Biology subjects

Leifer, A. M.

Publications and source records attributed to Leifer, A. M..

7 recordsLinked to original sources

bioRxiv2025

Synaptic and neural pathway redundancy enables the robustness of a sensory-motor reflex and promotes predation escape in C. elegans

As a basic unit of the nervous system, the sensory-motor reflex circuit is fast and robust. However, it is not entirely clear how this robustness is achieved, given that various genetic perturbations can disrupt the function of the sensory neurons. By mapping the molecular basis of neuronal connections in the touch response circuit of Caenorhabditis elegans, we found prevalent genetic redundancy at neural pathway, synaptic, and molecular levels, which ensures that sensory signals can be relayed to command interneurons that control motor output. We also discovered developmental remodeling of the anterior circuit, which leads to the pruning of larval synapses, establishment of a second pathway that activates additional interneurons, and lateralization of the circuit. Finally, we found that the synapses that appeared to be functionally redundant in a simple touch assay contribute to the extent of reversal response in an additive manner, which may help the organism escape from predators.

neuroscience↗

bioRxiv2025

High-speed whole-brain imaging in Drosophila

Recent advances in brain-wide recordings of small animals such as worms, fish, and flies have revealed complex activity involving large populations of neurons. In the Drosophila brain, with about 140,000 neurons, brain-wide recordings have been critical to uncovering widespread sensory and motor activity. However, current limitations in volumetric imaging rates hinder the accurate capture of fast neural dynamics. To improve the speed of volumetric imaging in Drosophila, we leverage the recently introduced light beads microscopy (LBM) method. We built a microscope and a LBM module tailored to fly brain experiments and used it to record brain-wide calcium signals in adult behaving flies at either 28 volumes per second or at 60 volumes per second (when selecting the central brain alone). We uncover fast-timescale auditory responses that are missed with standard volumetric imaging. We also demonstrate how temporal super-resolution can be combined with LBM data to uncover responses to single Drosophila courtship song pulses. This establishes LBM as a viable tool for capturing whole-brain activity at high spatial and temporal resolution in the fly.

neuroscience↗

bioRxiv2025

Functional Interrogation of Neuronal Subtypes via Intersectional Expression of Optogenetic Actuator Reveals Non-linear Components in a Linear Circuit

Investigating signal integration in a neural circuit is oftentimes challenging when the circuit contains neuronal subtypes that are transcriptomically similar, due to the lack of tools to express optogenetic actuators with high cellular specificity and to deliver light with high spatiotemporal accuracy. Here, we demonstrate the use of a split GAL4-based genetic "AND" gate to express Chrimson in specific touch receptor neuron (TRN) subtypes in the C. elegans touch response circuit. Combining this intersectional strategy for transgene expression with high-throughput optical targeting and behavioral quantification, we optogenetically interrogated the role of each TRN subtype in mediating the mechanosensor-induced escape response and in integrating signals that trigger the opposite motor output. Surprisingly, we found that although the response of the overall circuit linearly combines the competing anterior and posterior stimuli, this linearity is comprised of antagonistic non-linear contributions from the anterior and posterior sensors, which conspire to generate a linear response.

neuroscience↗

bioRxiv2024

A Blueprint of Sex-Specific Neuronal Regulation in the C. elegans Nervous System at Single-Cell Resolution

Sex-specific behaviors are often attributed to differences in neuronal wiring and molecular composition, yet how genetic sex shapes the molecular architecture of the nervous system at the individual neuron level remains unclear. Here, we use single-cell RNA sequencing to profile the transcriptome of sex-shared neurons in adult Caenorhabditis elegans males and hermaphrodites. We uncover widespread molecular dimorphism across the nervous system, including in previously unrecognized neuron-types such as the touch receptors. Neuropeptides and signaling-related genes exhibit strong sex-biased expression, particularly in males, reinforcing the notion that neuropeptides are crucial for diversifying connectome outputs. Despite these differences, neurotransmitter identities remain largely conserved, indicating that functional dimorphism arises through modulatory, not identity-defining, changes. We show that sex-biased expression of neurotransmitter-related genes correlates with bias in outgoing synaptic connectivity and identify regulatory candidates for synaptic wiring, including both shared and sex-specific genes. This dataset provides a molecular framework for understanding how subtle regulatory differences tune conserved circuits to drive sex-specific behaviors.

neuroscience↗

bioRxiv2024

Bridging the gap between the connectome and whole-brain activity in C. elegans

A fundamental goal of neuroscience is to understand how anatomy determines the functional properties of the nervous system. However, previous work has failed to show how the functional connections between neurons are derived from the connectome in the nematode C. elegans, raising questions about the extent to which anatomy is informative of signaling1-3. Here, we address this problem using a connectome-constrained dynamical model of the brain, which we fit to whole-brain recordings of neural activity during optogenetic perturbation of single neurons2. This dynamical model, which contains non-zero weights only between anatomically connected neurons, captured causal interactions between all pairs of neurons 82% as well as the reproducibility of the perturbation data themselves. This included interactions between anatomically unconnected neurons, which the model accounted for in terms of signal propagation over paths that include multiple neurons. Strikingly, alternative models fit using a shuffled connectome achieved much lower performance. Finally, we found that adding connections beyond those in the connectome did not improve the models ability to capture causal interactions. Our dynamical model thus provides a link between the connectivity of the C. elegans nervous system and its causal interactions and provides a blueprint for exploring the link between structure and function in other organisms.

neuroscience↗

bioRxiv2024

An inhibitory acetylcholine receptor gates context dependent mechanosensory processing in C. elegans

An animals current behavior influences its response to sensory stimuli, but the molecular and circuit-level mechanisms of this context-dependent decision-making is not well understood. In the nematode C. elegans, inhibitory feedback from turning associated neurons alter downstream mechanosensory processing to gate the animals response to stimuli depending on whether the animal is turning or moving forward [1-3]. Until now, the specific neurons and receptors that mediate this inhibitory feedback were not known. We use genetic manipulations, single-cell rescue experiments and high-throughput closed-loop optogenetic perturbations during behavior to reveal the specific neuron and receptor responsible for receiving inhibition and altering sensorimotor processing. An inhibitory acetylcholine gated chloride channel comprised of lgc-47 and acc-1 expressed in neuron RIM receives inhibitory signals from turning neurons and performs the gating that disrupts the worms mechanosensory evoked reversal response.

neuroscience↗

bioRxiv2023

TWISP: A Transgenic Worm for Interrogating Signal Propagation in C. elegans

Genetically encoded optical indicators and actuators of neural activity allow for all-optical investigations of signaling in the nervous system. But commonly used indicators, actuators and expression strategies are poorly suited for systematic measurements of signal propagation at brain scale and cellular resolution. Large scale measurements of the brain require indicators and actuators with compatible excitation spectra to avoid optical crosstalk. They must be highly expressed in every neuron but at the same time avoid lethality and permit the animal to reach adulthood. And finally, their expression must be compatible with additional fluorescent labels to locate and identify neurons, such as those in the NeuroPAL cell identification system. We present TWISP, a Transgenic Worm for Interrogating Signal Propagation, that address these needs and enables optical measurements of evoked calcium activity at brain scale and cellular resolution in the nervous system of the nematode Caenorhabditis elegans. We express in every neuron a non-conventional optical actuator, the gustatory receptor homolog GUR-3+PRDX-2 under the control of a drug-inducible system QF+hGR, and calcium indicator GCAMP6s, in a background with additional fluorophores of the NeuroPAL cell ID system. We show that this combination, but not others tested, avoids optical-crosstalk, creates strong expression in the adult, and generates stable transgenic lines for systematic measurements of signal propagation in the worm brain.

neuroscience↗