Latent pain sensitization (LS) engages pronociceptive signaling pathways in the dorsal horn that include N-methyl-D-aspartate receptor (NMDAR) → adenylyl cyclase-1 (AC1) → protein kinase A (PKA) and Exchange factor directly activated by cAMP (Epac). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal kappa opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302. LY2456302 reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but neither astrocytes (GFAP) nor microglial (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-...

Prolonged exposure to a stimulus causes desensitization of cortical neurons and results in perceptual changes. One example of this phenomenon is contrast adaptation, in which perceived differences between light and dark regions of a stimulus decrease. Blakemore, Muncey, and Ridley reported evidence for the "perceptual fading of a stabilized cortical image" in a 1971 Nature paper. Our goal was to replicate their second experiment, in which adaptation was measured across many contrasts, and develop an active learning exercise for undergraduate students. The experiment was coded using an open-source python package and psychophysical data were collected from two observers. On each trial, a sinusoidally modulated luminance grating appeared above fixation, and the task of the observer was to adjust the contrast of a grating below fixation until the two appeared identical. Between trials in the adaptation condition, a high contrast grating was presented in the top location; no such grating appeared between trials...

Loss-of-function mutations in endosomal Na+/H+ exchanger 6 (NHE6) cause the X-linked neurologic disorder Christianson syndrome (CS). Patients exhibit symptoms associated with both neurodevelopmental and neurodegenerative abnormalities. While loss of NHE6 has been shown to over-acidify the endosome lumen, and is associated with endolysosome neuropathology, NHE6-mediated mechanisms in endosome trafficking and lysosome function have been understudied. Here, we show that NHE6-null mouse neurons demonstrate worsening lysosome function with time in culture, likely as a result of defective endosome trafficking. NHE6-null neurons exhibit overall reduced lysosomal proteolysis despite over-acidification of the endosome and lysosome lumen. Akin to Nhx1 mutants in Saccharomyces cerevisiae, we observe decreased endosome-lysosome fusion in NHE6-null neurons. Also, we find premature activation of pH-dependent cathepsin D (CatD) in endosomes. While active CatD is increased in endosomes, CatD activation and CatD protein le...

Visual object recognition relies on elaborate sensory processes that transform retinal inputs to object representations, but it also requires decision-making processes that read out object representations and function over prolonged time scales. The computational properties of these decision-making processes remain underexplored for object recognition. Here, we study these computations by developing a stochastic multifeature face categorization task. Using quantitative models and tight control of spatiotemporal visual information, we demonstrate that human subjects (five males, eight females) categorize faces through an integration process that first linearly adds the evidence conferred by task-relevant features over space to create aggregated momentary evidence and then linearly integrates it over time with minimum information loss. Discrimination of stimuli along different category boundaries (e.g., identity or expression of a face) is implemented by adjusting feature weights of spatial integration. This...

Oscillatory networks underlie rhythmic behaviors (e.g., walking, chewing) and complex behaviors (e.g., memory formation, decision-making). Flexibility of oscillatory networks includes neurons switching between single- and dual-network participation, even generating oscillations at two distinct frequencies. Modulation of synaptic strength can underlie this neuronal switching. Here we ask whether switching into dual-frequency oscillations can also result from modulation of intrinsic neuronal properties. The isolated stomatogastric nervous system of male Cancer borealis crabs contains two well-characterized rhythmic feeding-related networks (pyloric, ∼1 Hz; gastric mill, ∼0.1 Hz). The identified modulatory projection neuron MCN5 causes the pyloric-only lateral posterior gastric (LPG) neuron to switch to dual pyloric/gastric mill bursting. Bath applying the MCN5 neuropeptide transmitter Gly1-SIFamide only partly mimics the LPG switch to dual activity because of continued LP neuron inhibition of LPG. Here, we f...

Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in murine dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of translation in vitro and in vivo . Inflammatory cues promote local translation of Arc in the skin. Arc-deficient male mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles (EVs), we hypothesized that intercellular Arc signaling regulates the inflammatory response in skin. We found ...

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER+ neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER+ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER+ neurons abrogated itch responses, indicating that GPER+ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MO...

How does the brain process continuous experiences so they can be remembered? Evidence suggests that people perceive their experience as a series of distinct and meaningful events. Information encountered within the same event shows greater temporal integration into memory as well as enhanced neural representational similarity. Although these data support the theory that the brain builds and maintains a mental model of the current event that represents recently encountered stimulus information, this hypothesis has not been directly tested. We used fMRI in humans ( N = 21, 13 female) to test whether within-event neural similarity indicates the persistence of stimulus representations in a mental model. Participants viewed trial-unique visual images that were grouped into events. We calculated neural pattern similarity across time in the category-selective visual cortex to measure stimulus persistence. Pattern similarity was enhanced within, compared with between, events in the object-sensitive left lateral oc...

Negative afterimages are perceptual phenomena that occur after physical stimuli disappear from sight. Their origin is linked to transient post-stimulus responses of visual neurons. The receptive fields (RFs) of these subcortical ON- and OFF-center neurons exhibit antagonistic interactions between central and surrounding visual space, resulting in selectivity for stimulus polarity and size. These two features are closely intertwined, yet their relationship to negative afterimage perception remains unknown. Here we tested whether size differentially affects the perception of bright and dark negative afterimages in humans of both sexes, and how this correlates with neural mechanisms in subcortical ON and OFF cells. Psychophysically, we found a size-dependent asymmetry whereby dark disks produce stronger and longer-lasting negative afterimages than bright disks of equal contrast at sizes >0.8°. Neurophysiological recordings from retinal and relay cells in female cat dorsal lateral geniculate nucleus showed tha...

Aging, disease, and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ∼95% of vestibular hair cells in adult mice, ∼20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for the recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations,...