Several populations of neurons are purported to degenerate in Parkinson’s disease (PD). One current hypothesis suggests that vulnerable neurons in PD share common characteristics including projecting to voluminous territories and having extremely long and branched axonal domains with large numbers of neurotransmitter release sites. In this study, we used a mouse in vitro culture system to compare the axonal domain of neuronal populations suspected to be vulnerable in PD to that of neuronal populations considered at a lesser risk. In the first category, we included dopamine (DA) neurons of the substantia nigra, noradrenergic neurons of the locus coeruleus, serotonin neurons of the raphe nuclei, and cholinergic neurons of the dorsal motor nucleus of the vagus. In the second category, we included DA neurons of the ventral tegmental area, cholinergic neurons of the hypoglossal nucleus, and cholinergic interneurons of the dorsal striatum. Validating their differential vulnerability, we find that, when compared ...

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans over age 80 who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively-healthy younger individuals, cognitively-average peers (“Normal Elderly”), and individuals with amnestic Mild Cognitive Impairment (aMCI). Postmortem sections of the ERC were stained with cresyl violet to visualize neurons, and immunostained with PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was employed to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups....

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD ( Mef2c -Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c -Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed dur...

Trafficking of transducin (Gαt) in rod photoreceptors is critical for adaptive and modulatory responses of the retina to varying light intensities. In addition to fine-tuning phototransduction gain in rod outer segments, light-induced translocation of Gαt to the rod synapse enhances rod to rod bipolar synaptic transmission. Here, we show that the rod-specific loss of Frmpd1 (FERM and PDZ domain containing 1), in the retina of both female and male mice, results in delayed return of Gαt from the synapse back to outer segments in the dark, compromising the capacity of rods to recover from light adaptation. Frmpd1 directly interacts with Gpsm2 (G-protein signaling modulator 2), and the two proteins are required for appropriate sensitization of rod-rod bipolar signaling under saturating light conditions. These studies provide insight into how the trafficking and function of Gαt is modulated to optimize the photoresponse and synaptic transmission of rod photoreceptors in a light-dependent manner. SIGNIFICANCE S...

How variable is the functionally-defined structure of early visual areas in human cortex and how much variability is shared between twins? Here we quantify individual differences in the best understood functionally-defined regions of cortex: V1, V2, V3. The Human Connectome Project 7T Retinotopy Dataset includes retinotopic measurements from 181 subjects (109 female, 72 male), including many twins. We trained four “anatomists” to manually define V1-V3 using retinotopic features. These definitions were more accurate than automated anatomical templates and showed that surface areas for these maps varied more than three-fold across individuals. This three-fold variation was little changed when normalizing visual area size by the surface area of the entire cerebral cortex. In addition to varying in size, we find that visual areas vary in how they sample the visual field. Specifically, the cortical magnification function differed substantially among individuals, with the relative amount of cortex devoted to cen...

Recent connectome analyses of the entire synaptic circuit in the nervous system have provided tremendous insights into how neural processing occurs through the synaptic relay of neural information. Conversely, the extent to which ephaptic transmission which does not depend on the synapses contributes to the relay of neural information, especially beyond a distance between adjacent neurons and to neural processing remains unclear. We show that ephaptic transmission mediated by extracellular potential changes in female Drosophila melanogaster can reach more than 200 μm, equivalent to the depth of its brain. Furthermore, ephaptic transmission driven by retinal photoreceptor cells mediates light-evoked firing rate increases in olfactory sensory neurons. These results indicate that ephaptic transmission contributes to sensory responses that can change momentarily in a context-dependent manner. SIGNIFICANCE STATEMENT: Although extracellular field potential activities are commonly observed in many nervous syst...

Compromised endocytosis in neurons leads to synapse overgrowth and altered organization of synaptic proteins. However, the molecular players and the signaling pathways which regulate the process remain poorly understood. Here, we show that σ2-adaptin, one of the subunits of the AP2-complex, genetically interacts with Mad, Medea and Dad (components of BMP signaling) to control neuromuscular junction (NMJ) growth in Drosophila . Ultrastructural analysis of σ2-adaptin mutants show an accumulation of large vesicles and membranous structures akin to endosomes at the synapse. We found that mutations in σ2-adaptin lead to an accumulation of Tkv receptors at the presynaptic membrane. Interestingly, the level of small GTPase Rab11 was significantly reduced in the σ2-adaptin mutant synapses. However, expression of Rab11 does not restore the synaptic defects of σ2-adaptin mutations. We propose a model in which AP2 regulates Tkv internalization and endosomal recycling to control synaptic growth. SIGNIFICANCE STATEMEN...

Many controlled, in vitro studies have demonstrated how postsynaptic responses to presynaptic spikes are not constant but depend on short-term synaptic plasticity (STP) and the detailed timing of presynaptic spikes. However, the effects of short-term plasticity (depression and facilitation) are not limited to short, sub-second timescales. The effects of STP appear on long timescales as changes in presynaptic firing rates lead to changes in steady-state synaptic transmission. Here we examine the relationship between natural variations in the presynaptic firing rates and spike transmission in vivo . Using large-scale spike recordings in awake male and female mice from the Allen Institute Neuropixels dataset, we first detect putative excitatory synaptic connections based on cross-correlations between the spike trains of millions of pairs of neurons. For the subset of pairs where a transient, excitatory effect was detected, we use a model-based approach to track fluctuations in synaptic efficacy and find that ...

Electrical activity in neurons is highly energy demanding and accompanied by rises in cytosolic Ca2+. Cytosolic Ca2+, in turn, secures energy supply by pushing mitochondrial metabolism either through augmented NADH (nicotinamide adenine dinucleotide) transfer into mitochondria via the malate–aspartate shuttle (MAS) or via direct activation of dehydrogenases of the TCA cycle after passing into the matrix through the mitochondrial Ca2+ uniporter (MCU). Another Ca2+-sensitive booster of mitochondrial ATP synthesis is the glycerol-3-phosphate shuttle (G3PS), whose role in neuronal energy supply has remained elusive. Essential components of G3PS are expressed in hippocampal neurons. Single neuron metabolic measurements in primary hippocampal cultures derived from rat pups of either sex reveal only moderate, if any, constitutive activity of G3PS. However, during electrical activity neurons fully rely on G3PS when MAS and MCU are unavailable. Under these conditions, G3PS is required for appropriate action potenti...

Tactile sensations can bias visual perception in the awake state while visual sensitivity is known to be facilitated by sleep. It remains unknown, however, whether the tactile sensation during sleep can bias the visual improvement after sleep. Here, we performed nap experiments in human participants ( n = 56, 18 males, 38 females) to demonstrate that repetitive tactile motion stimulation on the fingertip during slow wave sleep selectively enhanced subsequent visual motion detection. The visual improvement was associated with slow wave activity. The high activation at the high beta frequency was found in the occipital electrodes after the tactile motion stimulation during sleep, indicating a visual-tactile cross-modal interaction during sleep. Furthermore, a second experiment ( n = 14, 14 females) to examine whether a hand- or head-centered coordination is dominant for the interpretation of tactile motion direction showed that the biasing effect on visual improvement occurs according to the hand-centered co...