Weekly Papers on Philosophy of Mind (39)

A festival’s search for humanity in AI points to the absence of love – and something even more fundamental
An algorithm developed to detect electricity theft for companies in Latin America could also uncover billing errors

Abstract

Research from cognitive science and geoscience education has shown that sketching can improve spatial thinking skills and facilitate solving spatially complex problems. Yet sketching is rarely implemented in introductory geosciences courses, due to time needed to grade sketches and lack of materials that incorporate cognitive science research. Here, we report a design-centered, collaborative effort, between geoscientists, cognitive scientists, and artificial intelligence (AI) researchers, to characterize spatial learning challenges in geoscience and to design sketch activities that use a sketch-understanding program, CogSketch. We developed 26 CogSketch worksheets that use cognitive science–based principles to scaffold problem solving of spatially complex geoscience problems and report observations of an implementation in an introductory geoscience course where students used CogSketch or human-graded paper worksheets. Overall, this research highlights the principles of interdisciplinary design between cognitive scientists, geoscientists, and AI researchers that can inform the collaborative design process for others aiming to develop effective educational materials.

We’ve glimpsed mind-bending geometric structures that fleetingly encode our thoughts, memories and feelings – and could solve the greatest mystery of all

Abstract

Research on surprise relevant to the cognitive-evolutionary model of surprise proposed by Meyer, Reisenzein, and Schützwohl (1997) is reviewed. The majority of the assumptions of the model are found empirically supported. Surprise is evoked by unexpected (schema-discrepant) events and its intensity is determined by the degree if schema-discrepancy, whereas the novelty and the valence of the eliciting events probably do not have an independent effect. Unexpected events cause an automatic interruption of ongoing mental processes that is followed by an attentional shift and attentional binding to the events, which is often followed by causal and other event analysis processes and by schema revision. The facial expression of surprise postulated by evolutionary emotion psychologists has been found to occur rarely in surprise, for as yet unknown reasons. A physiological orienting response marked by skin conductance increase, heart rate deceleration, and pupil dilation has been observed to occur regularly in the standard version of the repetition-change paradigm of surprise induction, but the specificity of these reactions as indicators of surprise is controversial. There is indirect evidence for the assumption that the feeling of surprise consists of the direct awareness of the schema-discrepancy signal, but this feeling, or at least the self-report of surprise, is also influenced by experienced interference. In contrast, facial feedback probably does contribute substantially to the feeling of surprise and the evidence for the hypothesis that surprise is affected by the difficulty of explaining an unexpected event is, in our view, inconclusive. Regardless of how the surprise feeling is constituted, there is evidence that it has both motivational and informational effects. Finally, the prediction failure implied by unexpected events sometimes causes a negative feeling, but there is no convincing evidence that this is always the case, and we argue that even if it were so, this would not be a sufficient reason for regarding this feeling as a component, rather than as an effect of surprise.

Abstract

Kant, Wittgenstein, and Husserl all held that visual awareness of objects requires visual awareness of the space in which the objects are located. There is a lively debate in the literature on spatial perception whether this view is undermined by the results of experiments on a Balint’s syndrome patient, known as RM. I argue that neither of two recent interpretations of these results is able to explain RM’s apparent ability to experience motion. I outline some ways in which each interpretation may respond to this challenge, and suggest which way of meeting the challenge is preferable. I conclude that RM retains some awareness of the larger space surrounding the objects he sees.

Nature Neuroscience 20, 1395 (2017). doi:10.1038/nn.4628

Authors: Hiroshi M Shiozaki & Hokto Kazama

Abstract

According to philosophers who ground your anticipation of future experiences in psychological continuity and connectedness, it is rational to anticipate the experiences of someone other than yourself, such as a self that is the product of fission or of replication. In this article, I concur that it is rational to anticipate the experiences of the product of fission while denying the rationality of anticipating the experiences of a replica. In defending my position, I offer the following explanation of why you have good reason to anticipate the experiences of your post-fission successor but not your replica: in the former case, you become (i.e., substantially change into) somebody else, whereas, in the latter case, you are merely replaced by somebody else.

Abstract

Externalism is the thesis that the contents of intentional states and speech acts are not determined by the way the subjects of those states or acts are internally. It is a widely accepted but not entirely uncontroversial thesis. Among such theses in philosophy, externalism is notable for owing the assent it commands almost entirely to thought experiments, especially to variants of Hilary Putnam's famous Twin Earth scenario. This paper presents a thought experiment-free argument for externalism. It shows that externalism is a deductive consequence of a pair of widely accepted principles whose relevance to the issue has hitherto gone unnoticed.

Abstract

There is a long-standing view in epistemology that perception is a way of knowing (WOK). There is a less long-standing but increasingly popular view that knowledge attributions have a relativist semantics (RKA). I discuss three things here. First, I show that it is a consequence of the logic of RKA that WOK and RKA are incompatible. Second, I argue that, even if WOK is incompatible with the main rivals to RKA, this is not a consequence of the logics of these views. RKA comes with a hitherto unobserved philosophical consequence that its main rivals do not come with. Third, I consider some responses to the effect that it does not matter that RKA comes with this consequence, and argue that they are all unsatisfactory as they stand. I conclude that, at the very least, the onus is placed on relativists to engage with more epistemology than they currently do to show that we do not need to worry about the incompatibility of WOK and RKA. I conclude with some suggestions about the broader relevance and implications of this paper.

 Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients

brain [x] language [x] add tag

 Brain Advance Access

on 2017-9-27 12:00am

Abstract

Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adoptedfor the first timea functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocola picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohens d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.

Author: Edited by Maria de Ponte and Kepa Korta
ISBN: 9780198714217
Binding: Hardcover
Publication Date: 27 September 2017
Price: $85.00

Abstract

Variability is prevalent in early language acquisition, but, whether it supports or hinders learning is unclear; while target variability has been shown to facilitate word learning, variability in competitor items has been shown to make the task harder. Here, we tested whether background variability could boost learning in a referent selection task. Two groups of 2-year-old children saw arrays of one novel and two known objects on a screen, and they heard a novel or known label. Stimuli were identical across conditions, with the exception that in the constant color condition objects appeared on a uniform white background, and in the variable color condition backgrounds were different, uniform colors. At test, only children in the variable condition showed evidence of retaining label-object associations. These data support findings from the adult memory literature, which suggest that variability supports learning by decontextualizing representations. We argue that these data are consistent with dynamic systems accounts of learning in which low-level entropy adds sufficient noise to the developmental system to precipitate a change in behavior.

Abstract

Mandarin speakers, like most other language speakers around the world, use spatial terms to talk about time. However, the direction of their mental temporal representation along the front-back axis remains controversial because they use the spatial term “front” to refer to both earlier times (e.g., front-year means “the year before last”) and the future (e.g., front-road means “prospect”). Although the linguistic distinction between time- and ego-reference-point spatiotemporal metaphors in Mandarin suggests a promising clarification of the above controversy, there is little empirical evidence verifying this distinction. In this study, Mandarin speakers’ time- and ego-reference-point temporal representations on three axes (i.e., sagittal, lateral, and vertical) were separately examined through two tasks. In a time-reference-point task, Mandarin speakers judged whether the time point of the second picture was earlier or later than the time point of the first picture, while in an ego-reference-point task, they judged whether an event or phase had happened in the past or would happen in the future. The results indicate that Mandarin speakers construe an earlier-times-in-front-of-later-times temporal sequence and adopt the front-to-the-future orientation.

Abstract

Both mindreading and stereotyping are forms of social cognition that play a pervasive role in our everyday lives, yet too little attention has been paid to the question of how these two processes are related. This paper offers a theory of the influence of stereotyping on mental-state attribution that draws on hierarchical predictive coding accounts of action prediction. It is argued that the key to understanding the relation between stereotyping and mindreading lies in the fact that stereotypes centrally involve character-trait attributions, which play a systematic role in the action–prediction hierarchy. On this view, when we apply a stereotype to an individual, we rapidly attribute to her a cluster of generic character traits on the basis of her perceived social group membership. These traits are then used to make inferences about that individual’s likely beliefs and desires, which in turn inform inferences about her behavior.

Abstract

Irritability and nonviolent aggression are common behavioral features across the population, yet there is limited neurobiological research into subclinical phenotypes representing the lower edge of a symptom continuum ranging from slight irritability to criminal violence. We studied brain structural correlates of irritability in a large healthy cohort to test the hypothesis of associations with fronto-limbic brain structures implicated in mood regulation. In a large multicenter effort, we recruited 409 mentally healthy adults from the community, who received T1-weighted high-resolution 3 T MRI scans. These structural scans were automatically preprocessed for voxel- and surface-based morphometry measurements with the CAT 12 toolbox implemented in SPM 12. Subclinical aggressive symptoms were assessed using the SCL-90-R aggression/hostility subscale and then correlated with cortical volume (VBM), and cortical thickness and gyrification. VBM analysis showed significant (P < 0.05, FDR-corrected at peak-level) positive correlations of cortical volume with SCL-90-R aggression subscale values in large clusters spanning bilateral anterior cingulate and orbitofrontal cortices and left lingual and postcentral gyri. Surface-based morphometry yielded mostly uncorrected positive correlations with cortical thickness in bilateral precentral gyri and with gyrification in left insula and superior temporal gyrus. Our findings imply an association of subclinical aggressive symptoms with cortical volume in areas important for emotion awareness and regulation, which might also be related to cortical adaptation to mental stress. These results overlap with several findings on impulsive aggression in patients suffering from affective and disruptive behavior disorders. They also suggest a biological symptom continuum manifesting in these brain areas. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

In a “fake news” world, the neuroscientist Tali Sharot explains what convinces people—and what does not-- Read more on ScientificAmerican.com
The phrase “the eyes are the window to the soul” isn't just poetry-- Read more on ScientificAmerican.com

Modeling somatic and dendritic spike mediated plasticity at the single neuron and network level

Nature Communications, Published online: 26 September 2017;doi:10.1038/s41467-017-00740-z

Synaptic plasticity is the neuronal mechanism underlying learning. Here the authors construct biophysical models of pyramidal neurons that reproduce observed plasticity gradients along the dendrite and show that dendritic spike dependent LTP which is predominant in distal sections can prolong memory retention.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Nature 549, 7673 (2017). doi:10.1038/nature24016

Authors: Yang Shi, Kaoru Yamada, Shane Antony Liddelow, Scott T. Smith, Lingzhi Zhao, Wenjie Luo, Richard M. Tsai, Salvatore Spina, Lea T. Grinberg, Julio C. Rojas, Gilbert Gallardo, Kairuo Wang, Joseph Roh, Grace Robinson, Mary Beth Finn, Hong Jiang, Patrick M. Sullivan, Caroline Baufeld, Michael W. Wood, Courtney Sutphen, Lena McCue, Chengjie Xiong, Jorge L. Del-Aguila, John C. Morris, Carlos Cruchaga, Anne M. Fagan, Bruce L. Miller, Adam L. Boxer, William W. Seeley, Oleg Butovsky, Ben A. Barres, Steven M. Paul & David M. Holtzman

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

Nature Neuroscience 20, 1377 (2017). doi:10.1038/nn.4624

Authors: Jiangteng Lu, Jason Tucciarone, Nancy Padilla-Coreano, Miao He, Joshua A Gordon & Z Josh Huang

Donhauser, Justin (2017) Invisible disagreement: an inverted qualia argument for realism. Philosophical Studies, 174 (3). pp. 593-606.

Abstract

A crucial disanalogy between Twin Earth and Inverted Earth undermines qualia-internalism. A recent transplant to Inverted Earth has been equipped with color-inverting contact lenses, so that she is unable to see the colors of objects whereas a recent transplant to Twin Earth can see twater. It is implausible to think that time alone could rectify this perceptual shortcoming – that the passage of time could alter the contents of her visual perceptions or the meaning of her color terms. Thus, the thought experiment does not refute the close tie between phenomenology and representation in the case of color.

 

Abstract

Numerous studies have indicated an increased risk for stroke in patients with migraine, especially migraine with aura; however, many studies used self-reported migraine and only a few controlled for familial factors. We aimed to investigate migraine as a risk factor for stroke in a Swedish population-based twin cohort, and whether familial factors contribute to an increased risk. The study population included twins without prior cerebrovascular disease who answered a headache questionnaire during 1998 and 2002 for twins born 193558 and during 200506 for twins born between 1959 and 1985. Migraine with and without aura and probable migraine was defined by an algorithm mapping on to clinical diagnostic criteria according to the International Classification of Headache Disorders. Stroke diagnoses were obtained from the national patient and cause of death registers. Twins were followed longitudinally, by linkage of national registers, from date of interview until date of first stroke, death, or end of study on 31 Dec 2014. In total, 8635 twins had any migraineous headache, whereof 3553 had migraine with aura and 5082 had non-aura migraineous headache (including migraine without aura and probable migraine), and 44 769 twins had no migraine. During a mean follow-up time of 11.9 years we observed 1297 incident cases of stroke. The Cox proportional hazards model with attained age as underlying time scale was used to estimate hazard ratios with 95% confidence intervals for stroke including ischaemic and haemorrhagic subtypes related to migraine with aura, non-aura migraineous headache, and any migraineous headache. Analyses were adjusted for gender and cardiovascular risk factors. Where appropriate; within-pair analyses were performed to control for confounding by familial factors. The age- and gender-adjusted hazard ratio for stroke related to migraine with aura was 1.27 (95% confidence interval 1.001.62), P = 0.05, and 1.07 (95% confidence interval 0.911.26), P = 0.39 related to any migraineous headache. Multivariable adjusted analyses showed similar results. When stratified by gender and attained age of 50 or >50 years, the estimated hazard ratio for stroke was higher in twins younger than 50 years and in females; however, non-significant. In the within-pair analysis, the hazard ratio for stroke related to migraine with aura was attenuated [hazard ratio 1.09 (95% confidence interval 0.811.46), P = 0.59]. In conclusion, we observed no increased stroke risk related to migraine overall but there was a modestly increased risk for stroke related to migraine with aura, and within-pair analyses suggested that familial factors might contribute to this association.

Glennerster, A and Stazicker, J (2017) Perception and action without 3D coordinate frames. [Preprint]
From PhilPapers:
Sep 29th 2017 GMT
  1. How Counterpart Theory Saves Nonreductive Physicalism.Justin Tiehen - forthcoming - Mind.
    Nonreductive physicalism faces serious problems regarding causal exclusion, causal heterogeneity, and the nature of realization. In this paper I advance solutions to each of those problems. The proposed solutions all depend crucially on embracing modal counterpart theory. Hence, the paper’s thesis: counterpart theory saves nonreductive physicalism. I take as my inspiration the view that mental tokens are constituted by physical tokens in the same way statues are constituted by lumps of clay. I break from other philosophers who have pursued this (...)
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Sep 28th 2017 GMT
  1. Sharing Our Normative Worlds: A Theory of Normative Thinking.Ivan Gonzalez-Cabrera - 2017 - Dissertation, Australian National University
    This thesis focuses on the evolution of human social norm psychology. More precisely, I want to show how the emergence of our distinctive capacity to follow social norms and make social normative judgments is connected to the lineage explanation of our capacity to form shared intentions, and how such capacity is related to a diverse cluster of prototypical moral judgments. I argue that in explaining the evolution of this form of normative cognition we also require an understanding of the developmental (...)
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    LIMITS OF HUMAN SENSES, Consciousness and Awareness.Ulrich De Balbian - 2017 - Oxford: Academic Publishers.

    LIMITS OF HUMAN SENSES, Consciousness and Awareness -/- ULRICH DE BALBIAN -/- Meta-Philosophy Research Center My art makes the invisible visible, limits of human awareness -/- 1 Human consciousness and awareness is restricted by stereotypes and notions that cause philosophers and artists to exist in the dark ages as far as their perception and understanding of human inner and outer senses are concerned. Humans perceive 7 colors of rainbows with 16 to 37 or more colors, that are perceived by other (...)
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Sep 27th 2017 GMT
  1. MERLEAU-PONTY ON EMBODIED SUBJECTIVITY FROM THE PERSPECTIVE OF SUBJECT-OBJECT CIRCULARITY.Jan Halák - 2016 - Acta Universtitatis Carolinae Kinanthropologica 52 (2):26-40.
    The phenomenological point of view of the body is usually appreciated for having introduced the notion of the ‘lived’ body. We cannot merely analyze and explain the body as one of the elements of the world of objects. We must also describe it, for example, as the center of our perspective on the world, the place where our sensing is ‘localized’, the agens which directly executes our intentions. However, in Husserl, the idea of the body as lived primarily complements his (...)
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  2. Balint’s Syndrome, Visual Motion Perception, and Awareness of Space.Bartek Chomanski - forthcoming - Erkenntnis:1-20.
    Kant, Wittgenstein, and Husserl all held that visual awareness of objects requires visual awareness of the space in which the objects are located. There is a lively debate in the literature on spatial perception whether this view is undermined by the results of experiments on a Balint’s syndrome patient, known as RM. I argue that neither of two recent interpretations of these results is able to explain RM’s apparent ability to experience motion. I outline some ways in which each interpretation (...)
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  3. Can Bohmian Quantum Information Help Us to Understand Consciousness?Paavo Pylkkänen - 2016 - In Lecture Notes in Computer Science (LNCS). Springer Publishing Company. pp. 76-87.

    The paper explores whether David Bohm’ s proposal about quantum theoretical active information, and the mind-matter scheme he developed on the basis of it, can help us to explain consciousness. Here it is important to acknowledge that other researchers in philosophy of mind and consciousness studies have also made use of the concept of information in their theories of mind and consciousness. For example, Dretske and Barwise and Seligman have explored the possibility that information in the sense of factual semantic (...)
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Sep 25th 2017 GMT
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    Remembering with and Without Memory: A Theory of Memory and Aspects of Mind That Enable its Experience.Stan Klein - forthcoming - WIREs Cognitive Science.

    This article builds on ideas presented in Klein (2105a) concerning the importance of a more nuanced, conceptually rigorous approach to the scientific understanding and use of the construct “memory”. I first summarize my model, taking care to situate discussion within the terminological practices of contemporary philosophy of mind. I then elucidate the implications of the model for a particular operation of mind – the manner in which content presented to consciousness realizes its particular phenomenological character (i.e., mode of presentation). Finally, (...)
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  2. Not in the Mood for Intentionalism.Davide Bordini - 2017 - Midwest Studies in Philosophy 41 (1):60-81.

    According to intentionalism, the phenomenal character of experience is one and the same as the intentional content of experience. This view has a problem with moods (anxiety, depression, elation, irritation, gloominess, grumpiness, etc.). Mood experiences certainly have phenomenal character, but do not exhibit directedness, i.e., do not appear intentional. Standardly, intentionalists have re-described moods’ undirectedness in terms of directedness towards everything or the whole world (e.g., Crane, 1998; Seager, 1999). This move offers the intentionalist a way out, but is quite (...)
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  3. The Eudaimonian Question: On the Tragedy of Humanism.Raymond Aaron Younis - forthcoming
Sep 24th 2017 GMT
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    Minds Online: The Interface Between Web Science, Cognitive Science, and the Philosophy of Mind.Paul SmartRobert William Clowes & Richard Heersmink - 2017 - Foundations and Trends in Web Science 6 (1-2):1-234.

    Alongside existing research into the social, political and economic impacts of the Web, there is a need to study the Web from a cognitive and epistemic perspective. This is particularly so as new and emerging technologies alter the nature of our interactive engagements with the Web, transforming the extent to which our thoughts and actions are shaped by the online environment. Situated and ecological approaches to cognition are relevant to understanding the cognitive significance of the Web because of the emphasis (...)
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    Brain Science:
    The minuscule change allows the virus to more readily damage brain cells-- Read more on ScientificAmerican.com

          

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    The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain’s reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXT neurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXT axon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXT promotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.

    Abstract

    Recent advances in human neuroimaging research have revealed that white-matter connectivity can be described in terms of an integrated network, which is the basis of the human connectome. However, the developmental changes of this connectome in childhood are not well understood. This study made use of two independent longitudinal diffusion-weighted imaging data sets to characterize developmental changes in the connectome by estimating age-related changes in fractional anisotropy (FA) for reconstructed fibers (edges) between 68 cortical regions. The first sample included 237 diffusion-weighted scans of 146 typically developing children (4–13 years old, 74 females) derived from the Pediatric Longitudinal Imaging, Neurocognition, and Genetics (PLING) study. The second sample included 141 scans of 97 individuals (8–13 years old, 62 females) derived from the BrainTime project. In both data sets, we compared edges that had the most substantial age-related change in FA to edges that showed little change in FA. This allowed us to investigate if developmental changes in white matter reorganize network topology. We observed substantial increases in edges connecting peripheral and a set of highly connected hub regions, referred to as the rich club. Together with the observed topological differences between regions connecting to edges showing the smallest and largest changes in FA, this indicates that changes in white matter affect network organization, such that highly connected regions become even more strongly imbedded in the network. These findings suggest that an important process in brain development involves organizing patterns of inter-regional interactions. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

    Abstract

    Prenatal alcohol exposure (PAE) is associated with reduced overall brain volume. Although this has been reported consistently across studies, the status of cortical thickness after PAE is more variable. The cortex is asymmetric in typical controls, but it is unclear whether the left and right counter parts of the cortical gray matter are unevenly influenced in postpartum brain development after PAE. Brain MRI was acquired in a newly recruited sample of 157 participants (PAE: N = 78, 5.5–18.9 years, 40 females and controls:N = 79, 5.8–18.5 years, 44 females) across four Canadian sites in the NeuroDevNet project. The PAE group had other confounds such as psychiatric co-morbidity, different living environment, and so on, not present in the control group. In agreement with previous studies, the volumes of all brain structures were reduced in PAE compared to controls, including gray and white matter of cerebrum and cerebellum, and all deep gray matter including the hippocampus, amygdala, thalamus, caudate, putamen, and pallidum. The PAE group showed reductions in global and regional cortical thickness, while the pattern and degree of cortical thickness asymmetry were preserved in PAE participants with the greatest rightward asymmetry in the lateral parietal lobe and the greatest leftward asymmetry in the lateral frontal cortex. This persistent asymmetry reflects that the homologous left and right cortical regions followed typical relative developmental patterns in the PAE group despite being thinner bilaterally than controls. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

    Abstract

    The attentional bias to smoking cues contributes to smoking cue reactivity and cognitive declines underlines smoking behaviors, which were probably associated with the central executive network (CEN). However, little is known about the implication of the structural connectivity of the CEN in smoking cue reactivity and cognitive control impairments in smokers. In the present study, the white matter structural connectivity of the CEN was quantified in 35 smokers and 26 non-smokers using the diffusion tensor imaging and deterministic fiber tractography methods. Smoking cue reactivity was evaluated using cue exposure tasks, and cognitive control performance was assessed by the Stroop task. Relative to non-smokers, smokers showed increased fractional anisotropy (FA) values of the bilateral CEN fiber tracts. The FA values of left CEN positively correlated with the smoking cue-induced activation of the dorsolateral prefrontal cortex and right middle occipital cortex in smokers. Meanwhile, the FA values of left CEN positively correlated with the incongruent errors during Stroop task in smokers. Collectively, the present study highlighted the role of the structural connectivity of the CEN in smoking cue reactivity and cognitive control performance, which may underpin the attentional bias to smoking cues and cognitive deficits in smokers. The multimodal imaging method by forging links from brain structure to brain function extended the notion that structural connections can modulate the brain activity in specific projection target regions. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

    Aboozar Monavarfeshani, Courtney N. Knill, Ubadah Sabbagh, Jianmin Su, Michael A. Fox
    Abstract

    Neurological dysfunction following epileptic seizures is a well-recognized phenomenon. Several potential mechanisms have been suggested to explain postictal dysfunction, with alteration in cerebral blood flow being one possibility. These vascular disturbances may be long lasting and localized to brain areas involved in seizure generation and propagation, as supported by both animal and human studies. Therefore, measuring perfusion changes in the postictal period may help localize the seizure onset zone. Arterial spin labelling is a non-invasive, rapid and reproducible magnetic resonance imaging technique that measures cerebral perfusion. To this end, we measured postictal perfusion in patients with drug resistant focal epilepsy who were admitted to our seizure-monitoring unit for presurgical evaluation. Twenty-one patients were prospectively recruited and underwent arterial spin labelling scanning within 90 min of a habitual seizure. Patients also underwent a similar scan in the interictal period, after they were seizure-free for at least 24 h. The acquired scans were subtracted to identify the areas of significant postictal hypoperfusion. The location of the maximal hypoperfusion was compared to the presumed seizure onset zone to assess for concordance. Also, the localizing value of this technique was compared to other structural and functional imaging modalities. Postictal perfusion reductions of >15 units (ml/100 g/l) were seen in 15/21 patients (71.4%). In 12/15 (80%) of these patients, the location of the hypoperfusion was partially or fully concordant with the location of the presumed seizure onset zone. This technique compared favourably to other neuroimaging modalities, being similar or superior to structural magnetic resonance imaging in 52% of cases, ictal single-photon emission computed tomography in 60% of cases and interictal positron emission tomography in 71% of cases. Better arterial spin labelling results were obtained in patients in whom the seizure onset zone was discernible based on non-invasive data. Thus, this technique is a safe, non-invasive and relatively inexpensive tool to detect postictal hypoperfusion that may provide useful data to localize the seizure onset zone. This technique may be incorporated into the battery of conventional investigations for presurgical evaluation of patients with drug resistant focal epilepsy.

    Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner

    Nature Communications, Published online: 28 September 2017;doi:10.1038/s41467-017-00769-0

    Microglia cells in the brain regulate immune responses, but in ageing can negatively affect brain function. Here the authors show that the chronic presence of type I interferon in aged mouse brain impedes cognitive ability by altering microglia transcriptome and limiting Mef2C, a microglia ‘off’ signal.

    Nature Neuroscience 20, 1427 (2017). doi:10.1038/nn1017-1427a

    Author: Jennifer A Erwin, Apuã C M Paquola, Tatjana Singer, Iryna Gallina, Mark Novotny, Carolina Quayle, Tracy A Bedrosian, Francisco I A Alves, Cheyenne R Butcher, Joseph R Herdy, Anindita Sarkar, Roger S Lasken, Alysson R Muotri & Fred H Gage

    A technique that turns mouse brains transparent like glass has given the first-ever 3D view of how stroke cuts off blood supply in the brain
    Abstract

    Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.

    Abstract

    Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adoptedfor the first timea functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocola picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohens d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.

    Corrections

    Nature 549, 7673 (2017).http://www.nature.com/doifinder/10.1038/549444a

    The News story ‘Researchers unite in quest for ‘standard model’ of the brain’ (Nature549, 319–320; 2017) incorrectly located the Simons Foundation in Washington DC. It is in New York City.Both the News story ‘Researchers riled by lack of detail in

    Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

    Nature doi: 10.1038/nature24042

    Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin–plexin signalling instructs axon guidance and neuronal morphogenesis. However, semaphorins and plexins are also expressed in the adult brain. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b–PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin–plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.

    Nature doi: 10.1038/nature24017

    Diagnosis: Frontiers in blood testing

    Nature. doi:10.1038/549S16a

    Author: Emily Sohn

    Technological advances are creating an explosion in possibilities for the blood-based diagnosis of brain injuries, infections and cancers.

    Nature Neuroscience 20, 1319 (2017). doi:10.1038/nn.4640

    Authors: Baptiste N Jaeger & Sebastian Jessberger

    Upon injury of the developing mouse cerebellum, endogenous repair mechanisms can heal the brain and prevent behavioral motor deficits. At the right time, with the right cues, the brain can repair itself.

    Abstract

    Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior columnmedial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased inSLC52A2 patient fibroblasts, while global knockdown of the singleDrosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

    The procedure may not work for others in a similar condition-- Read more on ScientificAmerican.com

          

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    Angela Sirigu and her team stimulated the brain of a man who fell into a vegetative state after a car crash 2001. Now he can move his eyes and listen to music

    Abstract

    We investigated a controversy regarding the role of the dorsal striatum (DS) in deliberate decision-making versus late-stage, stimulus–response learning to the point of automatization. Participants learned to associate abstract images with right or left button presses explicitly before strengthening these associations through stimulus–response trials with (i.e., Session 1) and without (i.e., Session 2) feedback. In Session 1, trials were divided into response-selection and feedback events to separately assess decision versus learning processes. Session 3 evaluated stimulus–response automaticity using a location Stroop task. DS activity correlated with response-selection and not feedback events in Phase 1 (i.e., Blocks 1–3), Session 1. Longer response times (RTs), lower accuracy, and greater intertrial variability characterized Phase 1, suggesting deliberation. DS activity extinguished in Phase 2 (i.e., Blocks 4–12), Session 1, once RTs, response variability, and accuracy stabilized, though stimulus–response automatization continued. This was signaled by persisting improvements in RT and accuracy into Session 2. Distraction between Sessions 1 and 2 briefly reintroduced response uncertainty, and correspondingly, significant DS activity reappeared in Block 1 of Session 2 only. Once stimulus–response associations were again refamiliarized and deliberation unnecessary, DS activation disappeared for Blocks 2–8, Session 2. Interference from previously learned right or left button responses with incongruent location judgments in a location Stroop task provided evidence that automaticity of stimulus–specific button-press responses had developed by the end of Session 2. These results suggest that DS mediates decision making and not late-stage learning, reconciling two, independently evolving and well-supported literatures that implicate DS in different cognitive functions. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

    Abstract

    Irritability and nonviolent aggression are common behavioral features across the population, yet there is limited neurobiological research into subclinical phenotypes representing the lower edge of a symptom continuum ranging from slight irritability to criminal violence. We studied brain structural correlates of irritability in a large healthy cohort to test the hypothesis of associations with fronto-limbic brain structures implicated in mood regulation. In a large multicenter effort, we recruited 409 mentally healthy adults from the community, who received T1-weighted high-resolution 3 T MRI scans. These structural scans were automatically preprocessed for voxel- and surface-based morphometry measurements with the CAT 12 toolbox implemented in SPM 12. Subclinical aggressive symptoms were assessed using the SCL-90-R aggression/hostility subscale and then correlated with cortical volume (VBM), and cortical thickness and gyrification. VBM analysis showed significant (P < 0.05, FDR-corrected at peak-level) positive correlations of cortical volume with SCL-90-R aggression subscale values in large clusters spanning bilateral anterior cingulate and orbitofrontal cortices and left lingual and postcentral gyri. Surface-based morphometry yielded mostly uncorrected positive correlations with cortical thickness in bilateral precentral gyri and with gyrification in left insula and superior temporal gyrus. Our findings imply an association of subclinical aggressive symptoms with cortical volume in areas important for emotion awareness and regulation, which might also be related to cortical adaptation to mental stress. These results overlap with several findings on impulsive aggression in patients suffering from affective and disruptive behavior disorders. They also suggest a biological symptom continuum manifesting in these brain areas.Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

    The brain is required for normal muscle and nerve patterning during early Xenopus development

    Nature Communications, Published online: 25 September 2017;doi:10.1038/s41467-017-00597-2

    Functions of the embryonic brain prior to regulating behavior are unclear. Here, the authors use an amputation assay in Xenopus laevisto demonstrate that removal of the brain early in development alters muscle and peripheral nerve patterning, which can be rescued by modulating bioelectric signals.

    Abstract

    Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patients disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year ( = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients ( = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy ( = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

    Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

    Nature 549, 7673 (2017). doi:10.1038/nature24014

    Authors: Humsa S. Venkatesh, Lydia T. Tam, Pamelyn J. Woo, James Lennon, Surya Nagaraja, Shawn M. Gillespie, Jing Ni, Damien Y. Duveau, Patrick J. Morris, Jean J. Zhao, Craig J. Thomas & Michelle Monje

    High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K–mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K–mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.

    ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

    Nature 549, 7673 (2017). doi:10.1038/nature24016

    Authors: Yang Shi, Kaoru Yamada, Shane Antony Liddelow, Scott T. Smith, Lingzhi Zhao, Wenjie Luo, Richard M. Tsai, Salvatore Spina, Lea T. Grinberg, Julio C. Rojas, Gilbert Gallardo, Kairuo Wang, Joseph Roh, Grace Robinson, Mary Beth Finn, Hong Jiang, Patrick M. Sullivan, Caroline Baufeld, Michael W. Wood, Courtney Sutphen, Lena McCue, Chengjie Xiong, Jorge L. Del-Aguila, John C. Morris, Carlos Cruchaga, Anne M. Fagan, Bruce L. Miller, Adam L. Boxer, William W. Seeley, Oleg Butovsky, Ben A. Barres, Steven M. Paul & David M. Holtzman

    APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

    Cancer: Drain the swamp to beat glioma

    Nature 549, 7673 (2017). doi:10.1038/nature24141

    Authors: Michael D. Taylor & Vijay Ramaswamy

    Efforts to treat brain tumours by targeting cancer cells have had only modest clinical success. It emerges that targeting a protein secreted from neurons adjacent to the tumour might be a useful alternative approach. See Letter p.533

    Neuroscience: Mum's bacteria linked to baby's behaviour

    Nature 549, 7673 (2017). doi:10.1038/nature24139

    Authors: Craig M. Powell

    Infection during pregnancy increases the risk of neurodevelopmental disorders, such as autism, in offspring. Mouse studies now reveal a link between gut bacteria and atypical brain-circuit connections. See Article p.482 & Letter p.528

    Nature Neuroscience 20, 1418 (2017). doi:10.1038/nn.4632

    Authors: Bernard Ng, Charles C White, Hans-Ulrich Klein, Solveig K Sieberts, Cristin McCabe, Ellis Patrick, Jishu Xu, Lei Yu, Chris Gaiteri, David A Bennett, Sara Mostafavi & Philip L De Jager

    Nature Neuroscience 20, 1350 (2017). doi:10.1038/nn.4630

    Authors: Georgia Rapti, Chang Li, Alan Shan, Yun Lu & Shai Shaham

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