Trends in Neurosciences最新文献

Physical activity (PA) has emerged as a modifiable protective lifestyle factor for Alzheimer's disease (AD). In a recent study by Kim and colleagues, higher levels of PA were associated with reduced phosphorylated tau (ptau) 217 concentrations even after accounting for β-amyloid (Aβ) brain uptake, suggesting a link with tau pathophysiology; this link also mediated better general cognition.

Dysregulated progranulin expression is robustly associated with diseases of the central nervous system (CNS). Recent research has been progressing toward a mechanistic understanding of the role of progranulin in CNS disease pathophysiology. In this review we describe the consequences of dysregulated progranulin expression in experimental and disease states. Collectively, these studies reveal that progranulin has diverse roles as a cell signaling molecule that regulates lysosomal function, immune processes, and growth. Given the functional and pathological implications of aberrant progranulin expression, we also summarize the mechanisms of progranulin regulation. We then highlight therapeutic strategies for progranulin upregulation. Ultimately, we explore the relationship between progranulin function and regulation with the goals of identifying key open questions and facilitating rational therapeutic development.

The human brain is characterized by impressive cognitive abilities. The neocortex is the seat of higher cognition, and neocortex expansion is a hallmark of human evolution. While developmental programs are similar in different species, the timing of developmental transitions and the capacity of neural progenitor cells (NPCs) to proliferate differ, contributing to the increased production of neurons during human cortical development. Here, we review the epigenetic regulation of developmental transitions during corticogenesis, focusing mostly on humans while building on knowledge from studies in mice. We discuss metabolic-epigenetic interplay as a potential mechanism to integrate extracellular signals into neural chromatin. Moreover, we synthesize current understanding of how epigenetic and metabolic deregulation can cause neurodevelopmental disorders. Finally, we outline how developmental timing can be investigated using brain organoid models.

Microglia-neuron interactions are essential for maintaining brain homeostasis. In a recent study, Zhao and colleagues demonstrated that activation of Gi-G-protein-coupled receptors (Gi-GPCRs) on microglia suppresses microglial process dynamics, reduces neuronal activity, and disrupts network synchronization. These findings highlight the role of microglial Gi-GPCR signaling in neuromodulation and its role in network activity in the healthy brain.

The appropriate and rapid encoding of stimuli bearing a negative valence enables behaviors that are essential for survival. Recent advances in neuroscience using rodents as a model system highlight the relevance of cell type-specific neuronal activities in diverse brain networks for the encoding of aversion, as well as their importance for subsequent behavioral strategies. Within these networks, neuromodulators influence cell excitability, adjust fast synaptic neurotransmission, and affect plasticity, ultimately modulating behaviors. In this review we first discuss contemporary findings leveraging the use of cutting-edge neurotechnologies to define aversion-related neural circuits. The spatial and temporal dynamics of the release of neuromodulators and neuropeptides upon exposure to aversive stimuli are described within defined brain circuits. Together, these mechanistic insights update the present neural framework through which aversion drives motivated behaviors.

Neuromelanin is a unique pigment made by some human catecholamine neurons. These neurons survive with their neuromelanin content for a lifetime but can also be affected by age-related neurodegenerative conditions, as observed using new neuromelanin imaging techniques. The limited quantities of neuromelanin has made understanding its normal biology difficult, but recent rodent and primate models, as well as omics studies, have confirmed its importance for selective neuronal loss in Parkinson's disease (PD). We review the development of neuromelanin in dopamine versus noradrenaline neurons and focus on previously overlooked cellular organelles in neuromelanin formation and function. We discuss the role of neuromelanin in stimulating endogenous α-synuclein misfolding in PD which renders neuromelanin granules vulnerable, and can exacerbates other pathogenic processes.

In a recent study, Heiser et al. showed that hippocampal place cell stability and spatial encoding were disrupted in mice after brain-wide microstrokes. These findings suggest that hippocampal neurons are particularly vulnerable to dysfunction after stroke, even in the absence of local lesions. They also highlight the potential to improve place cell stability and rescue post-stroke memory function.

During development of the gyrencephalic brain, both the formation of cortical folds and the establishment of axonal tracts require large, coordinated mechanical deformations. Cortical folding enables a high ratio of cortical surface area to brain volume, which is thought to enhance overall processing power. Meanwhile, a complex network of axonal connections facilitates communication between distant brain regions. The mechanisms underlying the formation of brain folds and axon tract organization remain widely debated. However, evidence emerging from measurements of mechanical stress, combined with physical and mathematical models, suggests that constrained cortical expansion generates folds via mechanical instability. In this opinion article, we highlight recent models and experimental data suggesting that mechanical stress induced by cortical folding also mediates axonal growth. We propose a key role for mechanics in establishing brain morphology and the organization of white matter fascicles of the mature brain.

A recent study by González et al. provides causal evidence that the anterior cingulate cortex (ACC) is crucial for rats to maintain persistence in reward-seeking behaviors across both information- and effort-based choice tasks, highlighting a fundamental and unified role of the ACC in goal-directed decision-making.

Gut commensals regulate neurological disorders through dynamic bidirectional communication along the gut-brain axis. Recent evidence has highlighted the well-documented beneficial role of the commensal gut bacterium Akkermansia muciniphila and its components in promoting host health. However, numerous clinical studies have demonstrated a paradoxical role of A. muciniphila in individuals with various neurological conditions. In this opinion article, we review the correlation between the prevalence of this gut commensal and the development of several disorders, including stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). We focus on the potential mechanisms by which A. muciniphila may contribute to these diseases. An in-depth understanding of these correlations and the underlying pathogenic mechanisms could shed new light on the mechanisms of disease pathogenesis and provide a logical rationale for developing new therapies for these neurological conditions.