In 1981, I published a paper in the first issue of the Journal of Neuroscience with my postdoctoral mentor, Alan Pearlman. It reported a quantitative analysis of the receptive field properties of neurons in reeler mouse visual cortex and the surprising conclusion that although the neuronal somas were strikingly malpositioned, their receptive fields were unchanged. This suggested that in mouse cortex at least, neuronal circuits have very robust systems in place to ensure the proper formation of connections. This had the unintended consequence of transforming me from an electrophysiologist into a cellular and molecular neuroscientist who studied cell adhesion molecules and the molecular mechanisms they use to regulate axon growth. It took me a surprisingly long time to appreciate that your science is driven by the people around you and by the technologies that are locally available. As a professional puzzler, I like all different kinds of puzzles, but the most fun puzzles involve playing with other puzzlers....

Neurons are the “delicate and elegant…butterflies of the soul,” as Santiago Ramón y Cajal famously put it in his memoir ([Zwirn, 2015][1]). Neurons interconnect throughout the brain and body via the elaborate arborization of their dendrites and axon. Their cytoskeleton, the intricate array of

Persistent avoidance of stress-related stimuli following acute stress exposure predicts negative outcomes such as substance abuse and traumatic stress disorders. Previous work using a rat model showed that the central amygdala (CeA) plays an important role in avoidance of a predator odor stress-paired context. Here, we show that CeA projections to the lateral hypothalamus (LH) are preferentially activated in male rats that show avoidance of a predator odor-paired context (termed Avoider rats), that chemogenetic inhibition of CeA-LH projections attenuates avoidance in male Avoider rats, that chemogenetic stimulation of the CeA-LH circuit produces conditioned place avoidance (CPA) in otherwise naive male rats, and that avoidance behavior is associated with intrinsic properties of LH-projecting CeA cells. Collectively, these data show that CeA-LH projections are important for persistent avoidance of stress-related stimuli following acute stress exposure. SIGNIFICANCE STATEMENT This study in rats shows that a...

Motion perception is a vital part of our sensory repertoire in that it contributes to navigation, awareness of moving objects, and communication. Motion sense in carnivores and primates originates with primary visual cortical neurons selective for motion direction. More than 60 years after the discovery of these neurons, there is still no consensus on the mechanism underlying direction selectivity. This paper describes a model of the cat's visual system in which direction selectivity results from the well-documented orientation selectivity of inhibitory neurons: inhomogeneities in the orientation preference map for inhibitory neurons leads to spatially asymmetric inhibition, and thus to direction selectivity. Stimulation of the model with a drifting grating shows that direction selectivity results from the relative timing of excitatory and inhibitory inputs to a neuron. Using a stationary contrast-reversing grating reveals that the inhibitory input is spatially displaced in the preferred direction relative...

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons ( Par2Nav1.8 ), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical a...

Loss of auditory-nerve (AN) afferent cochlear innervation is a prevalent human condition that does not affect audiometric thresholds and therefore remains largely undetectable with standard clinical tests. AN loss is widely expected to cause hearing difficulties in noise, known as “hidden hearing loss,” but support for this hypothesis is controversial. Here, we used operant conditioning procedures to examine the perceptual impact of AN loss on behavioral tone-in-noise (TIN) sensitivity in the budgerigar ( Melopsittacus undulatus ; of either sex), an avian animal model with complex hearing abilities similar to humans. Bilateral kainic acid (KA) infusions depressed compound AN responses by 40–70% without impacting otoacoustic emissions or behavioral tone sensitivity in quiet. Surprisingly, animals with AN damage showed normal thresholds for tone detection in noise (0.1 ± 1.0 dB compared to control animals; mean difference ± SE), even under a challenging roving-level condition with random stimulus variation a...

The lateral line (LL) is a sensory system that allows fish and amphibians to detect water currents. LL responsiveness is modulated by efferent neurons that aid in distinguishing between external and self-generated stimuli, maintaining sensitivity to relevant cues. One component of the efferent system is cholinergic, the activation of which inhibits afferent activity. LL hair cells (HCs) share structural, functional, and molecular similarities with those of the cochlea, making them a popular model for studying human hearing and balance disorders. Because of these commonalities, one could propose that the receptor at the LL efferent synapse is a α9α10 nicotinic acetylcholine receptor (nAChR). However, the identities of the molecular players underlying ACh-mediated inhibition in the LL remain unknown. Surprisingly, through the analysis of single-cell expression studies and in situ hybridization, we describe that α9, but not the α10, subunits are enriched in zebrafish HCs. Moreover, the heterologous expression...

The capacity for sensory systems to encode relevant information that is invariant to many stimulus changes is central to normal, real-world, cognitive function. This invariance is thought to be reflected in the complex spatiotemporal activity patterns of neural populations, but our understanding of population-level representational invariance remains coarse. Applied topology is a promising tool to discover invariant structure in large datasets. Here, we use topological techniques to characterize and compare the spatiotemporal pattern of coactive spiking within populations of simultaneously recorded neurons in the secondary auditory region caudal medial neostriatum of European starlings ( Sturnus vulgaris ). We show that the pattern of population spike train coactivity carries stimulus-specific structure that is not reducible to that of individual neurons. We then introduce a topology-based similarity measure for population coactivity that is sensitive to invariant stimulus structure and show that this meas...

Functional connectivity of neural oscillations (oscillation-based FC) is thought to afford dynamic information exchange across task-relevant neural ensembles. Although oscillation-based FC is classically defined relative to a prestimulus baseline, giving rise to rapid, context-dependent changes in individual connections, studies of distributed spatial patterns show that oscillation-based FC is omnipresent, occurring even in the absence of explicit cognitive demands. Thus, the issue of whether oscillation-based FC is primarily shaped by cognitive state or is intrinsic in nature remains open. Accordingly, we sought to reconcile these observations by interrogating the ECoG recordings of 18 presurgical human patients (8 females) for state dependence of oscillation-based FC in five canonical frequency bands across an array of six task states. FC analysis of phase and amplitude coupling revealed a highly similar, largely state-invariant (i.e., intrinsic) spatial component across cognitive states. This spatial or...