Degeneration of locus Coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter ( DBH-hSNCA ). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in...

d-Serine (d-Ser) is a coagonist for NMDA-type glutamate receptors and is thus important for higher brain function. d-Ser is synthesized by serine racemase and degraded by d-amino acid oxidase. However, the significance of these enzymes and the relevant functions of d-amino acids remain unclear. Here, we show that in the nematode Caenorhabditis elegans , the serine racemase homolog SERR-1 and d-amino acid oxidase DAAO-1 control an adaptive foraging behavior. Similar to many organisms, C. elegans immediately initiates local search for food when transferred to a new environment. With prolonged food deprivation, the worms exhibit a long-range dispersal behavior as the adaptive foraging strategy. We found that serr-1 deletion mutants did not display this behavior, whereas daao-1 deletion mutants immediately engaged in long-range dispersal after food removal. A quantitative analysis of d-amino acids indicated that d-Ser and d-alanine (d-Ala) are both synthesized and suppressed during food deprivation. A behavior...

Synaptic ribbons are thought to provide vesicles for continuous release in some retinal nonspiking neurons, yet recent studies indicate that genetic removal of the ribbon has little effect on release kinetics. To investigate vesicle replenishment at synaptic ribbons, we used total internal reflection fluorescence microscopy to image synaptic vesicles and ribbons in retinal bipolar cells of goldfish ( Carassius auratus ) of both sexes. Analysis of vesicles released by trains of 30 ms depolarizations revealed that most releasable vesicles reside within 300 nm of the ribbon center. A single 30 ms step to 0 mV was sufficient to deplete the membrane-proximal vesicle pool, while triggering rapid stepwise movements of distal vesicles along the ribbon and toward the plasma membrane. Replenishment only becomes rate-limiting for recovery from paired-pulse depression for interstimulus intervals shorter than 250 ms. For longer interstimulus intervals, vesicle movement down the ribbon is fast enough to replenish releas...

A hallmark of high-level visual cortex is its functional organization of neighboring areas that are selective for single categories, such as faces, bodies, and objects. However, visual scenes are typically composed of multiple categories. How does a category-selective cortex represent such complex stimuli? Previous studies have shown that the representation of multiple stimuli can be explained by a normalization mechanism. Here we propose that a normalization mechanism that operates in a cortical region composed of neighboring category-selective areas would generate a representation of multi-category stimuli that varies continuously across a category-selective cortex as a function of the magnitude of category selectivity for its components. By using fMRI, we can examine this correspondence between category selectivity and the representation of multi-category stimuli along a large, continuous region of cortex. To test these predictions, we used a linear model to fit the fMRI response of human participants (...

Dopamine (DA) neurons of the VTA track cues and rewards to generate a reward prediction error signal during Pavlovian conditioning. Here we explored how these neurons respond to a self-paced, operant task in freely moving mice. The animal could trigger a reward-predicting cue by remaining in a specific location of an operant box for a brief time before moving to a spout for reward collection. VTA DA neurons were identified using DAT-Cre male mice that carried an optrode with minimal impact on the behavioral task. In vivo single-unit recordings revealed transient fast spiking responses to the cue and reward in correct trials, while for incorrect ones the activity paused, reflecting positive and negative error signals of a reward prediction. In parallel, a majority of VTA DA neurons simultaneously encoded multiple actions (e.g., movement velocity, acceleration, distance to goal, and licking) in sustained slow firing modulation. Applying a GLM, we show that such multiplexed encoding of rewarding and motor var...

“Trust” is the timely theme for this year's Peer Review Week. The COVID-19 pandemic has demonstrated both the need for speed of dissemination of new scientific findings and the need for rigorous peer review of findings that are achingly desired, but that are not supported by good experimental

Tian Wang, Yang Li, Guanzhong Yang, Weifeng Dai, Yi Yang, et al. (see pages [7436–7450][1]) The cerebral cortex has a laminar organization with layer-specific cell types and connectivity patterns. Although much is known about the overall organization of cortical circuits, how each layer

Cortical inhibition plays an important role in information processing in the brain. However, the mechanisms by which inhibition and excitation are coordinated to generate functions in the six layers of the cortex remain unclear. Here, we measured laminar-specific responses to stimulus orientations in primary visual cortex (V1) of awake monkeys (male, Macaca mulatta ). We distinguished inhibitory effects (suppression) from excitation, by taking advantage of the separability of excitation and inhibition in the orientation and time domains. We found two distinct types of suppression governing different layers. Fast suppression (FS) was strongest in input layers (4C and 6), and slow suppression (SS) was 3 times stronger in output layers (2/3 and 5). Interestingly, the two types of suppression were correlated with different functional properties measured with drifting gratings. FS was primarily correlated with orientation selectivity in input layers ( r = −0.65, p < 10−9), whereas SS was primarily correlated wi...

The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species specific. Moreover, use of intracerebroventricular (ICV) galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic wheel run...

The AMPA subtype of synaptic glutamate receptors (AMPARs) plays an essential role in cognition. Their function, numbers, and change at synapses during synaptic plasticity are tightly regulated by neuronal activity. Although we know that long-distance transport of AMPARs is essential for this regulation, we do not understand the associated regulatory mechanisms of it. Neuronal transmission is a metabolically demanding process in which ATP consumption and production are tightly coupled and regulated. Aerobic ATP synthesis unavoidably produces reactive oxygen species (ROS), such as hydrogen peroxide, which are known modulators of calcium signaling. Although a role for calcium signaling in AMPAR transport has been described, there is little understanding of the mechanisms involved and no known link to physiological ROS signaling. Here, using real-time in vivo imaging of AMPAR transport in the intact C. elegans nervous system, we demonstrate that long-distance synaptic AMPAR transport is bidirectionally regulat...