Showing papers by "Erik C. B. Johnson published in 2016"

A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer’s disease

Abstract: A small molecule named ISRIB has recently been described to enhance memory in rodents. In this study we aimed to test whether ISRIB would reverse learning and memory deficits in the J20 mouse model of human amyloid precursor protein (hAPP) overexpression, a model that simulates many aspects of Alzheimer's disease in which memory deficits are a hallmark feature. We did not observe a significant rescue effect with ISRIB treatment on spatial learning and memory as assessed in the Morris water maze in J20 mice. We also did not observe a significant enhancement of spatial learning or memory in nontransgenic mice with ISRIB treatment, although a trend emerged for memory enhancement in one cohort of mice. Future preclinical studies with ISRIB would benefit from additional robust markers of target engagement in the brain.

A minimum-error, energy-constrained neural code is an instantaneous-rate code

Abstract: Sensory neurons code information about stimuli in their sequence of action potentials (spikes). Intuitively, the spikes should represent stimuli with high fidelity. However, generating and propagating spikes is a metabolically expensive process. It is therefore likely that neural codes have been selected to balance energy expenditure against encoding error. Our recently proposed optimal, energy-constrained neural coder (Jones et al. Frontiers in Computational Neuroscience, 9, 61 2015) postulates that neurons time spikes to minimize the trade-off between stimulus reconstruction error and expended energy by adjusting the spike threshold using a simple dynamic threshold. Here, we show that this proposed coding scheme is related to existing coding schemes, such as rate and temporal codes. We derive an instantaneous rate coder and show that the spike-rate depends on the signal and its derivative. In the limit of high spike rates the spike train maximizes fidelity given an energy constraint (average spike-rate), and the predicted interspike intervals are identical to those generated by our existing optimal coding neuron. The instantaneous rate coder is shown to closely match the spike-rates recorded from P-type primary afferents in weakly electric fish. In particular, the coder is a predictor of the peristimulus time histogram (PSTH). When tested against in vitro cortical pyramidal neuron recordings, the instantaneous spike-rate approximates DC step inputs, matching both the average spike-rate and the time-to-first-spike (a simple temporal code). Overall, the instantaneous rate coder relates optimal, energy-constrained encoding to the concepts of rate-coding and temporal-coding, suggesting a possible unifying principle of neural encoding of sensory signals.

Peptide backbone modification in the bend region of amyloid-β inhibits fibrillogenesis but not oligomer formation.

Abstract: Current evidence suggests that oligomers of the amyloid-β (Aβ) peptide are involved in the cellular toxicity of Alzheimer's disease, yet their biophysical characterization remains difficult because of lack of experimental control over the aggregation process under relevant physiologic conditions. Here, we show that modification of the Aβ peptide backbone at Gly29 allows for the formation of oligomers but inhibits fibril formation at physiologic temperature and pH. Our results suggest that the putative bend region in Aβ is important for higher-order aggregate formation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Representation of Stimulus Speed and Direction in Vibrissal-Sensitive Regions of the Trigeminal Nuclei: A Comparison of Single Unit and Population Responses.

Abstract: The rat vibrissal (whisker) system is one of the oldest and most important models for the study of active tactile sensing and sensorimotor integration. It is well established that primary sensory neurons in the trigeminal ganglion respond to deflections of one and only one whisker, and that these neurons are strongly tuned for both the speed and direction of individual whisker deflections. During active whisking behavior, however, multiple whiskers will be deflected simultaneously. Very little is known about how neurons at central levels of the trigeminal pathway integrate direction and speed information across multiple whiskers. In the present work, we investigated speed and direction coding in the trigeminal brainstem nuclei, the first stage of neural processing that exhibits multi-whisker receptive fields. Specifically, we recorded both single-unit spikes and local field potentials from fifteen sites in spinal trigeminal nucleus interpolaris and oralis while systematically varying the speed and direction of coherent whisker deflections delivered across the whisker array. For 12/15 neurons, spike rate was higher when the whisker array was stimulated from caudal to rostral rather than rostral to caudal. In addition, 10/15 neurons exhibited higher firing rates for slower stimulus speeds. Interestingly, using a simple decoding strategy for the local field potentials and spike trains, classification of speed and direction was higher for field potentials than for single unit spike trains, suggesting that the field potential is a robust reflection of population activity. Taken together, these results point to the idea that population responses in these brainstem regions in the awake animal will be strongest during behaviors that stimulate a population of whiskers with a directionally coherent motion.