Fyn is an intermediate kinase that BDNF utilizes to promote oligodendrocyte myelination.

Fyn, a member of the Src family of nonreceptor tyrosine kinases, promotes central nervous system myelination during development; however the mechanisms mediating this effect remain unknown. Here we show that Fyn phosphorylation is modulated by BDNF in vivo. Concordant with this, we find that BDNF stimulates Fyn phosphorylation in myelinating cocultures, an effect dependent on oligodendroglial expression of TrkB. Importantly, PP2, a pharmacological inhibitor of Src family kinases, not only abrogated the promyelinating influence of BDNF in vitro, but also attenuated BDNF-induced phosphorylation of Erk1/2 in oligodendrocytes. Over-expression of Fyn in oligodendrocytes significantly promotes phosphorylation of Erk1/2, and promotes myelination to the extent that exogenous BDNF exerts no additive effect in vitro. In contrast, expression of a kinase-dead mutant of Fyn in oligodendrocytes significantly inhibited BDNF-induced activation of Erk1/2 and abrogated the promyelinating effect of BDNF. Analysis of white matter tracts in vivo revealed that phosphorylated Fyn primarily colocalized with mature oligodendrocytes, and was rarely observed in oligodendrocyte progenitor cells, a profile that closely parallels the detection of phosphorylated Erk1/2 in the developing central nervous system. Taken together, these data identify that Fyn kinase exerts a key role in mediating the promyelinating influence of BDNF. Here we identify a pathway in which BDNF activation of oligodendroglial TrkB receptors stimulates the phosphorylation of Fyn, a necessary step required to potentiate the phosphorylation of Erk1/2, which in turn regulates oligodendrocyte myelination.

TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination.

Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB.

Introducing the Neuroplastic Narrative: a non-pathologizing biological foundation for trauma-informed and adverse childhood experience aware approaches.

Most people accessing mental health services have adverse childhood experiences (ACEs) and/or histories of complex trauma. In recognition of this, there are calls to move away from medical model approaches and move toward trauma-informed approaches which privilege the impact of life experience over underlying pathology in the etiology of emotional and psychological suffering. Trauma-informed approaches lack a biological narrative linking trauma and adversity to later suffering. In its absence, this suffering is diagnosed and treated as a mental illness. This study articulates the Neuroplastic Narrative, a neuroecological theory that fills this gap, conceptualizing emotional and psychological suffering as the cost of surviving and adapting to the impinging environments of trauma and adversity. The Neuroplastic Narrative privileges lived experience and recognizes that our experiences become embedded in our biology through evolved mechanisms that ultimately act to preserve survival in the service of reproduction. Neuroplasticity refers to the capacity of neural systems to adapt and change. Our many evolved neuroplastic mechanisms including epigenetics, neurogenesis, synaptic plasticity, and white matter plasticity allow us to learn from, and adapt to, past experiences. This learning and adaption in turn allows us to better anticipate and physiologically prepare for future experiences that (nature assumes) are likely to occur, based on past experiences. However, neuroplastic mechanisms cannot discriminate between experiences; they function to embed experience regardless of the quality of that experience, generating vicious or virtuous cycles of psychobiological anticipation, to help us survive or thrive in futures that resemble our privileged or traumatic pasts. The etiology of suffering that arises from this process is not a pathology (a healthy brain is a brain that can adapt to experience) but is the evolutionary cost of surviving traumatizing environments. Misidentifying this suffering as a pathology and responding with diagnosis and medication is not trauma-informed and may cause iatrogenic harm, in part through perpetuating stigma and exacerbating the shame which attends complex trauma and ACEs. As an alternative, this study introduces the Neuroplastic Narrative, which is situated within an evolutionary framework. The Neuroplastic Narrative complements both Life History and Attachment Theory and provides a non-pathologizing, biological foundation for trauma-informed and Adverse Childhood Experience aware approaches.

The roles of extracellular related-kinases 1 and 2 signaling in CNS myelination.

Substantial progress has been made in identifying the intracellular signaling pathways that regulate central nervous system myelination. Recently, the mitogen activated protein kinase pathway, in particular the extracellular signal-related kinase 1 (Erk1) and Erk2, have been identified as critically important in mediating the effects of several growth factors that regulate oligodendroglial development and myelination. Here we will review the recent studies that identify the key role that Erk1/2 signaling plays in regulating oligodendroglial development, myelination and remyelination, discuss the potential mechanisms that Erk1/2 may utilize to influence myelination, and highlight some questions for further research. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.

Production and use of lentivirus to selectively transduce primary oligodendrocyte precursor cells for in vitro myelination assays.

Myelination is a complex process that involves both neurons and the myelin forming glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). We use an in vitro myelination assay, an established model for studying CNS myelination in vitro. To do this, oligodendrocyte precursor cells (OPCs) are added to the purified primary rodent dorsal root ganglion (DRG) neurons to form myelinating co-cultures. In order to specifically interrogate the roles that particular proteins expressed by oligodendrocytes exert upon myelination we have developed protocols that selectively transduce OPCs using the lentivirus overexpressing wild type, constitutively active or dominant negative proteins before being seeded onto the DRG neurons. This allows us to specifically interrogate the roles of these oligodendroglial proteins in regulating myelination. The protocols can also be applied in the study of other cell types, thus providing an approach that allows selective manipulation of proteins expressed by a desired cell type, such as oligodendrocytes for the targeted study of signaling and compensation mechanisms. In conclusion, combining the in vitro myelination assay with lentiviral infected OPCs provides a strategic tool for the analysis of molecular mechanisms involved in myelination.