A rod-shaped appendage called a primary cilium projects from the soma of most central neurons in the mammalian brain. The importance of cilia within the nervous system is highlighted by the fact that human syndromes linked to primary cilia dysfunction, collectively termed ciliopathies, are associated with numerous neuropathologies, including hyperphagia-induced obesity, neuropsychiatric disorders, and learning and memory deficits. Neuronal cilia are enriched with signaling molecules, including specific G-protein-coupled receptors (GPCRs) and their downstream effectors, suggesting that they act as sensory organelles that respond to neuromodulators in the extracellular space. We previously showed that GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet–Biedl syndrome (BBS). Based on this finding, we hypothesized that mislocalization of ciliary GPCRs may impact receptor signaling and contribute to the BBS phenotypes. Here, we show that disrupting localization of the ci...

The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species), tert-butylhydroquinone (promotes disposal of reactive oxygen species), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo–treated mice. Moreover, the tri-comb...

Individual differences among human brains exist at many scales, spanning gene expression, white matter tissue properties, and the size and shape of cortical areas. One notable example is an approximately 3-fold range in the size of human primary visual cortex (V1), a much larger range than is found in overall brain size. A previous study ([Andrews et al., 1997][1]) reported a correlation between optic tract (OT) cross-section area and V1 size in postmortem human brains, suggesting that there may be a common developmental mechanism for multiple components of the visual pathways. We evaluated the relationship between properties of the OT and V1 in a much larger sample of living human brains by analyzing the Human Connectome Project (HCP) 7 Tesla Retinotopy Dataset (including 107 females and 71 males). This dataset includes retinotopic maps measured with functional MRI (fMRI) and fiber tract data measured with diffusion MRI (dMRI). We found a negative correlation between OT fractional anisotropy (FA) and V1 s...

The sunk cost effect refers to the fact that human decisions are consistently influenced by previous irrecoverable and irrelevant costs. Recent neuroimaging experiments suggest that the dorsolateral prefrontal cortex (dlPFC) plays a pivotal role in the sunk cost effect yet the causal and neurocomputational role of the dlPFC remains elusive. In this study, two cohorts of healthy human male and female adults were recruited to complete a novel two-step decision-making task during the anodal-sham or cathodal-sham high-definition transcranial direct current stimulation (HD-tDCS) over the dlPFC, respectively. Consistent with previous studies, we showed that the sunk cost deterred participants from making further investment and therefore engendered a de-escalation effect. Such behavior can be captured by a weighted mental accounting model with a recalibrated reference point in which the direction and magnitude of the sunk cost effects hinge on the decision weights apportioned to the option values. Interestingly, ...

Maria Mancini, Jyoti C. Patel, Alison H. Affinati, Paul Witkovsky, and Margaret E. Rice (see pages [6668–6679][1]) The hormone leptin is released by adipocytes in proportion to the amount of stored fat, and it acts in the brain to regulate food intake and energy expenditure. The rewarding value

The Drosophila connectome project aims to map the synaptic connectivity of entire larval and adult fly neural networks, which is essential for understanding nervous system development and function. So far, the project has produced an impressive amount of electron microscopy data that has facilitated reconstructions of specific synapses, including many in the larval locomotor circuit. While this breakthrough represents a technical tour de force, the data remain underutilized, partly because of a lack of functional validation of reconstructions. Attempts to validate connectivity posited by the connectome project, have mostly relied on behavioral assays and/or GFP reconstitution across synaptic partners (GRASP) or GCaMP imaging. While these techniques are useful, they have limited spatial or temporal resolution. Electrophysiological assays of synaptic connectivity overcome these limitations. Here, we combine patch-clamp recordings with optogenetic stimulation in male and female larvae, to test synaptic connec...

Object and action perception in cluttered dynamic natural scenes relies on efficient allocation of limited brain resources to prioritize the attended targets over distractors. It has been suggested that during visual search for objects, distributed semantic representation of hundreds of object categories is warped to expand the representation of targets. Yet, little is known about whether and where in the brain visual search for action categories modulates semantic representations. To address this fundamental question, we studied brain activity recorded from five subjects (one female) via functional magnetic resonance imaging while they viewed natural movies and searched for either communication or locomotion actions. We find that attention directed to action categories elicits tuning shifts that warp semantic representations broadly across neocortex and that these shifts interact with intrinsic selectivity of cortical voxels for target actions. These results suggest that attention serves to facilitate tas...

Glycine receptor-mediated inhibitory neurotransmission is key for spinal cord function. Recent observations suggested that by largely elusive mechanisms also glycinergic synapses display synaptic plasticity. We imaged receptor fields at ultrahigh-resolution at freeze-fractured membranes, tracked surface and internalized glycine receptors (GlyR), and studied differential regulations of GlyRβ interactions with the scaffold protein gephyrin and the F-BAR domain protein syndapin I and thereby reveal key principles of this process. S403 phosphorylation of GlyRβ, known to be triggered by synaptic signaling, caused a decoupling from gephyrin scaffolds but simultaneously promoted association of syndapin I with GlyRβ. In line, kainate treatments used to trigger rearrangements of glycine receptors in murine syndapin I KO spinal cords (mixed sex) showed even more severe receptor field fragmentation than already observed in untreated syndapin I KO spinal cords. Syndapin I deficiency furthermore resulted in more disper...

Errors can elicit post-error adjustments that serve to optimize performance by preventing further errors. An essential but unsolved issue is that whether post-error adjustments are domain-general or domain-specific, which was investigated in the present study through eliciting different types of errors. Behavioral and electrophysiological data were recorded when male and female subjects performed the Eriksen flanker task. For this study, we examined the aforementioned issue by combining event-related potential and multivariate pattern analysis. The results indicated that post-error slowing, error-related negativity, and error positivity were comparable between congruent and incongruent errors, indicating that errors triggered domain-general interference mechanisms, whereas post-error accuracy and late positive potential elicited by incongruent errors were larger than those elicited by congruent errors, exhibiting domain-specific control adjustment mechanisms. Importantly, no successful decoding soon after ...

When listening to continuous speech, the human brain can track features of the presented speech signal. It has been shown that neural tracking of acoustic features is a prerequisite for speech understanding and can predict speech understanding in controlled circumstances. However, the brain also tracks linguistic features of speech, which may be more directly related to speech understanding. We investigated acoustic and linguistic speech processing as a function of varying speech understanding by manipulating the speech rate. In this paradigm, acoustic and linguistic speech processing is affected simultaneously but in opposite directions: When the speech rate increases, more acoustic information per second is present. In contrast, the tracking of linguistic information becomes more challenging when speech is less intelligible at higher speech rates. We measured the EEG of 18 participants (4 male) who listened to speech at various speech rates. As expected and confirmed by the behavioral results, speech und...