Professional musicians are a popular model for investigating experience-dependent plasticity in human large-scale brain networks. A minority of musicians possess absolute pitch, the ability to name a tone without reference. The study of absolute pitch musicians provides insights into how a very specific talent is reflected in brain networks. Previous studies of the effects of musicianship and absolute pitch on large-scale brain networks have yielded highly heterogeneous findings regarding the localization and direction of the effects. This heterogeneity was likely influenced by small samples and vastly different methodological approaches. Here, we conducted a comprehensive multimodal assessment of effects of musicianship and absolute pitch on intrinsic functional and structural connectivity using a variety of commonly used and state-of-the-art multivariate methods in the largest sample to date ( n = 153 female and male human participants; 52 absolute pitch musicians, 51 non-absolute pitch musicians, and 50...

In humans, the occipital middle-temporal region (hMT+/V5) specializes in the processing of visual motion, while the planum temporale (hPT) specializes in auditory motion processing. It has been hypothesized that these regions might communicate directly to achieve fast and optimal exchange of multisensory motion information. Here we investigated, for the first time in humans (male and female), the presence of direct white matter connections between visual and auditory motion-selective regions using a combined fMRI and diffusion MRI approach. We found evidence supporting the potential existence of direct white matter connections between individually and functionally defined hMT+/V5 and hPT. We show that projections between hMT+/V5 and hPT do not overlap with large white matter bundles, such as the inferior longitudinal fasciculus and the inferior frontal occipital fasciculus. Moreover, we did not find evidence suggesting the presence of projections between the fusiform face area and hPT, supporting the funct...

Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. In vitro and in vivo experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter...

Cortical circuits generate patterned activities that reflect intrinsic brain dynamics that lay the foundation for any, including stimuli-evoked, cognition and behavior. However, the spatiotemporal organization properties and principles of this intrinsic activity have only been partially elucidated due to previous poor resolution of experimental data and limited analysis methods. Here we investigated continuous wave patterns in the 0.5-4Hz (delta) frequency range on data from high spatiotemporal resolution optical voltage imaging of the upper cortical layers in anesthetized mice. Waves of population activities propagate in heterogeneous directions to coordinate neuronal activities between different brain regions. The complex wave patterns show characteristics of both stereotypy and variety. The location and type of wave patterns determine the dynamical evolution when different waves interact with each other. Local wave patterns of source, sink or saddle emerge at preferred spatial locations. Specifically, ‘...

Our recent work suggests that non-lesional epileptic brain tissue is capable of generating normal neurophysiological responses during cognitive tasks, which are then seized by ongoing pathological epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine if the PVH tissue also exhibits normal neurophysiological responses and network-level integration with other non-lesional cortical regions. As part of routine clinical assessment, three adult patients with PVH underwent implantation of intracranial electrodes and participated in experimental cognitive tasks. We obtained simultaneous recordings from PVH and remote cortical sites during rest as well as controlled experimental conditions. In all three subjects (2 female), cognitive experimental conditions evoked significant electrophysiological responses in discrete locations within the PVH tissue that were correlated with responses seen in non-epileptic cortical sites. Moreover, the responsiv...

Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of co-expression with Trpv1 (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In ex vivo bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordin...

To assemble the nervous system’s functional circuits, the neuronal axonal growth cones must be precisely guided to their proper targets, which can be achieved through cell-surface guidance receptor activation by ligand binding in the periphery. We investigated the function of paxillin, a focal adhesion protein, as an essential growth cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situ mRNA detection, we first show paxillin expression in LMC neurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Paxillin loss- and gain-of-function using in-ovo electroporation in chick LMC neurons, of either sex, perturbed LMC axon trajectory selection demonstrating an essential role of paxillin in motor axon guidance. In addition, a neuron-specific paxillin deletion in mice led to LMC axon trajectory selection errors. We also show that knocking down paxillin attenuates the growth preference ...

Fast-adapting type 1 (FA-1) and slowly-adapting type 1 (SA-1) first-order tactile neurons provide detailed spatiotemporal tactile information when we touch objects with fingertips. The distal axon of these neuron types branches in the skin and innervates many receptor organs associated with fingerprint ridges (Meissner corpuscles and Merkel cell neurite complexes, respectively), resulting in heterogeneous receptive fields whose sensitivity topography includes many highly sensitive zones or ‘subfields’. In experiments on humans of both sexes, using raised dots that tangentially scanned the receptive field we examined the spatial acuity of the subfields of FA-1 and SA-1 neurons and its constancy across scanning speed and direction. We report that the sensitivity of the subfield arrangement for both neuron types on average corresponds to a spatial period of ∼0.4 mm and provide evidence that a subfield's spatial selectivity arises because its associated receptor organ measures mechanical events limited to a si...

Survival depends on the ability to adaptively react or execute actions based on previous aversive salient experiences. Although lateral habenula (LHb) activity has been broadly implicated in the regulation of aversively motivated responses, it is not clear under which conditions this brain structure is necessary to regulate defensive responses to a threat. To address this issue, we combined pharmacological inactivations with behavioral tasks that involve aversive and appetitive events and evaluated defensive responses in rats. We found that LHb pharmacological inactivation did not affect cued threat conditioning (fear) and extinction (safety) learning and memory, anxiety-like or reward-seeking behaviors. Surprisingly, we found that LHb inactivation abolished reactive defensive responses (tone-elicited freezing) only when threat (conditioning) and safety memories (extinction and latent inhibition) compete during retrieval. Consistently, we found that LHb inactivation impaired active defensive responses (pla...

Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending upon their microenvironment, and exposure to interleukin-4 and -13 (IL4/IL13) has been used to elicit repair. Unexpectedly, while lipopolysaccharide (LPS)-exposed macrophages and microglia killed neural cells in culture, the addition of LPS to IL4/IL13-treated macrophages and microglia profoundly elevated IL10, repair metabolites, HBEGF trophic factor, antioxidants, and matrix-remodeling proteases. In C57BL/6 female mice the generation of M(LPS/IL4/IL13) macrophages required TLR4 and MyD88 signaling, downstream activation of PI3K/mTOR and MAP kinases, and convergence upon phospho-CREB, STAT6 and NFE2. Following mouse spinal cord demyelination, local LPS/IL4/IL13 deposition markedly increased lesional phagocytic macrophages/microglia, lactate and HBEGF, matrix remodeling, oligodendrogenesis and remyelination. Our data show that a promine...