Biology subjects

Richardson, W. D.

Publications and source records attributed to Richardson, W. D..

7 recordsLinked to original sources

bioRxiv2026

Intact learning and memory in mice incapable of de novo myelination

Motor skill learning stimulates and requires generation of oligodendrocytes (OLs) from their precursors (OLPs) in the adult mouse brain, but the functional role(s) of the newly formed OLs is not known. We asked whether new compact myelin sheaths are required, by genetic block of myelin basic protein (MBP) synthesis in adult OLPs and their newly-differentiating OL progeny, using tamoxifen-inducible Cre-lox recombination. Newly-differentiating OLs in these Mbp-cKO mice are unable to assemble compact myelin or normal nodes of Ranvier. Despite this, Mbp-cKOs learned a motor skill just as well as their wild type littermates. They also demonstrated normal contextual fear conditioning. Therefore, neither motor nor fear learning depends on rapid saltatory conduction in newly-myelinated circuits. Mbp-cKOs also formed normal long-term motor and contextual fear memories. Moreover, OL lineage-specific knockout of Monocarboxylate transporter-1 (Mct1), believed to be responsible for transferring metabolic substrates from OLs into axons, did not affect learning or memory consolidation. Myelin regulatory factor (Myrf)-cKOs, in which newly-differentiating OLs die and are rapidly eliminated, confirmed that newly formed OLs are required for learning and memory. Together, the data suggest that learning and memory depends on a non-canonical property of pre-myelinating or myelinating OLs, distinct from myelins cardinal role in speeding action potentials.

neuroscience↗

bioRxiv2024

Adult oligodendrogenesis gates arcuate neuronal glucose sensing through remodelling of the blood-hypothalamus barrier via ADAMTS4

Brain glucose sensing is critical for survival during hypoglycaemia and tunes the level of defended blood glucose, which goes up in diabetes. Neuronal glucose sensing neurons and mechanisms have been identified, but how these neurons access blood concentrations of glucose to adjust their output and maintain glucose homeostasis is unclear. Here, we demonstrate that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. We show that genetic blockade of new OL production in adult mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and neuronal glucose sensing in the arcuate nucleus of the hypothalamus (ARH). Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, newly formed OLs exert their glucoregulatory actions via the synthesis of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase expressed exclusively by OLs and dependent on adult OL genesis to maintain its expression in the ME. Both lack of Adamts4 and ADAMTS4 gain-of-function are associated with impaired glucose homeostasis and remodelling of the blood-hypothalamus barrier, indicating that optimal ADAMTS4 expression is required for the integrity of vascular permeability and normal glycaemic control. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME OLs contribute to the regulation of glucose homeostasis.

neuroscience↗

bioRxiv2024

The INO80 chromatin remodeling complex regulates histone H2A.Z mobility and the G1-S transition in oligodendrocyte precursors

Chromatin remodelling complexes (CRCs) participate in oligodendrocyte (OL) differentiation, survival and maintenance. We asked whether CRCs also control proliferation of OL precursors (OPs) - focusing on the INO80 complex, which is known to regulate proliferation of a variety of other cell types during development and disease. CRISPR/Cas9-mediated inactivation of Ino80 in vitro, or Cre-mediated deletion in vivo, slowed the OP cell cycle substantially by prolonging G1, without inducing OL differentiation. RNAseq analysis revealed that E2F target genes were dysregulated in OPs from INO80-deficient mice, but correlated RNAseq and ATAC-seq uncovered no general correlation beween gene expression and altered nucleosome positioning at transcription start sites. Fluorescence photobleaching experiments in cultured OPs demonstrated that histone H2A.Z mobility increased following loss of INO80, suggesting that INO80 regulates the cell cycle machinery in OPs through H2A.Z/ H2A exchange. We also present evidence that INO80 associates with OLIG2, a master regulator of OL development.

neuroscience↗

bioRxiv2023

Ablation of oligodendrogenesis in adult mice alters brain microstructure and activity independently of behavioural deficits

Oligodendrocytes continue to differentiate from their precursor cells even in adulthood, a process that can be modulated by neuronal activity and experience. Yet, our understanding of the functional role of adult oligodendrogenesis remains limited. Previous work has indicated that conditional ablation of oligodendrogenesis in adult mice can lead to learning and memory deficits in a range of behavioural tasks. Our results, reported here, have replicated a key finding that learning to run on a complex wheel with unevenly spaced rungs is disrupted by ablation of oligodendrogenesis. However, using ex vivo MRI (MTR and DTI), we also found that ablating oligodendrogenesis by itself alters brain microstructure, independent of behavioural experience. Furthermore, in vivo EEG recording in behaviourally naive mice with ablated oligodendrogenesis revealed altered brain activity in the form of increased EEG power density across a broad frequency range. Together, our data indicate that disrupting the formation of new oligodendrocytes directly alters brain microstructure and activity. This suggests a role for adult oligodendrogenesis in the maintenance of brain function and indicates that task-independent changes to brain structure and function might contribute to the learning and memory deficits associated with oligodendrogenesis ablation.

neuroscience↗

bioRxiv2023

Oligodendrocyte dynamics dictate individual performance outcomes of working memory training in mice

Motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursors (OLPs). We asked whether OL production is also required for non-motor learning and cognition, using T-maze and radial arm maze tasks that tax spatial working memory. Maze training stimulated OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation; myelin sheath formation was also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impaired training-induced improvements in maze performance. Remarkably, there was a strong positive correlation between working memory performance of individual mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in the mPFC, underscoring the key role of OL lineage cells in cognitive performance.

neuroscience↗

bioRxiv2022

Median eminence myelin continuously turns over in adult mice

ObjectiveOligodendrocyte progenitor cell differentiation is regulated by nutritional signals in the adult median eminence (ME), but the consequences on local myelination are unknown. The aim of this study was to characterise myelin plasticity in the ME of adult mice in health or in response to chronic nutritional challenge. MethodsWe assessed new oligodendrocyte and myelin generation and stability in the ME of healthy adult male mice using bromodeoxyuridine labelling and genetic fate mapping tools. We assessed the contribution of microglia to ME myelin plasticity in PLX5622-treated C57BL6/J mice and in Pdgfra-Cre/ERT2;R26R-eYFP;Myrffl/fl mice, where adult oligodendrogenesis is genetically blunted. Finally, we investigated how 45% high fat diet or 70% caloric restriction feeding paradigms impact ME oligodendrocyte lineage progression and myelination in C57BL6/J mice. ResultsWe show that myelinating oligodendrocytes (OLs) are continuously and rapidly generated in the adult ME. Paradoxically, OL number and myelin amounts remain remarkably stable in the adult ME. In fact, the high rate of new OL and myelin generation in the ME is offset by continuous turnover of both. We show that microglia are required for continuous OL and myelin production, and that ME myelin plasticity regulates the recruitment of local immune cells. Finally, we provide evidence that ME myelination is regulated by the bodys energetic status, decreased in calorie-restricted animals, and increased in mice fed a high fat diet. ConclusionsThis study uncovers a previously unappreciated form of ME structural plasticity and mechanism of myelin remodeling in the adult brain.

neuroscience↗

bioRxiv2019

Specific oligodendrocyte populations have differential spatial distribution and susceptibility to injury

Oligodendrocytes (OLs), the myelinating cells of the central nervous system, are transcriptionally heterogeneous,1 the origin and functional consequences of which are unknown. Functional heterogeneity of MOLs might correlate with the local environment or their interactions with different neuron types.2 Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system and differential susceptibility to traumatic spinal cord injury. We also show that the generation of distinct MOL populations is independent of the OPC developmental origin. We found that OPCs originating from the previously described developmental waves3-5 have comparable potential to differentiate into the main MOL populations. Furthermore, we found that MOL type 2 (MOL2) is enriched in the spinal cord and almost absent in the brain, while MOL5/6 is enriched with age in all analyzed regions. MOL2 and MOL5/6 also have differential preference for motor and sensory tracts in the spinal cord. In the context of disease, we found that MOL2 and MOL5/6 have differential susceptibility to traumatic spinal cord injury, where MOL2 are lost and MOL5/6 increased their contribution to the OL lineage. Importantly, MOL2 susceptibility is disease specific, as we found MOL2 is not lost in a mouse model of multiple sclerosis. Our results demonstrate that the MOL populations, previously described by single-cell transcriptomics,1 have distinct spatial preference and responses. We anticipate our study to pave the way for a better understanding of the MOL populations-specific functional roles in development, health, and disease, allowing for better targeting of the OL subtypes important for the regeneration and repair of the central nervous system.

neuroscience↗