Biology subjects

Zemelman, B. V.

Publications and source records attributed to Zemelman, B. V..

5 recordsLinked to original sources

bioRxiv2023

Entorhinal cortex glutamatergic and GABAergic projections bidirectionally control discrimination and generalization of hippocampal representations

Discrimination and generalization are crucial brain-wide functions for memory and object recognition that utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LECGLU) and GABAergic (LECGABA) projections are essential for object recognition memory. Silencing LECGLU during in vivo two-photon imaging increased the population of active CA3 pyramidal cells but decreased activity rates, suggesting a sparse coding function through local inhibition. Silencing LECGLU also decreased place cell remapping between different environments validating this circuit drives pattern separation and context discrimination. Optogenetic circuit mapping confirmed that LECGLU drives dominant feedforward inhibition to prevent CA3 somatic and dendritic spikes. However, conjunctively active LECGABA suppresses this local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LECGABA thus promotes pattern completion and context generalization. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic cortico-hippocampal inputs bidirectionally modulate pattern separation and completion, providing neuronal representations with a dynamic range for context discrimination and generalization.

neuroscience↗

bioRxiv2023

Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses

Cerebellar damage early in life often causes long-lasting motor, social, and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviors. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviors. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is the direct postsynaptic target of the cerebellum, sending cerebellar outputs to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The hemizygous deletion of the tuberous sclerosis complex-1 (Tsc1) gene in the Purkinje cell--known to cause Purkinje cell hypoactivity and autistic behaviors--did not alter cerebellothalamic synapses or intrinsic membrane properties of thalamic neurons. However, the ablation of Purkinje cells in the developing cerebellum strengthened the cerebellothalamic synapses and enhanced thalamic suprathreshold activities. These results suggest that the cerebellothalamic circuit is resistant to moderate perturbation in the developing cerebellum, such as the reduced firing rate of Purkinje cells, and that autistic behaviors are not necessarily linked to thalamic abnormality. Still, Purkinje cell loss alters the thalamic circuit, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum.

neuroscience↗

bioRxiv2022

Primate neocortex performs balanced sensory amplification

Sensory cortex amplifies relevant features of external stimuli. This sensitivity and selectivity arise through the transformation of inputs by cortical circuitry. We characterize the circuit mechanisms and dynamics of cortical amplification by making large-scale simultaneous measurements of single cells in awake primates and by testing computational models. By comparing network activity in both driven and spontaneous states with models, we identify the circuit as operating in a regime of balanced amplification. Incoming inputs are strongly but transiently amplified by recurrent excitation. Inhibition acts to counterbalance this excitation by rapidly quenching responses, thereby permitting tracking of time-varying stimuli. One-Sentence SummarySensory cortex uses balanced excitatory and inhibitory circuitry to boost weak signals while maintaining fast sensory dynamics in a changing environment.

neuroscience↗

bioRxiv2019

Ultrastructure of light-activated axons following optogenetic stimulation to produce late-phase long-term potentiation

Analysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale has proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 in a subset of hippocampal CA3 neurons and used trains of light to induce late-phase long-term potentiation (L-LTP) in area CA1. L-LTP was shown to be specific to the labeled axons by severing CA3 inputs, which prevented back-propagating recruitment of unlabeled axons. Membrane-associated mAPEX2 tolerated microwave-enhanced chemical fixation and drove tyramide signal amplification to deposit Alexa Fluor dyes in the light-activated axons. Subsequent post-embedding immunogold labeling resulted in outstanding ultrastructure and clear distinctions between labeled (activated), and unlabeled axons without obscuring subcellular organelles. The gold-labeled axons in potentiated slices were reconstructed through serial section electron microscopy; presynaptic vesicles and other constituents could be quantified unambiguously. The genetic specification, reliable physiology, and compatibility with established methods for ultrastructural preservation make this an ideal approach to link synapse ultrastructure and function in intact circuits.

neuroscience↗

bioRxiv2017

SArKS: Discovering Gene Expression Regulatory Motifs And Domains By Suffix Array Kernel Smoothing

MotivationWe set out to develop an algorithm that can mine differential gene expression data to identify candidate cell type-specific DNA regulatory sequences. Differential expression is usually quantified as a continuous score--fold-change, test-statistic, p-value--comparing biological classes. Unlike existing approaches, our de novo strategy, termed SArKS, applies nonparametric kernel smoothing to uncover promoter motifs that correlate with elevated differential expression scores. SArKS detects motifs by smoothing sequence scores over sequence similarity. A second round of smoothing over spatial proximity reveals multi-motif domains (MMDs). Discovered motifs can then be merged or extended based on adjacency within MMDs. False positive rates are estimated and controlled by permutation testing.\n\nResultsWe applied SArKS to published gene expression data representing distinct neocortical neuron classes in M. musculus and interneuron developmental states in H. sapiens. When benchmarked against several existing algorithms for correlative motif discovery using a cross-validation procedure, SArKS identified larger motif sets that formed the basis for regression models with higher correlative power.\n\nAvailabilityhttps://github.com/denniscwylie/sarks.\n\nContactdenniswylie@austin.utexas.edu.\n\nSupplementary informationappended to document.

bioinformatics↗