Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7(−/−) fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.

Objective: Despite its long and auspicious place in the history of psychiatry, dissociative identity disorder (DID) has been associated with controversy. This paper aims to examine the empirical data related to DID and outline the contextual challenges to its scientific investigation. Method: The overview is limited to DID-specific research in which one or more of the following conditions are met: 1) a sample of participants with DID was systematically investigated, 2) psychometrically-sound measures were utilised, 3) comparisons were made with other samples, 4) DID was differentiated from other DID: An empirical overview 2 disorders, including other Dissociative Disorders, 5) extraneous variables were controlled or 6) DID diagnosis was confirmed. Following an examination of challenges to research, data is organised around the validity and phenomenology of DID, its aetiology and epidemiology, the neurobiological and cognitive correlates of the disorder, and finally its treatment. Results: DID was found to be a complex yet valid disorder across a range of markers. It can be accurately discriminated from other disorders, especially when structured diagnostic interviews assess identity alterations and amnesia. DID is aetiologically associated with a complex combination of developmental and cultural factors, including severe childhood relational trauma. The prevalence of DID appears highest in emergency psychiatric settings and affects approximately 1% of the general population. Psychobiological studies are beginning to identify clear correlates of DID associated with diverse brain areas and cognitive functions. They are also providing an understanding of the potential metacognitive origins of amnesia. Phase-oriented empirically-guided treatments are emerging for DID. Conclusions: The empirical literature on DID is accumulating, although some areas remain under-investigated.Existing data show DID as a complex, valid, and not uncommon disorder, associated with developmental and cultural variables, that is amenable to psychotherapeutic intervention. KeywordsDissociative identity disorder, validity, phenomenology, aetiology, psychobiology, [see Taylor, 1983 ], Janet, 1907Prince, 1905). More recently DID has become the subject of considerable debate (e.g., Dalenberg et al., 2012;Gleaves, 1996;McHugh and Putnam, 1995;Merskey, 1992), especially around its validity, aetiology and prevalence. Often This overview is designed to provide a current "broad-brush" outline of the scientific foundation of DID by focusing on DID-specific research. Thus the overview excludes opinion pieces and papers without DID data and is confined to studies identified in searches of major psychological (e.g., Psycinfo) and psychiatric databases (e.g., Medline) which investigated individuals with DID where one or more of the following conditions were met: 1) a sample of participants with DID was systematically investigated, 2) psychometrically-sound measures were utilised, 3) comparisons were made with other samples, 4) DID was differentiat...

Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1–9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1–6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.

MicroRNAs (miRNAs) are non-coding RNAs originally involved in RNA silencing and post-transcriptional regulation of gene expression. We have shown in previous work that the miRNA let-7b can act as a signalling molecule for Toll-like receptor 7, thereby initiating innate immune pathways and apoptosis in the central nervous system. Here, we investigated whether different members of the miRNA family let-7, abundantly expressed in the brain, are released into the human cerebrospinal fluid (CSF) and whether quantitative differences in let-7 copies exist in neurodegenerative diseases. RNA isolated from CSF of patients with Alzheimer´s disease (AD) and from control patients with frontotemporal lobe dementia (FTLD), major depressive episode (MDE) without clinical or neurobiological signs of AD, and healthy individuals, was reverse transcribed with primers against nine let-7 family members, and miRNAs were quantified and analyzed comparatively by quantitative PCR. let-7 miRNAs were present in CSF from patients with AD, FTLD, MDE, and healthy controls. However, the amount of individual let-7 miRNAs in the CSF varied substantially. CSF from AD patients contained higher amounts of let-7b and let-7e compared to healthy controls, while no differences were observed regarding the other let-7 miRNAs. No increase in let-7b and let-7e was detected in CSF from FTLD patients, while in CSF from MDE patients, let-7b and let-7e copy levels were elevated. In CSF from AD patients, let-7b and let-7e were associated with extracellular vesicles. let-7 family members present in the CSF mediated neurotoxicity in vitro, albeit to a variable extent. Taken together, neurotoxic let-7 miRNAs are differentially and specifically released in AD, but also in MDE patients. Thus, these miRNAs may mirror common neuropathological paths and by this serve to unscramble mechanisms of different neurodegenerative diseases.

Highlights d let-7 miRNAs act as Toll-like receptor (TLR) 7 signaling molecules in glioma d Extracellular let-7 miRNAs differentially modulate microglial biology d The sequence motif UUGU is responsible for let-7-induced microglial activation d Select let-7 miRNAs attenuate glioma growth by directly activating microglial TLR7