Annual review of neuroscience最新文献

Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte endfeet contain specialized organelles and proteins, including local protein translation machinery and highly organized scaffold proteins, which anchor channels, transporters, receptors, and enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by the loss of polarization of specific endfoot proteins, vascular dysregulation, BBB disruption, altered waste clearance, or, in extreme cases, loss of endfoot coverage. A role for astrocyte endfeet has been demonstrated or postulated in many of these conditions. This review provides an overview of the development, composition, function, and pathological changes of astrocyte endfeet and highlights the gaps in our knowledge that future research should address.

Radial cell columns are a hallmark feature of cortical architecture in many mammalian species. It has long been held, based on the lack of orientation columns, that such functional units are absent in rodent primary visual cortex (V1). These observations led to the view that rodent visual cortex has a fundamentally different network architecture than that of carnivores and primates. While columns may be lacking in rodent V1, we describe in this review that modular clusters of inputs to layer 1 and projection neurons in the layers below are prominent features of the mouse visual cortex. We propose that modules organize thalamocortical inputs, intracortical processing streams, and transthalamic communications that underlie distinct sensory and sensorimotor functions.

How neurons detect the direction of motion is a prime example of neural computation: Motion vision is found in the visual systems of virtually all sighted animals, it is important for survival, and it requires interesting computations with well-defined linear and nonlinear processing steps-yet the whole process is of moderate complexity. The genetic methods available in the fruit fly Drosophila and the charting of a connectome of its visual system have led to rapid progress and unprecedented detail in our understanding of how neurons compute the direction of motion in this organism. The picture that emerged incorporates not only the identity, morphology, and synaptic connectivity of each neuron involved but also its neurotransmitters, its receptors, and their subcellular localization. Together with the neurons' membrane potential responses to visual stimulation, this information provides the basis for a biophysically realistic model of the circuit that computes the direction of visual motion.

Rapid advances in the neural control of social behavior highlight the role of interconnected nodes engaged in differential information processing to generate behavior. Many innate social behaviors are essential to reproductive fitness and therefore fundamentally different in males and females. Programming these differences occurs early in development in mammals, following gonadal differentiation and copious androgen production by the fetal testis during a critical period. Early-life programming of social behavior and its adult manifestation are separate but yoked processes, yet how they are linked is unknown. This review seeks to highlight that gap by identifying four core mechanisms (epigenetics, cell death, circuit formation, and adult hormonal modulation) that could connect developmental changes to the adult behaviors of mating and aggression. We further propose that a unique social behavior, adolescent play, bridges the preweaning to the postpubertal brain by engaging the same neural networks underpinning adult reproductive and aggressive behaviors.

A holy grail of regenerative medicine is to replenish the cells that are lost due to disease. The adult mammalian central nervous system (CNS) has, however, largely lost such a regenerative ability. An emerging strategy for the generation of new neurons is through glia-to-neuron (GtN) conversion in vivo, mainly accomplished by the regulation of fate-determining factors. When inhibited, PTBP1, a factor involved in RNA biology, was reported to induce rapid and efficient GtN conversion in multiple regions of the adult CNS. Remarkably, PTBP1 inhibition was also claimed to greatly improve behaviors of mice with neurological diseases or aging. These phenomenal claims, if confirmed, would constitute a significant advancement in regenerative medicine. Unfortunately, neither GtN conversion nor therapeutic potential via PTBP1 inhibition was validated by the results of multiple subsequent replication studies with stringent methods. Here we review these controversial studies and conclude with recommendations for examining GtN conversion in vivo and future investigations of PTBP1.

All mammalian cell membranes contain cholesterol to maintain membrane integrity. The transport of this hydrophobic lipid is mediated by lipoproteins. Cholesterol is especially enriched in the brain, particularly in synaptic and myelin membranes. Aging involves changes in sterol metabolism in peripheral organs and also in the brain. Some of those alterations have the potential to promote or to counteract the development of neurodegenerative diseases during aging. Here, we summarize the current knowledge of general principles of sterol metabolism in humans and mice, the most widely used model organism in biomedical research. We discuss changes in sterol metabolism that occur in the aged brain and highlight recent developments in cell type-specific cholesterol metabolism in the fast-growing research field of aging and age-related diseases, focusing on Alzheimer's disease. We propose that cell type-specific cholesterol handling and the interplay between cell types critically influence age-related disease processes.

Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.

The spinal cord is home to the intrinsic networks for locomotion. An animal in which the spinal cord has been fully severed from the brain can still produce rhythmic, patterned locomotor movements as long as some excitatory drive is provided, such as physical, pharmacological, or electrical stimuli. Yet it remains a challenge to define the underlying circuitry that produces these movements because the spinal cord contains a wide variety of neuron classes whose patterns of interconnectivity are still poorly understood. Computational models of locomotion accordingly rely on untested assumptions about spinal neuron network element identity and connectivity. In this review, we consider the classes of spinal neurons, their interconnectivity, and the significance of their circuit connections along the long axis of the spinal cord. We suggest several lines of analysis to move toward a definitive understanding of the spinal network.

The extent to which we are affected by perceptual input of which we are unaware is widely debated. By measuring neural responses to sensory stimulation, neuroscientific data could complement behavioral results with valuable evidence. Here we review neuroscientific findings of processing of high-level information, as well as interactions with attention and memory. Although the results are mixed, we find initial support for processing object categories and words, possibly to the semantic level, as well as emotional expressions. Robust neural evidence for face individuation and integration of sentences or scenes is lacking. Attention affects the processing of stimuli that are not consciously perceived, and such stimuli may exogenously but not endogenously capture attention when relevant, and be maintained in memory over time. Sources of inconsistency in the literature include variability in control for awareness as well as individual differences, calling for future studies that adopt stricter measures of awareness and probe multiple processes within subjects.

Recent advances in fluorescence imaging permit large-scale recording of neural activity and dynamics of neurochemical release with unprecedented resolution in behaving animals. Calcium imaging with highly optimized genetically encoded indicators provides a mesoscopic view of neural activity from genetically defined populations at cellular and subcellular resolutions. Rigorously improved voltage sensors and microscopy allow for robust spike imaging of populational neurons in various brain regions. In addition, recent protein engineering efforts in the past few years have led to the development of sensors for neurotransmitters and neuromodulators. Here, we discuss the development and applications of these genetically encoded fluorescent indicators in reporting neural activity in response to various behaviors in different biological systems as well as in drug discovery. We also report a simple model to guide sensor selection and optimization.