Biology subjects

Witten, D.

Publications and source records attributed to Witten, D..

4 recordsLinked to original sources

bioRxiv2025

Lateral Hypothalamic Glutamate and GABA Neurons Cooperatively Shape Striatum-Wide Dopamine Dynamics During Consumption

The lateral hypothalamic area (LHA) contains GABAergic and glutamatergic neurons that converge on the midbrain dopamine system and exert opposing influences on consummatory feeding behavior. However, the activity dynamics of these populations during consumption and their impact on striatal dopamine release remain poorly understood. Here, we show that LHA GABAergic and glutamatergic neurons independently scale their activity during the consumption of rewarding and aversive solutions while cooperatively regulating dopamine release along the anterior-posterior axis of the striatum in mice. Dopamine release exhibited widespread modulation during consumption, with anterior striatal regions showing stronger representation of solution value and its recent history--an effect dependent on LHA activity. These findings suggest that the LHA acts as a central regulator of striatal dopamine release during consumption, providing a mechanism through which hypothalamic circuits influence motivational and consummatory behaviors.

neuroscience↗

bioRxiv2023

Condition-dependent fitness effects of large synthetic chromosome amplifications

Whole-chromosome aneuploidy and large segmental amplifications can have devastating effects in multicellular organisms, from developmental disorders and miscarriage to cancer. Aneuploidy in single-celled organisms such as yeast also results in proliferative defects and reduced viability. Yet, paradoxically, CNVs are routinely observed in laboratory evolution experiments with microbes grown in stressful conditions. The defects associated with aneuploidy are often attributed to the imbalance of many differentially expressed genes on the affected chromosomes, with many genes each contributing incremental effects. An alternate hypothesis is that a small number of individual genes are large effect drivers of these fitness changes when present in an altered copy number. To test these two views, we have employed a collection of strains bearing large chromosomal amplifications that we previously assayed in nutrient-limited chemostat competitions. In this study, we focus on conditions known to be poorly tolerated by aneuploid yeast--high temperature, treatment with the Hsp90 inhibitor radicicol, and growth in extended stationary phase. To identify potential genes with a large impact on fitness, we fit a piecewise constant model to fitness data across chromosome arms, filtering breakpoints in this model by magnitude to focus on regions with a large impact on fitness in each condition. While fitness generally decreased as the length of the amplification increased, we were able to identify 91 candidate regions that disproportionately impacted fitness when amplified. Consistent with our previous work with this strain collection, nearly all candidate regions were condition specific, with only five regions impacting fitness in multiple conditions.

genetics↗

bioRxiv2020

Inferring spikes from calcium imaging in dopamine neurons

Calcium imaging has led to discoveries about neural correlates of behavior in subcortical neurons, including dopamine (DA) neurons. However, spike inference methods have not been tested in most populations of subcortical neurons. To address this gap, we simultaneously performed calcium imaging and electrophysiology in DA neurons in brain slices, and applied a recently developed spike inference algorithm to the GCaMP fluorescence. This revealed that individual spikes can be inferred accurately in this population. Next, we inferred spikes in vivo from calcium imaging from these neurons during Pavlovian conditioning, as well as during navigation in virtual reality. In both cases, we quantitatively recapitulated previous in vivo electrophysiological observations. Our work provides a validated approach to infer spikes from calcium imaging in DA neurons, and implies that aspects of both tonic and phasic spike patterns can be recovered.

neuroscience↗

bioRxiv2020

Inferring Neural Population Spiking Rate from Wide-Field Calcium Imaging

Wide-field calcium imaging techniques allow recordings of high-resolution neuronal activity across one or more brain regions. However, since the recordings capture light emission generated by the fluorescence of the calcium indicator, the neural activity that drives the calcium changes is masked by the calcium indicator dynamics. Here we develop and evaluate new methods to deconvolve the calcium traces and estimate the underlying neural spiking rate. Our methods take into account both the noise in the recordings and the temporal dynamics of the calcium indicator response. Our first proposal estimates firing rates that are constant over discrete time bins. The size of each time bin depends on the data and is determined dynamically. Our second proposal estimates the rate as a continuous function and is meant for studies that look for slow rate fluctuations rather than abrupt changes. We compare our results with those of two alternative approaches: direct deconvolution using a first differences approach, and the Lucy-Richardson image recovery method, adapted to recover temporal dynamics. We show that our methods outperform competitors on synthetic data as well as on wide-field calcium recordings in which the spikes were recorded in parallel using multi-channel silicon probe.

neuroscience↗