Nature Reviews. Neuroscience

The presymptomatic phase of Alzheimer disease (AD) starts with the deposition of amyloid-β in the cortex and begins a decade or more before the emergence of cognitive decline. The trajectory towards dementia and neurodegeneration is shaped by the pathological load and the resilience of neural circuits to the effects of this pathology. In this Perspective, I focus on recent advances that have uncovered the vulnerability of neural circuits at early stages of AD to hyperexcitability, particularly when the brain is in a low-arousal states (such as sleep and anaesthesia)...

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Adolescence is a time during which we transition to independence, explore new activities and begin pursuit of major life goals. Goal-directed learning, in which we learn to perform actions that enable us to obtain desired outcomes, is central to many of these processes. Currently, our understanding of goal-directed learning in adolescence is itself in a state of transition, with the scientific community grappling with inconsistent results. When we examine metrics of goal-directed learning through the second decade of life, we find that many studies agree there are steady gains in performance in the teenage years, but others report that adolescent goal-directed learning is already adult-like, and some find adolescents can outperform adults...

A fundamental goal of research in neuroscience is to uncover the causal structure of the brain. This focus on causation makes sense, because causal information can provide explanations of brain function and identify reliable targets with which to understand cognitive function and prevent or change neurological conditions and psychiatric disorders. In this research, one of the most frequently used causal concepts is 'mechanism' - this is seen in the literature and language of the field, in grant and funding inquiries that specify what research is supported, and in journal guidelines on which contributions are considered for publication...

Data-driven disease progression models are an emerging set of computational tools that reconstruct disease timelines for long-term chronic diseases, providing unique insights into disease processes and their underlying mechanisms. Such methods combine a priori human knowledge and assumptions with large-scale data processing and parameter estimation to infer long-term disease trajectories from short-term data. In contrast to 'black box' machine learning tools, data-driven disease progression models typically require fewer data and are inherently interpretable, thereby aiding disease understanding in addition to enabling classification, prediction and stratification...

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Synapses are a key component of neural circuits, facilitating rapid and specific signalling between neurons. Synaptic engineering - the synthetic insertion of new synaptic connections into in vivo neural circuits - is an emerging approach for neural circuit interrogation. This approach is especially powerful for establishing causality in neural circuit structure-function relationships, for emulating synaptic plasticity and for exploring novel patterns of circuit connectivity. Contrary to other approaches for neural circuit manipulation, synaptic engineering targets specific connections between neurons and functions autonomously with no user-controlled external activation...

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Ever-present in our environments, light entrains circadian rhythms over long timescales, influencing daily activity patterns, health and performance. Increasing evidence indicates that light also acts independently of the circadian system to directly impact physiology and behaviour, including cognition. Exposure to light stimulates brain areas involved in cognition and appears to improve a broad range of cognitive functions. However, the extent of these effects and their mechanisms are unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as the primary conduit through which light impacts non-image-forming behaviours and are a prime candidate for mediating the direct effects of light on cognition...

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For many years, neuroscientists have investigated the behavioural, computational and neurobiological mechanisms that support value-based decisions, revealing how humans and animals make choices to obtain rewards. However, many decisions are influenced by factors other than the value of physical rewards or second-order reinforcers (such as money). For instance, animals (including humans) frequently explore novel objects that have no intrinsic value solely because they are novel and they exhibit the desire to gain information to reduce their uncertainties about the future, even if this information cannot lead to reward or assist them in accomplishing upcoming tasks...

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The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before...

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