Peripheral somatosensory neurons innervate the skin and sense the environment. Whereas many studies focus on initial axon outgrowth and pathfinding, how signaling pathways contribute to maintenance of the established axon arbors and terminals within the skin is largely unknown. This question is particularly relevant to the many types of neuropathies that affect mature neuronal arbors. We show that a receptor tyrosine kinase (RTK), c-Kit, contributes to maintenance, but not initial development, of cutaneous axons in the larval zebrafish before sex determination. Downregulation of Kit signaling rapidly induced retraction of established axon terminals in the skin and a reduction in axonal density. Conversely, misexpression of c-Kit ligand in the skin in larval zebrafish induced increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon maintenance. We found Src family kinases (SFKs) act directly downstream to mediate Kit’s role in regulating cutaneous axon densit...

To avoid information loss, the auditory system must adapt the broad dynamic range of natural sounds to the restricted dynamic range of auditory nerve fibers. How it solves this dynamic range problem is not fully understood. Recent electrophysiological studies showed that dynamic-range adaptation occurs at the auditory-nerve level, but the amount of adaptation found was insufficient to prevent information loss. We used the physiological matlab® Auditory Periphery model to study the contribution of efferent reflexes to dynamic range adaptation. Simulating the healthy human auditory periphery provided adaptation predictions that suggest that the acoustic reflex shifts rate-level functions towards a given context level and the medial olivo-cochlear reflex sharpens the response of nerve fibers around that context level. A simulator of hearing was created to decode model-predicted firing of the auditory nerve back into an acoustic signal, for use in psychophysical tasks. Speech reception thresholds in noise obta...

There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and non-human primates compared to traditional mu opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in non-inflammatory pain patients (Stein et al., 1989). It was recently identified that G protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in non-inflamed nociceptors (Brackley et al., 2016; Brackley et al., 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine’s effects ...

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 ...

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 ultra-high 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 KO furthermore resulted in more dispersed rece...

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal. Significance Statement Alterations in...

Neurofilaments are abundant space-filling cytoskeletal polymers that are transported into and along axons. During postnatal development, these polymers accumulate in myelinated axons causing an expansion of axon caliber which is necessary for rapid electrical transmission. Studies on cultured nerve cells have shown that axonal neurofilaments move rapidly and intermittently along microtubule tracks in both anterograde and retrograde directions. However, it is unclear if neurofilament transport is also bidirectional in vivo . Here, we describe a pulse-spread fluorescence photoactivation method to address this in peripheral nerves dissected from hThy1-paGFP-NFM transgenic mice, which express a photoactivatable fluorescent neurofilament protein. Neurofilaments were photoactivated in short segments of myelinated axons in tibial nerves at 2, 4, 8 and 16 weeks of age. The proximal and distal spread of the fluorescence due to the movement of the fluorescent neurofilaments was measured over time. We show that the d...

According to a prominent view in neuroscience, visual stimuli are coded by discrete cortical networks that respond preferentially to specific categories, such as faces or objects. However, it remains unclear how these category-selective networks respond when viewing conditions are cluttered, i.e., when there is more than one stimulus in the visual field. Here, we asked three questions: (1) Does clutter reduce the response and selectivity for faces as a function of retinal location? (2) Is the preferential response to faces uniform across the visual field? And (3) Does the ventral visual pathway encode information about the location of cluttered faces? We used f MRI to measure the response of the face-selective network in awake, fixating macaques (2 female, 5 male). Across a series of four experiments, we manipulated the presence and absence of clutter, as well as the location of the faces relative to the fovea. We found that clutter reduces the response to peripheral faces. When presented in isolation, wit...

Functional MRI (fMRI) plays a key role in the study of attention. However, there remains a puzzling discrepancy between attention effects measured with fMRI and with electrophysiological methods. While electrophysiological studies find that attention increases sensory gain, amplifying stimulus-evoked neural responses by multiplicatively scaling the contrast-response function (CRF), fMRI appears to be insensitive to these multiplicative effects. Instead, fMRI studies typically find that attention produces an additive baseline shift in the blood-oxygen-level-dependent (BOLD) signal. These findings suggest that attentional effects measured with fMRI reflect top-down inputs to visual cortex, rather than the modulation of sensory gain. If true, this drastically limits what fMRI can tell us about how attention improves sensory coding. Here, we examined whether fMRI is sensitive to multiplicative effects of attention using a feature-based attention paradigm designed to preclude any possible additive effects. We m...

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 under-utilised, partly due to a lack of functional validation of reconstructions. Attempts to validate connectivity posited by the connectome project, have mostly relied on behavioural assays and/or 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 connectivity proposed by connectome reconstructions. ...