Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premat...

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant ( gch1 –/–), using CRISPR/Cas technology. gch1 –/– zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1 –/– larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1 –/– larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1 –/–. The results of our study sugges...

Aphasia recovery after stroke depends on the condition of the remaining, extralesional brain network. Network control theory (NCT) provides a unique, quantitative approach to assess the interaction between brain networks. In this longitudinal, large-scale, whole-brain connectome study, we evaluated whether controllability measures of language-related regions are associated with treated aphasia recovery. Using probabilistic tractography and controlling for the effects of structural lesions, we reconstructed whole-brain diffusion tensor imaging (DTI) connectomes from 68 individuals (20 female, 48 male) with chronic poststroke aphasia who completed a three-week language therapy. Applying principles of NCT, we computed regional (1) average and (2) modal controllability, which decode the ability of a region to (1) spread control input through the brain network and (2) to facilitate brain state transitions. We tested the relationship between pretreatment controllability measures of 20 language-related left hemis...

Texture is an important visual attribute for surface pattern discrimination and therefore object segmentation, but the neural bases of texture perception are largely unknown. Previously, we demonstrated that the responses of V4 neurons to naturalistic texture patches are sensitive to four key features of human texture perception: coarseness, directionality, regularity, and contrast. To begin to understand how distinct texture perception emerges from the dynamics of neuronal responses, in 2 macaque monkeys (1 male, 1 female), we investigated the relative contribution of the four texture attributes to V4 responses in terms of the strength and timing of response modulation. We found that the different feature dimensions are associated with different temporal dynamics. Specifically, the response modulation associated with directionality and regularity was significantly delayed relative to that associated with coarseness and contrast, suggesting that the latter are fundamentally simpler feature dimensions. The ...

Humans have the remarkable ability to selectively focus on a single talker in the midst of other competing talkers. The neural mechanisms that underlie this phenomenon remain incompletely understood. In particular, there has been longstanding debate over whether attention operates at an early or late stage in the speech processing hierarchy. One way to better understand this is to examine how attention might differentially affect neurophysiological indices of hierarchical acoustic and linguistic speech representations. In this study, we do this by using encoding models to identify neural correlates of speech processing at various levels of representation. Specifically, we recorded EEG from fourteen human subjects (nine female and five male) during a “cocktail party” attention experiment. Model comparisons based on these data revealed phonetic feature processing for attended, but not unattended speech. Furthermore, we show that attention specifically enhances isolated indices of phonetic feature processing,...

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted amongst patient populations treated with serotonergic drugs. However, those in the field lack a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on ...

Theta oscillations are one of the brain rhythms involved in memory formation, sensorimotor integration and control of locomotion and behavioural states. Generation and spatiotemporal synchronisation of theta oscillations rely on the interactions between nuclei forming a large neural network, part of which is pontine nucleus incertus (NI). Here we identified distinct populations of NI neurons, based on the relationship of their firing to the hippocampal waves, with the special focus on theta oscillations, and the direction and type of interaction with the medial septum (MS) in male, urethane anaesthetised rats. By recording NI neuronal firing and hippocampal LFP we described NI neurons that fire action potentials in a theta phase-independent or theta phase-locked and delta wave-independent or delta wave-locked manner. Among hippocampal activity independent NI neurons, irregular, slow-firing and regular, fast-firing cells were observed, while hippocampal oscillations/waves locked NI neurons could be of burst...

Malfunctioning synaptic plasticity is one of the major mechanisms contributing to the development of chronic pain. We studied spike-timing dependent depression (tLTD) in the ACC of male mice, a brain region involved in processing emotional aspects of pain. tLTD onto layer 5 pyramidal neurons depended on postsynaptic calcium-influx through GluN2B-containing NMDARs and retrograde signaling via nitric oxide to reduce presynaptic release probability. After chronic constriction injury of the sciatic nerve, a model for neuropathic pain, tLTD was rapidly impaired; and this phenotype persisted even beyond the time of recovery from mechanical sensitization. Exclusion of GluN2B-containing NMDARs from the postsynaptic site specifically at projections from the anterior thalamus to the ACC caused the tLTD phenotype, whereas signaling downstream of nitric oxide synthesis remained intact. Thus, transient neuropathic pain can leave a permanent trace manifested in the disturbance of synaptic plasticity in a specific affere...

Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties ( e.g . spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptati...

The neuropeptide oxytocin (Oxt) plays important roles in modulating social behaviors. Oxytocin receptor (Oxtr) is abundantly expressed in the brain and its relationship to socio-behavioral controls has been extensively studied using mouse brains. Several genetic tools to visualize and/or manipulate Oxtr-expressing cells, such as fluorescent reporters and Cre recombinase drivers, have been generated by ES-cell based gene targeting or bacterial artificial chromosome (BAC) transgenesis. However, these mouse lines displayed some differences in their Oxtr expression profiles probably due to the complex context and integrity of their genomic configurations in each line. Here we apply our sophisticated genome-editing techniques to the Oxtr locus, systematically generating a series of knock-in mouse lines, in which its endogenous transcriptional regulations are intactly preserved and evaluate their expression profiles to ensure the reliability of our new tools. We employ the epitope tagging strategy, with which C-...