Reviews & Analysis

TDP-43 forms cytoplasmic aggregates in degenerating neurons of frontotemporal dementia (FTD) patients. Laferrière et al. now establish that TDP-43 assemblies from distinct FTD subtypes have different structures, neurotoxicities, and seeding activities, which correlate with FTD severity. Thus, distinct pathological TDP-43 assemblies akin to prion strains might underpin distinct FTD subtypes.

In 2010, Johnson and Kenny provided conclusive evidence that extended access to a Western-style diet promotes addictive-like behavior in rats by downregulating D₂ receptors while promoting obesity. This focused attention on the parallels between drug addiction and overeating and fueled a decade of food addiction research.

The locus coeruleus is known to be an essential source of neuromodulation that influences sensory processing, including the enhancement of feature selectivity associated with attentional focus. A new study shows that the primary sensory thalamus encompasses one circuit that underlies this enhancement.

Knowledge of the role of glial–neuronal interactions in the physiology of food intake and energy metabolism is emerging. This review highlights the role of astrocytes, microglia, and tanycytes in central control of systemic metabolism.

A satisfactory understanding of how natural stimuli are encoded by neural circuits has remained elusive. Advances in machine learning provide new approaches to this problem by merging constraints imposed by stimulus statistics and behavioral goals.

Landmark papers in 2005 and 2009 provided the first evidence of links between development, training, and white-matter plasticity in humans, contributing to a shift in our understanding of brain wiring that has inspired fundamental research into the role of genes, the environment, and the mechanisms underlying training-related plasticity.

In an unfamiliar situation, animals display variable choice behavior. Based on computational modeling and empirical data, a new study suggests that the variability in decision-making across individuals is driven by differences in internal neural dynamics in the medial frontal cortex.

The combination of spinal epidural stimulation and physical therapy is restoring walking function to people with spinal cord injury. With intensive rehabilitation, some participants are able to walk in their communities during stimulation and even regain control over previously paralyzed movement in the absence of stimulation.

Two recent studies have expanded our understanding of the circuits controlling urination: one described a projection from brainstem to spinal cord that relaxes the urethral sphincter, and the other revealed a subpopulation of brainstem-projecting layer 5 pyramidal neurons in primary motor cortex that direct the initiation of urination.

What you choose depends on what information your brain considers and what it neglects when computing the value of actions. An early theory used this insight for a computational account of habits versus deliberation. It has ultimately helped uncover how choice in the brain goes beyond such simple dichotomies.

A new theory derives the sequential nature of hippocampal replay from first principles and, moreover, predicts the specific patterns of replay that are actually observed in multiple different experiments.

Somatic mutations occur after fertilization and are present in only some cells of an individual. Somatic mutations contribute to normal and abnormal brain development, including neurodevelopmental disorders like autism spectrum disorder.

In this issue of Nature Neuroscience, Menegas et al. demonstrate a role for midbrain dopamine neurons projecting to the tail of the striatum in encoding stimulus novelty and threat avoidance. From this study emerges a model whereby distinct dopaminergic projections to striatum influence behavior along at least two axes, one representing value and one representing threat.

Many neurodegenerative diseases involve the seeded propagation and spread of abnormally shaped proteins within the nervous system. The resulting disease reflects the interaction between the misfolded proteins and the host milieu.

Microglia are the sentinels, housekeepers, and defenders of the brain. In this review we consider the immune checkpoints that control microglial functions and discuss how their imbalance and subsequent neuroinflammation leads to neurodegeneration.

Older people often have more than one form of neuropathology. The authors describe how insights from the genomic architecture of syndromically defined neurodegenerative diseases can be integrated to inform person-specific trajectories of brain aging.

Neurodegenerative diseases cause progressive loss of brain functions associated with aging. Here we review intricate genotype–phenotype relationships, shared pathogenic mechanisms, and emerging therapeutic opportunities and challenges.

While the role of protein synthesis in synaptic plasticity and memory is well-established, protein degradation processes have been less studied. A seminal 2003 Nature Neuroscience paper showed that ubiquitin-dependent degradation of synaptic proteins is engaged during activity-regulated synaptic remodeling.

The authors review the current state of rodent models for AD, PD, FTD, and ALS. Limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders are discussed.

Neurodegenerative diseases impact specific cell populations within the brain. However, not all cells within the population are impacted, a phenomenon called selective cellular vulnerability. The molecular basis of this vulnerability is discussed.