Faculty Bibliography

Memory reactivations and replay, widely reported in the hippocampus and cortex across species, have been implicated in memory consolidation, planning, and spatial and skill learning. Technological advances in electrophysiology, calcium imaging, and human neuroimaging techniques have enabled neuroscientists to measure large-scale neural activity with increasing spatiotemporal resolution and have provided opportunities for developing robust analytic methods to identify memory replay. In this article, we first review a large body of historically important and representative memory replay studies from the animal and human literature. We then discuss our current understanding of memory replay functions in learning, planning, and memory consolidation and further discuss the progress in computational modeling that has contributed to these improvements. Next, we review past and present analytic methods for replay analyses and discuss their limitations and challenges. Finally, looking ahead, we discuss some promising analytic methods for detecting nonstereotypical, behaviorally nondecodable structures from large-scale neural recordings. We argue that seamless integration of multisite recordings, real-time replay decoding, and closed-loop manipulation experiments will be essential for delineating the role of memory replay in a wide range of cognitive and motor functions.

We present a descriptive model of choice derived from neuroscientific models of efficient value representation in the brain. Our basic model, a special case of Expected Utility Theory, can capture a number of behaviors predicted by Prospect Theory. It achieves this with only two parameters: a time-indexed "payoff expectation" (reference point) and a free parameter we call "predisposition". A simple extension of the model outside the domain of Expected Utility also captures the Allais Paradox. Our models shed new light on the computational origins and evolution of risk attitudes and aversion to outcomes below reward expectation (reference point). It delivers novel explanations of the endowment effect, the observed heterogeneity in probability weighting functions, and the Allais Paradox, all with fewer parameters and higher descriptive accuracy than Prospect Theory.

The neuromodulator dopamine (DA) is essential for regulating learning, motivation, and movement. Despite its importance, however, the mechanisms by which DA influences the activity of target cells to alter behavior remain poorly understood. In this review, we describe recent methodological advances that are helping to overcome challenges that have historically hindered the field. We discuss how the employment of these methods is shedding light on the complex dynamics of extracellular DA in the brain, as well as how DA signaling alters the electrical, biochemical, and population activity of target neurons in vivo. These developments are generating novel hypotheses about the mechanisms through which DA release modifies behavior.

A recent study has shown that, in the fly Drosophila, olfactory neurons stop signaling when smells get too strong. This changes the way we think about odor encoding across concentrations.

Insects use their antennae to smell odors,¹

It is increasingly important to study the impact of environmental inhalation exposures on human health in natural or man-made disasters in civilian populations. The members of the World Trade Center Environmental Health Center (WTC EHC; WTC Survivors) had complex exposures to environmental disaster from the destruction of WTC towers and can serve to reveal the effects of WTC exposure on the entire spectrum of lung functions. We aimed to investigate the associations between complex WTC exposures and measures of spirometry and oscillometry in WTC Survivors and included 3605 patients enrolled between Oct 1, 2009 and Mar 31, 2018. We performed latent class analysis and identified five latent exposure groups. We applied linear and quantile regressions to estimate the exposure effects on the means and various quantiles of pre-bronchodilator (BD) % predicted forced expiratory volume in one second (FEV₁), forced vital capacity (FVC) and FEV₁/FVC ratio, as well as the resistance at an oscillating frequency of 5 Hz (R₅), frequency dependence of resistance R_5-20, and reactance area (AX). Compared with Group 5, which had low or unknown exposure and was treated as the reference group, Group 1, the local workers with both acute and chronic exposures, had a lower median of % predicted FVC (-3.6; 95% CI: -5.4, -1.7) and higher (more abnormal) measures of AX at 10th quantile (0.77 cmH₂O L^-1 s; 95% CI: 0.41, 1.13) and 25th quantile (0.80 cmH₂O L^-1 s; 95% CI: 0.41, 1.20). Results suggested heterogeneous exposures to the WTC disaster had differential effects on the distributions of lung functions in the WTC Survivors. These findings could provide insights for future investigation of environmental disaster exposures.

In 2016, China launched long-term care insurance (LTCI) pilot programs in 15 cities across the country. In this Commentary, we provide an overview of these pilots regarding the target insured population, sources of financing, beneficiary eligibility criteria, and benefit design. We offer perspectives on the strengths and limitations, implementation challenges, and future prospects of these ongoing pilots. Also, we highlight the needs for addressing several key policy issues and challenges before further expanding these programs toward national implementation. These include solidifying the LTCI financing pool for independence and self-sustainability, balancing national priorities and local needs in LTCI design, reducing coverage gaps and disparities, ensuring quality of care through pay-for-performance and regulatory oversight, and strengthening independent evaluation of LTCI implementation and impacts.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases^1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired⁵. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Animals use information about gravity and other destabilizing forces to balance and navigate through their environment. Measuring how brains respond to these forces requires considerable technical knowledge and/or financial resources. We present a simple alternative: Tilt In Place Microscopy (TIPM). TIPM is a low-cost and non-invasive way to measure neural activity following rapid changes in body orientation. Here we used TIPM to study vestibulospinal neurons in larval zebrafish during and immediately after roll tilts. Vestibulospinal neurons responded with reliable increases in activity that varied as a function of ipsilateral tilt amplitude. TIPM differentiated tonic (i.e. sustained tilt) from phasic responses, revealing coarse topography of stimulus sensitivity in the lateral vestibular nucleus. Neuronal variability across repeated sessions was minor relative to trial-to-trial variability, allowing us to use TIPM for longitudinal studies of the same neurons across two developmental timepoints. There, we observed global increases in response strength, and systematic changes in the neural representation of stimulus direction. Our data extend classical characterization of the body tilt representation by vestibulospinal neurons and establish TIPM's utility to study the neural basis of balance, especially in developing animals.Significance Statement:Vestibular sensation influences everything from navigation to interoception. Here we detail a straightforward, validated and nearly-universal approach to image how the nervous system senses and responds to body tilts. We use our new method to replicate and expand upon past findings of tilt sensing by a conserved population of spinal-projecting vestibular neurons. The simplicity and broad compatibility of our approach will democratize the study of the brain's response to destabilization, particularly across development.