RESUMO
The blood barriers of the nervous system protect neural environments but can hinder therapeutic accessibility. The blood-brain barrier (BBB) is well characterized, consisting of endothelial cells with specialized tight junctions and low levels of transcytosis, properties conferred by contacting pericytes and astrocytes. In contrast, the blood-nerve barrier (BNB) of the peripheral nervous system is poorly defined. Here, we characterize the structure of the mammalian BNB, identify the processes that confer barrier function, and demonstrate how the barrier can be opened in response to injury. The homeostatic BNB is leakier than the BBB, which we show is due to higher levels of transcytosis. However, the barrier is reinforced by macrophages that specifically engulf leaked materials, identifying a role for resident macrophages as an important component of the BNB. Finally, we demonstrate the exploitation of these processes to effectively deliver RNA-targeting therapeutics to peripheral nerves, indicating new treatment approaches for nervous system pathologies.
Assuntos
Barreira Hematoneural , Células Endoteliais , Animais , Barreira Hematoneural/fisiologia , Células Endoteliais/fisiologia , Barreira Hematoencefálica/fisiologia , Macrófagos , Pericitos/fisiologia , MamíferosRESUMO
Age-related hearing loss (ARHL) is a threat to future human wellbeing. Multiple factors contributing to the terminal auditory decline have been identified; but a unified understanding of ARHL - or the homeostatic maintenance of hearing before its breakdown - is missing. We here present an in-depth analysis of homeostasis and ageing in the antennal ears of the fruit fly Drosophila melanogaster. We show that Drosophila, just like humans, display ARHL. By focusing on the phase of dynamic stability prior to the eventual hearing loss we discovered a set of evolutionarily conserved homeostasis genes. The transcription factors Onecut (closest human orthologues: ONECUT2, ONECUT3), Optix (SIX3, SIX6), Worniu (SNAI2) and Amos (ATOH1, ATOH7, ATOH8, NEUROD1) emerged as key regulators, acting upstream of core components of the fly's molecular machinery for auditory transduction and amplification. Adult-specific manipulation of homeostatic regulators in the fly's auditory neurons accelerated - or protected against - ARHL.
Assuntos
Envelhecimento , Antenas de Artrópodes/fisiologia , Drosophila melanogaster/fisiologia , Perda Auditiva/genética , Audição/genética , Homeostase , Neurônios/fisiologia , Animais , Proteínas de Drosophila/genética , Feminino , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Interferência de RNA , Análise de Sequência de RNA , Som , Fatores de Tempo , Transativadores/genética , Fatores de Transcrição/genética , TranscriptomaRESUMO
Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels.
Assuntos
Dosagem de Genes/genética , Potenciação de Longa Duração/genética , Plasticidade Neuronal/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Animais , Benzoxazóis/farmacologia , Butiratos/farmacologia , Células Cultivadas , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/agonistas , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores X de Retinoides/metabolismo , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacosRESUMO
Peripheral nerves are highly regenerative, in contrast to the poor regenerative capabilities of the central nervous system (CNS). Here, we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the peripheral nervous system, the myelinating Schwann cell (mSC), does not turn over in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like Schwann cells (SCs) that orchestrate the regenerative response. Lineage analysis shows that these newly migratory, progenitor-like cells redifferentiate to form new tissue at the injury site and maintain their lineage, but can switch to become a non-myelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population.This article has an associated 'The people behind the papers' interview.
