Volume 21 Issue 10, October 2018

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.

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.

How we value our own rewards depends on what others have. A new study shows that neurons in the medial prefrontal cortex selectively monitor the value of rewards received by oneself or by another individual, whereas midbrain dopaminergic neurons integrate these values to generate social subjective reward values.

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.

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.

Adequate blood supply and vascular integrity are key to normal brain functioning. Cerebral blood flow and blood–brain barrier disruption contribute to Alzheimer’s disease and other neurodegenerative disorders as reviewed in humans and animal models.

A newly recognized process in neurodegenerative disease is accumulation of misfolded protein aggregates that self-replicate to spread damage between cells and tissues. This process has implications in designing strategies for treatment and diagnosis.

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.

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.

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.

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.

Louveau et al. demonstrate that meningeal lymphatics drain CSF-derived macromolecules and immune cells and play a key role in regulating neuroinflammation. Meningeal lymphatics may represent a new therapeutic target for multiple sclerosis.

The authors report TNFα-dependent hyperactivity in cortical microcircuits during remission in a mouse model of multiple sclerosis, a maladaptive response to the immune attack with behavioral changes.

Goel et al found similar deficits in visual discrimination in humans and in a mouse model of FXS. In mice, a robust decrease in PV cell activity mediated this impairment, suggesting that manipulating inhibition may improve sensory processing in FXS.

The authors report that impaired hippocampal synchrony in a mouse model of schizophrenia is due to parvalbumin interneuron hypoexcitability. Rescuing interneuron excitability during adulthood restores wild-type-like network dynamics and behavior.

Menegas et al. show that dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Their results indicate that there are two axes of reinforcement learning using dopamine, the value axis and the threat axis.

Cerebellar climbing fibers provide predictive, context-specific instructional signals that do not rely exclusively on motor errors to support learning of arbitrary sensorimotor associations.

Behavior is the result of a Bayesian computation that weights past experience and current sensory information by their reliabilities. Here single-neuron activity in eye movement cortex exemplifies how the brain implements a Bayesian computation.

Applying a social Pavlovian conditioning procedure for macaques, this study shows that medial prefrontal neurons selectively monitor self-reward or other-reward information and that dopamine neurons integrate this information into subjective value.

Mongillo et al. use theoretical modeling to link structure & activity in a cortical network. They find that activity patterns are predominantly controlled by inhibitory connections, making the network robust to ongoing changes in excitatory synapses.

Hunt, Malalasekera et al. recorded populations of prefrontal neurons from monkeys performing a visual attention-guided-choice task. The results revealed that distinct computations in three PFC subregions as information was sampled guided the eventual decision.

The BRAINcode consortium found that tens of thousands of transcribed noncoding elements (TNEs) from the ‘dark matter’ of our genome are active in dopamine neurons. They may be linked to schizophrenia, Parkinson’s disease, and addiction.