Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostas...

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down’s syndrome, Alzheimer’s and Parkinson’s diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, in order to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3−CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q, a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processe...

At any given moment our sensory systems receive multiple, often rhythmic, inputs from the environment. Processing of temporally structured events in one sensory modality can guide both behavioural and neural processing of events in other sensory modalities, but whether this occurs remains unclear. Here, we used human electroencephalography (EEG) to test the cross-modal influences of a continuous auditory frequency-modulated (FM) sound on visual perception and visual cortical activity. We report systematic fluctuations in perceptual discrimination of brief visual stimuli in line with the phase of the FM sound. We further show that this rhythmic modulation in visual perception is related to an accompanying rhythmic modulation of neural activity recorded over visual areas. Importantly, in our task, perceptual and neural visual modulations occurred without any abrupt and salient onsets in the energy of the auditory stimulation and without any rhythmic structure in the visual stimulus. As such, the results prov...

Social behavior is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions, such as inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation are relatively well understood, but less is known about how these regions interact while processing dynamic social interactions. To investigate whether the functional connectivity between brain regions is modulated by social context, we collected fMRI data from male monkeys ( Macaca mulatta ) viewing videos of social interactions labeled as “affiliative,” “aggressive,” or “ambiguous.” We show activation related to the perception of social interactions along both banks of the superior temporal sulcus, parietal cortex, medial and lateral frontal cortex, and the caudate nucleus. Within this network, we show that fronto-temporal functional connectivity is significantly modulated by social context. Cruc...

Hemianopia, loss of vision in half of the visual field, results from damage to the visual pathway posterior to the optic chiasm. Despite negative effects on quality of life, few rehabilitation options are currently available. Recently, several long-term training programs have been developed that show visual improvement within the blind field, although little is known of the underlying neural changes. Here, we have investigated functional and structural changes in the brain associated with visual rehabilitation. Seven human participants with occipital lobe damage enrolled in a visual training program to distinguish which of two intervals contained a drifting Gabor patch presented within the blind field. Participants performed ∼25 min of training each day for 3–6 months and undertook psychophysical tests and a magnetic resonance imaging scan before and after training. A control group undertook psychophysical tests before and after an equivalent period without training. Participants who were not at ceiling on...

The Russian farm-fox experiment is an unusually long-running and well-controlled study designed to replicate wolf-to-dog domestication. As such, it offers an unprecedented window onto the neural mechanisms governing the evolution of behavior. Here we report evolved changes to gray matter morphology resulting from selection for tameness versus aggressive responses toward humans in a sample of 30 male fox brains. Contrasting with standing ideas on the effects of domestication on brain size, tame foxes did not show reduced brain volume. Rather, gray matter volume in both the tame and aggressive strains was increased relative to conventional farm foxes bred without deliberate selection on behavior. Furthermore, tame- and aggressive-enlarged regions overlapped substantially, including portions of motor, somatosensory, and prefrontal cortex, amygdala, hippocampus, and cerebellum. We also observed differential morphologic covariation across distributed gray matter networks. In one prefrontal-cerebellum network, t...

William N. Grimes, Didem Göz Aytürk, Mrinalini Hoon, Takeshi Yoshimatsu, Clare Gamlin, et al. (see pages [6018–6037][1]) The retina is a complex structure with an astounding number of cell types. For example, an inventory based on electron micrograph reconstructions (Helmstaedter et al., 2013

Neuropeptide secretion from dense-core vesicles (DCVs) controls many brain functions. Several components of the DCV exocytosis machinery have recently been identified, but the participation of a SEC1/MUNC18 (SM) protein has remained elusive. Here, we tested the ability of the three exocytic SM proteins expressed in the mammalian brain, MUNC18-1/2/3, to support neuropeptide secretion. We quantified DCV exocytosis at a single vesicle resolution on action potential (AP) train-stimulation in mouse CNS neurons (of unknown sex) using pHluorin-tagged and/or mCherry-tagged neuropeptide Y (NPY) or brain-derived neurotrophic factor (BDNF). Conditional inactivation of Munc18-1 abolished all DCV exocytosis. Expression of MUNC18-1, but not MUNC18-2 or MUNC18-3, supported DCV exocytosis in Munc18-1 null neurons. Heterozygous (HZ) inactivation of Munc18-1 , as a model for reduced MUNC18-1 expression, impaired DCV exocytosis, especially during the initial phase of train-stimulation, when the release was maximal. These dat...

Although the anterior temporal lobe (ATL) comprises several anatomic and functional subdivisions, it is often reduced to a homogeneous theoretical entity, such as a domain-general convergence zone, or “hub,” for semantic information. Methodological limitations are largely to blame for the imprecise mapping of function to structure in the ATL. There are two major obstacles to using fMRI to identify the precise functional organization of the ATL: the difficult choice of stimuli and tasks to activate, and dissociate, specific regions within the ATL; and poor signal quality because of magnetic field distortions near the sinuses. To circumvent these difficulties, we developed a data-driven parcellation routine using resting-state fMRI data (24 females, 64 males) acquired using a sequence that was optimized to enhance signal in the ATL. Focusing on patterns of functional connectivity between each ATL voxel and the rest of the brain, we found that the ATL comprises at least 34 distinct functional parcels that are...

Visual word recognition, at a minimum, involves the processing of word form and lexical information. Opinions diverge on the spatiotemporal distribution of and interaction between the two types of information. Feedforward theory argues that they are processed sequentially, whereas interactive theory advocates that lexical information is processed fast and modulates early word form processing. To distinguish between the two theories, we applied stereoelectroencephalography (SEEG) to 33 human adults with epilepsy (25 males and eight females) during visual lexical decisions. The stimuli included real words (RWs), pseudowords (PWs) with legal radical positions, nonwords (NWs) with illegal radical positions, and stroked-changed words (SWs) in Chinese. Word form and lexical processing were measured by the word form effect (PW versus NW) and lexical effect (RW versus PW), respectively. Gamma-band (60 ∼ 140 Hz) SEEG activity was treated as an electrophysiological measure. A word form effect was found in eight left...