in the retinotopic organization of gene expression, and additionally impairs the processing of visual information. We further show that retinal waves are necessary for higher order processing of sensory information by impacting the state-dependent activity of layer 1 interneurons, a neuronal type that shapes neocortical state-modulation, as well as for state-dependent gain modulation of visual responses of excitatory neurons. Together, these results demonstrate that a brief targeted perinatal disruption of patterned spontaneous activity alters early cortical gene expression as well as synaptic and physiological development, and compromises both fundamental and, notably, higher-order functions of visual cortex after eye-opening.

neuroscience↗

bioRxiv2024

The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian function in vivo

To survive, organisms must adapt to a staggering diversity of environmental signals, ranging from sensory information to pathogenic infection, across the lifespan. At the same time, organisms intrinsically generate biological oscillations, such as circadian rhythms, without input from the environment. While the nervous system is well-suited to integrate extrinsic and intrinsic cues, how the brain balances these influences to shape biological function system-wide is not well understood at the molecular level. Here, we demonstrate that the cytokine receptor Fn14, previously identified as a mediator of sensory experience-dependent synaptic refinement during brain development, regulates neuronal activity and function in adult mice in a time-of-day-dependent manner. We show that a subset of excitatory pyramidal (PYR) neurons in the CA1 subregion of the hippocampus increase Fn14 expression when neuronal activity is heightened. Once expressed, Fn14 constrains the activity of these same PYR neurons, suggesting that Fn14 operates as a molecular brake on neuronal activity. Strikingly, differences in PYR neuron activity between mice lacking or expressing Fn14 were most robust at daily transitions between light and dark, and genetic ablation of Fn14 caused aberrations in circadian rhythms, sleep-wake states, and sensory-cued and spatial memory. At the cellular level, microglia contacted fewer, but larger, excitatory synapses in CA1 in the absence of Fn14, suggesting that these brain-resident immune cells may dampen neuronal activity by modifying synaptic inputs onto PYR neurons. Finally, mice lacking Fn14 exhibited heightened susceptibility to chemically induced seizures, implicating Fn14 in disorders characterized by hyperexcitation, such as epilepsy. Altogether, these findings reveal that cytokine receptors that mediates inflammation in the periphery, such as Fn14, can also play major roles in healthy neurological function in the adult brain downstream of both extrinsic and intrinsic cues. HighlightsO_LINeuronal activity induces Fn14 expression in pyramidal neurons of the hippocampus C_LIO_LIFn14 constrains neuronal activity near daily transitions between light and dark C_LIO_LILoss of Fn14 lengthens the endogenous circadian period and disrupts sleep-wake states and memory C_LIO_LIMicroglia contact excitatory synapses in an Fn14-dependent manner C_LI

neuroscience↗

bioRxiv2022

Oligodendrocyte precursor cells engulf synaptic inputs in an experience- and microglia-dependent manner

Oligodendrocyte precursor cells (OPCs) are a highly proliferative class of non-neuronal progenitors that largely give rise to myelinating oligodendrocytes. Although OPCs persist across the lifespan, their functions beyond oligodendrogenesis remain to be fully characterized. Here, we show that OPCs contribute to neural circuit remodeling by internalizing presynaptic thalamocortical inputs in both the developing and adult mouse visual cortex. Inputs internalized by OPCs localize to lysosomal compartments, consistent with OPC engulfment of synapses occuring through phagocytosis. We further show that engulfment by OPCs is heightened during experience-dependent plasticity, and that this experience-dependent increase in engulfment requires microglia. These data identify a new function for OPCs beyond the generation of oligodendrocytes and reveal that distinct non-neuronal populations collaborate to modulate synaptic connectivity.

neuroscience↗

bioRxiv2021

The cytokine receptor Fn14 regulates neuronal transcription during development and brain function in the adult

Cytokine signaling pathways that promote inflammation in peripheral tissues are repurposed to coordinate the refinement of synaptic connections in the developing brain. However, the downstream mechanisms through which these pathways mediate neural circuit maturation remain to be fully defined. Here, we demonstrate that Fn14, a cytokine receptor that promotes inflammation outside of the central nervous system, shapes the transcriptional profiles and chromatin landscapes of neurons in the developing brain. Single-nucleus RNA-sequencing revealed hundreds of misregulated genes in the thalamocortical neurons of the visual thalami of mice lacking either Fn14 or its microglial derived cytokine ligand TWEAK, including genes encoding proteins with critical roles in synaptic function, histone modification, and chromatin remodeling. Whole-genome analysis uncovered significant alterations in chromatin accessibility in the brains of mice lacking Fn14 or in wild-type mice following microglial depletion, and chromatin changes due to both manipulations were enriched near genes encoding regulators of synaptic function. Loss of microglia also led to the retention of excess synapses, suggesting that microglia may link modifications in neuronal chromatin to the functional refinement of neural circuits. Consistent with Fn14 shaping brain function beyond the visual system, Fn14 knockout mice displayed impairments in memory task proficiency as well as heightened sensitivity to pharmacologically induced seizures. Taken together, these results define a previously undescribed interaction between microglia, cytokine signaling, and the neuronal epigenome that is likely to contribute to neural circuit refinement and function in the brain.

neuroscience↗