In the mature mouse retina, Otx2 is expressed in both retinal pigmented epithelium (RPE) and photoreceptor (PR) cells, and Otx2 knock-out (KO) in the RPE alone results in PR degeneration. To study the cell-autonomous function of OTX2 in PRs, we performed PR-specific Otx2 KO (cKO) in adults. As expected, the protein disappears completely from PR nuclei but is still observed in PR inner and outer segments while its level concomitantly decreases in the RPE, suggesting a transfer of OTX2 from RPE to PRs in response to Otx2 ablation in PRs. The ability of OTX2 to transfer from RPE to PRs was verified by viral expression of tagged-OTX2 in the RPE. Transferred OTX2 distributed across the PR cytoplasm, suggesting functions distinct from nuclear transcription regulation. PR-specific Otx2 cKO did not alter the structure of the retina but impaired the translocation of PR arrestin-1 on illumination changes, making mice photophobic. RNA-seq analyses following Otx2 KO revealed downregulation of genes involved in the cyt...

Mutations in the voltage-gated sodium channel gene SCN1A are associated with human epilepsy disorders, but how most of these mutations alter channel properties and result in seizures is unknown. This study focuses on two different mutations occurring at one position within SCN1A . R1648C (R-C) is associated with the severe disorder Dravet syndrome, and R1648H (R-H), with the milder disorder GEFS+. To explore how these different mutations contribute to distinct seizure disorders, Drosophila lines with the R-C or R-H mutation, or R1648R (R-R) control substitution in the fly sodium channel gene para were generated by CRISPR-Cas9 gene editing. The R-C and R-H mutations are homozygous lethal. Animals heterozygous for R-C or R-H mutations displayed reduced life spans and spontaneous and temperature-induced seizures not observed in R-R controls. Electrophysiological recordings from adult GABAergic neurons in R-C and R-H mutants revealed the appearance of sustained neuronal depolarizations and altered firing frequ...

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and i...

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...

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISIs) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e., morning and afternoon sessions on 2 d, 5–7 d apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intraobserver nor interobserver measures of SICI differed significantly between examinations, except for T-SICI at ISI 3 ms ( p  = 0.00035) and A-SICI at ISI 2.5 ms ( p  = 0.0103). Intraday reliability was poor-to-good for A-SICI and mod...

Normal aging is associated with a decline in memory and motor learning ability. However, the exact form of these impairments (e.g., the short-term temporal stability and affected learning mechanisms) is largely unknown. Here, we used a sensorimotor adaptation task to examine changes in the temporal stability of two forms of learning (explicit and implicit) because of normal aging. Healthy young subjects (age range, 19–28 years; 20 individuals) and older human subjects (age range, 63–85 years; 19 individuals) made reaching movements in response to altered visual feedback. On each trial, subjects turned a rotation dial to select an explicit aiming direction. Once selected, the display was removed and subjects moved the cursor from the start position to the target. After initial training with the rotational feedback perturbation, subjects completed a series of probe trials at different delay periods to systematically assess the short-term retention of learning. For both groups, the explicit aiming showed no s...

Epilepsy affects 3.4 million people in the United States, and, despite the availability of numerous antiepileptic drugs, 36% of patients have uncontrollable seizures, which severely impact quality of life. High-frequency oscillations (HFOs) are a potential biomarker of epileptogenic tissue that could be useful in surgical planning. As a result, research into the efficacy of HFOs as a clinical tool has increased over the last 2 decades. However, detection and identification of these transient rhythms in intracranial electroencephalographic recordings remain time-consuming and challenging. Although automated detection algorithms have been developed, their results are widely inconsistent, reducing reliability. Thus, manual marking of HFOs remains the gold standard, and manual review of automated results is required. However, manual marking and review are time consuming and can still produce variable results because of their subjective nature and the limitations in functionality of existing open-source softwar...

Relapse is a major challenge to the treatment of substance use disorders. A progressive increase in cue-induced drug craving, termed incubation of craving, is observed after withdrawal from multiple drugs of abuse in humans and rodents. Incubation of cocaine craving involves the strengthening of excitatory synapses onto nucleus accumbens (NAc) medium spiny neurons via postsynaptic accumulation of high-conductance Ca2+-permeable AMPA receptors. This enhances reactivity to drug-associated cues and is required for the expression of incubation. Additionally, incubation of cocaine craving is associated with loss of the synaptic depression normally triggered by stimulation of metabotropic glutamate receptor 5 (mGlu5), leading to endocannabinoid production, and expressed presynaptically via cannabinoid receptor 1 activation. Previous studies have found alterations in mGlu5 and Homer proteins associated with the loss of this synaptic depression. Here we conducted coimmunoprecipitation studies to investigate associ...

Visual representations can be generated via feedforward or feedback processes. The extent to which these processes result in overlapping representations remains unclear. Previous work has shown that imagined stimuli elicit similar representations as perceived stimuli throughout the visual cortex. However, while representations during imagery are indeed only caused by feedback processing, neural processing during perception is an interplay of both feedforward and feedback processing. This means that any representational overlap could be because of overlap in feedback processes. In the current study, we aimed to investigate this issue by characterizing the overlap between feedforward- and feedback-initiated category representations during imagined stimuli, conscious perception, and unconscious processing using fMRI in humans of either sex. While all three conditions elicited stimulus representations in left lateral occipital cortex (LOC), significant similarities were observed only between imagery and consci...

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knock-out (KO) for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells (PCs) and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region on electrical stimulation of the whisker pad in a...