A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences (ILDs) are used to compute spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) because of an inbred mutation in the Cadherin 23 gene ( Cdh23 ) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice. Here, we show that two- to four-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation...

Mutations of SCN1A , which encodes the voltage-gated sodium channel Nav1.1, can cause epilepsy disorders such as Dravet syndrome (DS) that are comorbid with wide-ranging neurologic dysfunction. Many studies suggest that Nav1.1 haploinsufficiency causes forebrain GABAergic interneuron hypoexcitability, while pyramidal neuron physiology is mostly unaltered, and that this serves as a primary cell physiology phenotype linking mutation to disease. We hypothesized that deficits in inhibition would alter synaptic integration during activation of the hippocampal microcircuit, thus disrupting cellular information processing and leading to seizures and cognitive deficits. We tested this hypothesis using ex vivo whole-cell recordings from CA1 pyramidal neurons in a heterozygous Scn1a knock-out mouse model and wild-type (WT) littermates, measuring responses to single and patterned synaptic stimulation and spontaneous synaptic activity. Overall, our experiments reveal a surprising normalcy of excitatory and inhibitory ...

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knock-in ( Crmp1k i /ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out ( Crmp1 −/−) mice, respectively. Crmp1ki / ki / SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1 −/−/ SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki / ki / SOD1G93A mice but not in Crmp1 −/−/ SOD1G93A mice. In agreement with these phenotypic findings, residual ...

Endosomal transport and positioning cooperate in the establishment of neuronal compartment architecture, dynamics, and function, contributing to neuronal intracellular logistics. Furthermore, dysfunction of endo-lysosomal has been identified as a common mechanism in neurodegenerative diseases. Here, we analyzed endo-lysosomal transport when α-synuclein (α-syn) fibrillar polymorphs, β-amyloid (Aβ) fibrils, and oligomers were externally applied on primary cultures of mouse cortical neurons. To measure this transport, we used a simple readout based on the spontaneous endocytosis in cultured neurons of fluorescent nanodiamonds (FNDs), a perfectly stable nano-emitter, and the subsequent automatic extraction and quantification of their directed motions at high-throughput. α-Syn fibrillar polymorphs, Aβ fibrils, and oligomers induce a 2-fold decrease of the fraction of nanodiamonds transported along microtubules, while only slightly reducing their interaction with cortical neurons. This important decrease in movi...

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKM ζ . However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse specificity. In this article, we address the issue of synapse specificity during memory maintenance. Assuming that the long-term maintenance of synaptic plasticity is accomplished by a molecular switch, we carry out analytical calculations and perform simulations using the reaction-diffusion package in NEURON to determine the limits of synapse specificity during maintenance. Moreover, we explore the effects of the diffusion and degradation rates of proteins and of the geometrical characteristics of dendritic spines on synapse specificity. We conclu...

Adaptation plays an important role in sensory systems as it dynamically modifies sensitivity to allow the detection of stimulus changes. The vomeronasal system controls many social behaviors in most mammals by detecting pheromones released by conspecifics. Stimuli activate a transduction cascade in vomeronasal neurons that leads to spiking activity. Whether and how these neurons adapt to stimuli is still debated and largely unknown. Here, we measured short-term adaptation performing current-clamp whole-cell recordings by using diluted urine as a stimulus, as it contains many pheromones. We measured spike frequency adaptation in response to repeated identical stimuli of 2–10 s duration that was dependent on the time interval between stimuli. Responses to paired current steps, bypassing the signal transduction cascade, also showed spike frequency adaptation. We found that voltage-gated Na+ channels in VSNs undergo slow inactivation processes. Furthermore, recovery from slow inactivation of voltage-gated Na+ ...

Food choice is one of the most fundamental and most frequent value-based decisions for all animals including humans. However, the neural circuitry involved in food-based decisions is only recently being addressed. Given the relatively fast dynamics of decision formation, electroencephalography (EEG)-informed fMRI analysis is highly beneficial for localizing this circuitry in humans. Here, by using the EEG correlates of evidence accumulation in a simultaneously recorded EEG-fMRI dataset, we found a significant role for the right temporal-parietal operculum (PO) and medial insula including gustatory cortex (GC) in binary choice between food items. These activations were uncovered by using the “EEG energy” (power 2 of EEG) as the BOLD regressor and were missed if conventional analysis with the EEG signal itself were to be used, in agreement with theoretical predictions for EEG and BOLD relations. No significant positive correlations were found with higher powers of EEG (powers 3 or 4) pointing to specificity ...

Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3–/–) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3–/– mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reduct...

Although visual object recognition is well studied and relatively well understood, much less is known about how shapes are recognized by touch and how such haptic stimuli might be compared with visual shapes. One might expect that the processes of visual and haptic object recognition engage similar brain structures given the advantages of avoiding redundant brain circuitry and indeed there is some evidence that this is the case. A potentially fruitful approach to understanding the differences in how shapes might be neurally represented is to find an algorithmic method of comparing shapes, which agrees with human behavior and determines whether that method differs between different modality conditions. If not, it would provide further evidence for a shared representation of shape. We recruited human participants to perform a one-back same–different visual and haptic shape comparison task both within (i.e., comparing two visual shapes or two haptic shapes) and across (i.e., comparing visual with haptic shape...

As Huntington’s disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL; motor) and ventral posteromedial nucleus (VPM; somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and wild-type (WT) mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared with WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting...