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Gilmer, J.

Publications and source records attributed to Gilmer, J..

3 recordsLinked to original sources

Hindmarsh-Rose neuronal network with spike-timing-dependent plasticity demonstrates coordinated reset neuromodulation

Computational models of brain structures impacted by Parkinson's disease are useful for studying pathological synchronization and exploring potential therapies. We use the Hindmarsh-Rose neuronal model to simulate synchronized activity in the subthalamic nucleus, capturing key features of the pathological rhythms observed in Parkinson's disease. Our model incorporates chemical synapses whose strengths evolve according to a spike-timing-dependent plasticity (STDP) rule. We apply coordinated reset stimulation with rapidly varying sequences (RVS CR) and examine its ability to weaken synaptic weights, thereby reducing neuronal synchrony. This stimulation technique delivers phase-shifted stimuli to distinct sites in a random sequence. We explore how stimulation frequency and the number of stimulation sites affect the efficacy of RVS CR at desynchronizing the network and observe good agreement with previous studies. We demonstrate that RVS CR efficacy is sensitive to the depression-to-potentiation ratio in the STDP rule, which may be an important parameter to tune when reconciling simulations with experimental data. Numerical simulation of neuronal networks is constrained by computational resources when models demand large networks. This work proposes a model that demonstrates similar utility with a relatively small network, enabling researchers to study pathological neuronal activity and treatments more efficiently.

neuroscience↗

A resource to enable chemical biology and drug discovery of WDR Proteins

Protein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment and computation to enable discovery of ligands for WD40 repeat (WDR) proteins, one of the largest human protein families. This resource includes expression clones, purification protocols, and a comprehensive assessment of the druggability for hundreds of WDR proteins. We solved 21 high resolution crystal structures, and have made available a suite of biophysical, biochemical, and cellular assays to facilitate the discovery and characterization of small molecule ligands. To this end, we use the resource in a hit-finding pilot involving DNA-encoded library (DEL) selection followed by machine learning (ML). This led to the discovery of first-in-class, drug-like ligands for 9 of 20 targets. This result demonstrates the broad ligandability of WDRs. This extensive resource of reagents and knowledge will enable further discovery of chemical tools and potential therapeutics for this important class of proteins.

biochemistry↗

Learning improves decoding of odor identity with phase-referenced oscillations in the olfactory bulb

Local field potential oscillations reflect temporally coordinated neuronal ensembles-- coupling distant brain regions, gating processing windows, and providing a reference for spike timing-based codes. In phase amplitude coupling (PAC), the amplitude of the envelope of a faster oscillation is larger within a phase window of a slower carrier wave. Here, we characterized PAC, and the related theta phase-referenced high gamma and beta power (PRP), in the olfactory bulb of mice learning to discriminate odorants. PAC changes throughout learning, and odorant-elicited changes in PRP increase for rewarded and decrease for unrewarded odorants. Contextual odorant identity (is the odorant rewarded?) can be decoded from peak PRP in animals proficient in odorant discrimination, but not in naive mice. As the animal learns to discriminate the odorants the dimensionality of PRP decreases. Therefore, modulation of phase-referenced chunking of information in the course of learning plays a role in early sensory processing in olfaction. SignificanceEarly processing of olfactory information takes place in circuits undergoing slow frequency theta oscillations generated by the interplay of olfactory input modulated by sniffing and centrifugal feedback from downstream brain areas. Studies in the hippocampus and cortex suggest that different information "chunks" are conveyed at different phases of the theta oscillation. Here we show that in the olfactory bulb, the first processing station in the olfactory system, the amplitude of high frequency gamma oscillations encodes for information on whether an odorant is rewarded when it is observed at the peak phase of the theta oscillation. Furthermore, encoding of information by the theta phase-referenced gamma oscillations becomes more accurate as the animal learns to differentiate two odorants.

neuroscience↗