Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction o...

Response inhibition is a primary executive control function that allows the withholding of inappropriate responses, and requires appropriate perception of the external environment to achieve a behavioral goal. It remains unclear, however, how response inhibition is achieved when goal-relevant information involves perceptual uncertainty. Twenty-six human participants of both sexes performed a go/no-go task where visually presented random-dot motion stimuli involved perceptual uncertainties. The right inferior frontal cortex (rIFC) was involved in response inhibition, and the middle temporal (MT) region showed greater activity when dot motions involved less uncertainty. A neocortical temporal region in the superior temporal sulcus (STS) specifically showed greater activity during response inhibition in more perceptually certain trials. In this STS region, activity was greater when response inhibition was successful than when it failed. Directional effective connectivity analysis revealed that in more coheren...

hMT+/V5 is a region in the middle occipito-temporal cortex that responds preferentially to visual motion in sighted people. In case of early visual deprivation, hMT+/V5 enhances its response to moving sounds. Whether hMT+/V5 contains information about motion directions and whether the functional enhancement observed in the blind is motion specific, or also involves sound source location, remains unsolved. Moreover, the impact of this crossmodal reorganization of hMT+/V5 on the regions typically supporting auditory motion processing, like the human Planum Temporale (hPT), remains equivocal. We used a combined functional and diffusion MRI approach and individual in-ear recordings to study the impact of early blindness on the brain networks supporting spatial hearing, in male and female humans. Whole-brain univariate analysis revealed that the anterior portion of hMT+/V5 responded to moving sounds in sighted and blind people, while the posterior portion was selective to moving sounds only in blind participant...

The whiskers of rodents are a key sensory organ that provides critical tactile information for animal navigation and object exploration throughout life. Previous work has explored the developmental sensory-driven activation of the primary sensory cortex processing whisker information (wS1), also called barrel cortex. This body of work has shown that the barrel cortex is already activated by sensory stimuli during the first postnatal week. However, it is currently unknown when over the course of development these stimuli begin being processed by higher-order cortical areas, such as secondary whisker somatosensory area (wS2). Here we investigate the developmental engagement of wS2 by whisker stimuli and the emergence of corticocortical communication from wS1 to wS2. Using in vivo wide-field imaging and multielectrode recordings in control and conditional KO mice of either sex with thalamocortical innervation defects, we find that wS1 and wS2 are able to process bottom-up information coming from the thalamus ...

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...

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 ...

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+ ...

Visual word recognition has been proposed to have a functional and spatial organization corresponding to hierarchical language-like word forms in the left fusiform gyrus (FG) during visual word recognition in alphabetic languages. However, it is still unclear whether the similar functional gradients of word-like representation exist during Chinese character recognition. In this study, we adopted univariate activation analysis and representational similarity analysis (RSA) methods to investigate the functional organization in the FG for Chinese character recognition using task fMRI data. Native Chinese readers were visually presented with four types of character-like stimuli (i.e., real characters, pseudo-characters, false characters, and stroke combinations). After analysis, we observed a posterior-to-anterior functional gradient in the left FG corresponding to the degree of likeness of stimuli to character. Additionally, distinct subregions of the left FG harbor different orthographic codes. The middle pa...

The generation of surrogate data, i.e., the modification of data to destroy a certain feature, can be considered as the implementation of a null-hypothesis whenever an analytical approach is not feasible. Thus, surrogate data generation has been extensively used to assess the significance of spike correlations in parallel spike trains. In this context, one of the main challenges is to properly construct the desired null-hypothesis distribution and to avoid altering the single spike train statistics. A classical surrogate technique is uniform dithering (UD), which displaces spikes locally and uniformly distributed, to destroy temporal properties on a fine timescale while keeping them on a coarser one. Here, we compare UD against five similar surrogate techniques in the context of the detection of significant spatiotemporal spike patterns. We evaluate the surrogates for their performance, first on spike trains based on point process models with constant firing rate, and second on modeled nonstationary artifi...

The migration of neurons from their birthplace to their correct destination is one of the most crucial steps in brain development. Incomplete or incorrect migration yields ectopic neurons, which cause neurologic deficits or are negligible at best. However, the granule cells (GCs) in the cerebellar cortex may challenge this traditional view of ectopic neurons. When animals are born, GCs proliferate near the pia mater and then migrate down to the GC layer located deep in the cerebellar cortex. However, some GC-like cells stay in the molecular layer, a layer between the pia mater and GC layer, even in normal adult animals. These cells were named ectopic GCs nearly 50 years ago, but their abundance and functional properties remain unclear. Here, we have examined GCs in the molecular layer (mGCs) with a specific marker for mature GCs and transgenic mice in which GCs are sparsely labeled with a fluorescent protein. Contrary to the previous assumption that mGCs are a minor neuronal population, we have found that ...