Correction to: the role of the complement system in traumatic brain injury: a review

Abstract After publication of the article [1], it was brought to our attention that Tables 1 and 2 were missing from the final manuscript, These tables can be seen below and have now been added to the revised version of the article

Neuroimmune regulation of adult hippocampal neurogenesis by Complement Component 3 and Complement C3a Receptor

New neurons are added to the dentate gyrus of the hippocampus throughout adult life, through the process known as adult hippocampal neurogenesis (AHN). This important form of structural plasticity supports learning and memory in mammalian species. AHN is tightly regulated by a myriad of factors, including the immune system. Previous evidence suggests that signalling via Complement Component 3 (C3) and Complement C3a Receptor (C3aR) may regulate AHN under physiological conditions, although the mechanism of this putative regulation is unclear. In addition, C3a/C3aR signalling may regulate neuronal morphology. Using C3-/- and C3aR-/- mice, I used a combined in vitro and in vivo approach to investigate the role of C3/C3aR signalling in AHN. In Chapter 2, I demonstrate that C3a/C3aR signalling is able to directly influence hippocampal precursor cells in primary cultures. Furthermore, in the adult mouse brain, there is an increase in the number of immature neurons in the absence of C3 and C3aR, suggesting that C3a/C3aR signalling exerts an anti-neurogenic effect in the healthy brain. In Chapter 3 I report that the dendritic arborisation of newborn neurons is altered in the absence of C3aR, but not C3, suggesting involvement of an alternative ligand. Therefore, C3aR signalling via an as yet-unidentified ligand is important for maintaining the normal neuronal morphology of adult born neurons. Both the net levels of AHN and immature neuronal morphology have important functional consequences for cognitive and affective processes involving the hippocampus, which I investigate in Chapter 4. I report superior performance of C3-/- and C3aR-/- mice in a hippocampus-dependent spatial discrimination task, consistent with their elevated levels of AHN. Furthermore, C3a/C3aR deficiency was associated with abnormal anxiety phenotypes. In conclusion,these results demonstrate a novel mechanism for neuroimmune regulation of AHN, which is of functional consequence to learning, memory and affective behaviour

Complement dependent synaptic reorganisation during critical periods of brain development and risk for psychiatric disorder

We now know that the immune system plays a major role in the complex processes underlying brain development throughout the lifespan, carrying out a number of important homeostatic functions under physiological conditions in the absence of pathological inflammation or infection. In particular, complement-mediated synaptic pruning during critical periods of early life may play a key role in shaping brain development and subsequent risk for psychopathology, including neurodevelopmental disorders such as schizophrenia and autism spectrum disorders. However, these disorders vary greatly in their onset, disease course, and prevalence amongst sexes suggesting complex interactions between the immune system, sex and the unique developmental trajectories of circuitries underlying different brain functions which are yet to be fully understood. Perturbations of homeostatic neuroimmune interactions during different critical periods in which regional circuits mature may have a plethora of long-term consequences for psychiatric phenotypes, but at present there is a gap in our understanding of how these mechanisms may impact on the structural and functional changes occurring in the brain at different developmental stages. In this article we will consider the latest developments in the field of complement mediated synaptic pruning where our understanding is beginning to move beyond the visual system where this process was first described, to brain areas and developmental periods of potential relevance to psychiatric disorders

The effectiveness of virtual reality interventions for improvement of neurocognitive performance post-traumatic brain injury: a systematic review

Objective: To evaluate current evidence for the effectiveness of virtual reality (VR) interventions in improving neurocognitive performance in individuals who have sustained a traumatic brain injury (TBI). Methods: A systematic literature search across multiple databases (PubMed, EMBASE, Web of Science) for articles of relevance. Studies were evaluated according to study design, patient cohort, VR intervention, neurocognitive parameters assessed, and outcome. VR interventions were evaluated qualitatively with respect to methodology and extent of immersion and quantitatively with respect to intervention duration. Outcomes: Our search yielded 324 articles, of which only 13 studies including 132 patients with TBI met inclusion criteria. A wide range of VR interventions and cognitive outcome measures is reported. Cognitive measures included learning and memory, attention, executive function, community skills, problem solving, route learning, and attitudes about driving. Several studies (n = 10) reported statistically significant improvements in outcome, and 2 studies demonstrated successful translation to real-life performance. Conclusions: VR interventions hold significant potential for improving neurocognitive performance in patients with TBI. While there is some evidence for translation of gains to activities of daily living, further studies are required to confirm the validity of cognitive measures and reliable translation to real-life performance

Cingulum microstructure predicts cognitive control in older age and mild cognitive impairment

Cognitive control, an important facet of human cognition, provides flexibility in response to varying behavioral demands. Previous work has focused on the role of prefrontal cortex, notably the anterior cingulate cortex. However, it is now clear that this is one node of a distributed cognitive network. In this emerging network view, structural connections are inherent elements, but their role has not been emphasized. Furthermore, lesion and functional imaging studies have contributed little knowledge about anatomical segregation, functional specialization, and behavioral importance of white matter connections. The relationship between cognitive control and microstructure of connections within the cingulum, a major white matter tract and conduit of projections to prefrontal sites, was probed in vivo inhumans with diffusion MRI. Twenty healthy controls and 25 individuals with amnestic mild cognitive impairment (MCI), an early stage of age-associated cognitive deterioration, underwent cognitive testing, including several measures of cognitive control. For each individual, the anterior, middle, posterior, and parahippocampal portions of the cingulum bundle were reconstructed separately using deterministic tractography and anatomical landmarks. Micro structural variation in the left anterior cingulum was closely related to inter individual control based on verbal or symbolic rules. Errors in a task that involved maintenance of spatial rules were largely restricted to patients with MCI and were related, additionally, to right anterior cingulum microstructure. Cognitive control in MCI was also independently related to posterior parahippocampal connections. These results show how specific subpopulations of connections are critical in cognitive control and illustrate fine-grained anatomical specializations in the white matter infrastructure of this network

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology

Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice

Adult hippocampal neurogenesis (AHN) is a form of ongoing plasticity in the brain that supports specific aspects of cognition. Disruptions in AHN have been observed in neuropsychiatric conditions presenting with inflammatory components and are associated with impairments in cognition and mood. Recent evidence highlights important roles of the complement system in synaptic plasticity and neurogenesis during neurodevelopment and in acute learning and memory processes. In this work we investigated the impact of the complement C3/C3aR pathway on AHN and its functional implications for AHN-related behaviours. In C3−/− mice, we found increased numbers and accelerated migration of adult born granule cells, indicating that absence of C3 leads to abnormal survival and distribution of adult born neurons. Loss of either C3 or C3aR affected the morphology of immature neurons, reducing morphological complexity, though these effects were more pronounced in the absence of C3aR. We assessed functional impacts of the cellular phenotypes in an operant spatial discrimination task that assayed AHN sensitive behaviours. Again, we observed differences in the effects of manipulating C3 or C3aR, in that whilst C3aR−/− mice showed evidence of enhanced pattern separation abilities, C3−/− mice instead demonstrated impaired behavioural flexibility. Our findings show that C3 and C3aR manipulation have distinct effects on AHN that impact at different stages in the development and maturation of newly born neurons, and that the dissociable cellular phenotypes are associated with specific alterations in AHN-related behaviours

Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR−/−) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3−/−) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology

The role of the complement system in traumatic brain injury: a review

Traumatic brain injury (TBI) is an important cause of disability and mortality in the western world. While the initial injury sustained results in damage, it is the subsequent secondary cascade that is thought to be the significant determinant of subsequent outcomes. The changes associated with the secondary injury do not become irreversible until some time after the start of the cascade. This may present a window of opportunity for therapeutic interventions aiming to improve outcomes subsequent to TBI. A prominent contributor to the secondary injury is a multifaceted inflammatory reaction. The complement system plays a notable role in this inflammatory reaction; however, it has often been overlooked in the context of TBI secondary injury. The complement system has homeostatic functions in the uninjured central nervous system (CNS), playing a part in neurodevelopment as well as having protective functions in the fully developed CNS, including protection from infection and inflammation. In the context of CNS injury, it can have a number of deleterious effects, evidence for which primarily comes not only from animal models but also, to a lesser extent, from human post-mortem studies. In stark contrast to this, complement may also promote neurogenesis and plasticity subsequent to CNS injury. This review aims to explore the role of the complement system in TBI secondary injury, by examining evidence from both clinical and animal studies. We examine whether specific complement activation pathways play more prominent roles in TBI than others. We also explore the potential role of complement in post-TBI neuroprotection and CNS repair/regeneration. Finally, we highlight the therapeutic potential of targeting the complement system in the context of TBI and point out certain areas on which future research is needed

Subject knowledge and pedagogy:incorporating Montessori pedagogy into your classroom

This chapter interpolates Shulman's work on what is subject knowledge with examples of subject knowledge in religious education that may be useful. Subject knowledge may be perceived as ‘information I already know or can access’, but a skilful teacher will realise how to link it cross-curricularly, how to develop the need to maintain current subject knowledge and how to use the pedagogy to teach it effectively in the classroom. This chapter suggests that a confident teacher is one who is equipped with sufficient, all-round knowledge, who does not fret when questioned during teaching, can model how children can develop their own subject knowledge and one who seeks to improve in the three types of knowledge