RESUMEN
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Asunto(s)
Analgésicos Opioides , Vaina de Mielina , Vías Nerviosas , Plasticidad Neuronal , Recompensa , Área Tegmental Ventral , Animales , Femenino , Masculino , Ratones , Analgésicos Opioides/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Ratones Endogámicos C57BL , Morfina/farmacología , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Núcleo Accumbens/citología , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Núcleo Accumbens/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/citología , Oligodendroglía/efectos de los fármacos , Optogenética , Área Tegmental Ventral/fisiología , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Linaje de la CélulaRESUMEN
Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.
Asunto(s)
Neuronas Motoras , Sinapsis , Animales , Ratones , Transducción de Señal , Activación de Complemento , Terminales Presinápticos , Ratones NoqueadosRESUMEN
Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.
Asunto(s)
Distonía Muscular Deformante , Distonía , Trastornos Distónicos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/metabolismo , Distonía/genética , Trastornos Distónicos/genética , Humanos , Mutación , Factor de Transcripción YY1/genéticaRESUMEN
Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1-/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding ß-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing ß-glucuronidase rescues Thap1-/- OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.