Aphasia is a prevalent cognitive syndrome caused by stroke. The rarity of premorbid imaging and heterogeneity of lesion obscures the links between the local effects of the lesion, global anatomic network organization, and aphasia symptoms. We applied a simulated attack approach in humans to examine the effects of 39 stroke lesions (16 females) on anatomic network topology by simulating their effects in a control sample of 36 healthy (15 females) brain networks. We focused on measures of global network organization thought to support overall brain function and resilience in the whole brain and within the left hemisphere. After removing lesion volume from the network topology measures and behavioral scores [the Western Aphasia Battery Aphasia Quotient (WAB-AQ), four behavioral factor scores obtained from a neuropsychological battery, and a factor sum], we compared the behavioral variance accounted for by simulated poststroke connectomes to that observed in the randomly permuted data. Global measures of anato...

In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modeling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult female flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered a role of postsynaptic partners of R7 to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structur...

N-Methyl-D-aspartic (NMDA) receptors are ionotropic glutamate receptors widely expressed in the central nervous system, where they mediate phenomena as diverse as neurotransmission, information processing, synaptogenesis, and cellular toxicity. They function as glutamate-gated Ca2+-permeable channels, which require glycine as co-agonist, and can be modulated by many diffusible ligands and cellular cues, including mechanical stimuli. Previously, we found that in cultured astrocytes, shear stress initiates NMDA receptor-mediated Ca2+ entry in the absence of added agonists, suggesting that more than being mechanosensitive, NMDA receptors may be mechanically activated. Here, we used controlled expression of rat recombinant receptors and non-invasive on-cell single-channel current recordings to show that mild membrane stretch can substitute for the neurotransmitter glutamate in gating NMDA receptor currents. Notably, stretch-activated currents maintained the hallmark features of the glutamate-gated currents, in...

Extinguishing the previously acquired fear is critical for organism’s adaptation to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically-situated, δ subunit-containing GABAARs (GABAA(δ)Rs), had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic subregion (IL), sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also show...

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (N=628, ages 8-21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization re...

Despite ample behavioral evidence of atypical facial emotion processing in individuals with autism spectrum disorder (ASD), the neural underpinnings of such behavioral heterogeneities remain unclear. Here, I have used brain-tissue mapped artificial neural network (ANN) models of primate vision to probe candidate neural and behavior markers of atypical facial emotion recognition in ASD at an image-by-image level. Interestingly, the ANNs' image-level behavioral patterns better matched the neurotypical subjects' behavior than those measured in ASD. This behavioral mismatch was most remarkable when the ANN behavior was decoded from units that correspond to the primate inferior temporal (IT) cortex. ANN-IT responses also explained a significant fraction of the image-level behavioral predictivity associated with neural activity in the human amygdala (from epileptic patients without ASD)— strongly suggesting that the previously reported facial emotion intensity encodes in the human amygdala could be primarily dri...

At the request of the authors, The Journal of Neuroscience is retracting “Tracking Age Differences in Neural Distinctiveness across Representational Levels,” by Malte Kobelt, Verena R. Sommer, Attila Keresztes, Markus Werkle-Bergner, and Myriam C. Sander, which appeared on pages [3499–3511][1

Our ability to effectively retrieve complex semantic knowledge meaningfully impacts our daily lives, yet the neural processes that underly successful access and transient failures in access remain only partially understood. In this fMRI study, we contrast activation during successful semantic access, unsuccessful semantic access because of transient access failures (i.e., “tip-of-the-tongue,” “feeling-of-knowing”), and trials where the semantic knowledge was not possessed. Twenty-four human participants (14 female) were presented 240 trivia-based questions relating to person, place, object, or scholastic knowledge domains. Analyses of the recall event indicated a relatively greater role of a dorsomedial section of the prefrontal cortex in unsuccessful semantic access and relatively greater recruitment of the pars orbitalis of the inferior frontal gyrus in successful access. Successful access was also associated with increased activation in knowledge domain-selective areas. Generally, knowledge domain-selec...

Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as “Par complexes.” In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differe...

Neuronal excitability relies on coordinated action of functionally distinction channels. Voltage-gated sodium (NaV) and potassium (KV) channels have distinct but complementary roles in firing action potentials: NaV channels provide depolarizing current while KV channels provide hyperpolarizing current. Mutations and dysfunction of multiple NaV and KV channels underlie disorders of excitability, including pain and epilepsy. Modulating ion channel trafficking may offer a potential therapeutic strategy for these diseases. A fundamental question, however, is whether these channels with distinct functional roles are transported independently or packaged together in the same vesicles in sensory axons. We have used Optical Pulse-Chase Axonal Long-distance imaging to investigate trafficking of NaV and KV channels and other axonal proteins from distinct functional classes in live rodent sensory neurons (from male and female rats). We show that, similar to NaV1.7 channels, NaV1.8 and KV7.2 channels are transported i...