Biology subjects

Bush, N. E.

Publications and source records attributed to Bush, N. E..

7 recordsLinked to original sources

bioRxiv2025

An inspiration-off attractor supports the robust and flexible control of breathing

Breathing is a fundamental motor rhythm necessary to sustain life. The rhythm and pattern of breathing arises from the coordination of a bilaterally symmetric, rostro-caudally extended column of heterogeneous neural populations in the medulla called the Ventral Respiratory Column (VRC). By recording from the extent of the VRC using Neuropixels during optogenetic and physiological manipulations, and projecting the population activity into a dynamical latent space, we find that GABAergic lung-stretch feedback circuits promote rhythmic population activity by creating a temporary stable fixed point in the latent state that terminates diaphragmatic contraction. Stimulation of GABAergic circuits either intrinsic to the VRC (VRCGABA) or via afferent pathways from GABAergic neurons of the Nucleus of the Solitary Tract (NTSGABA) advance or delay breathing when activated with specific respiratory phase through temporary stabilization of this fixed point. Lastly, we show that activation of glutamatergic signaling opposes the effects of inhibitory signaling by destabilizing this expiratory fixed point to promote rapid inspiration. Together, we decompose the functional impact of different respiratory control subpopulations to reveal an integrated network level mechanism for respiratory control in vivo.

neuroscience↗

bioRxiv2025

Biomechanical simplification of the motor control of whisking

1.Animal nervous systems must coordinate the sequence and timing of numerous muscles - a challenging control problem. The challenge is particularly acute for highly mobile sensing structures with many degrees of freedom, such as eyes, pinnae, hands, forepaws, and whiskers, because these low-mass, distal sensors require complex muscle coordination. This work examines how the geometry of the rat whisker array simplifies coordination required for "whisking" behavior 1-3. During whisking, 33 intrinsic ("sling") muscles are the primary drivers 4-12 of the rapid, rhythmic protractions of the large mystacial vibrissae (whiskers), which vary more than sixfold in length and threefold in base diameter 13-16. Although whisking is a rhythmic, centrally-patterned behavior 17-24, rodents can change the position, shape, and size of the whisker array, indicating considerable voluntary control 25-34. To begin quantifying how the arrays biomechanics contribute to whisking movements, we used three-dimensional anatomical reconstructions of follicle and sling muscle geometry to simulate the movement resulting from a "uniform motor command," defined as equal firing rates across all sling muscle motor neurons. This simulation provides a baseline profile of protraction under anatomically realistic but uniformly driven conditions. It does not isolate neural from biomechanical contributions but helps identify deviations that suggest active control. Simulations reveal that all follicles rotate through approximately equal angles, regardless of size. The angular fanning of the whiskers at their bases increases monotonically throughout protraction, while maximum distance between whisker tips occurs at approximately 90% of resting muscle length, after which whisker tips converge and sensing resolution increases monotonically.

neuroscience↗

bioRxiv2023

Modeling effects of variable preBötzinger Complex network topology and cellular properties on opioid-induced respiratory depression and recovery

The pre-Botzinger complex (preBotC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBotC to perform several in silico experiments exploring how differences in network topology and the intrinsic properties of preBotC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBotC networks in silico exhibit variable responses to simulated opioids, similar to the preBotC network in vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBotC network that may regulate its susceptibility to opioids. Significance StatementThe neural network in the brainstem that generates the breathing rhythm is disrupted by opioid drugs. However, this response can be surprisingly unpredictable. By constructing computational models of this rhythm-generating network, we illustrate how random differences in the distribution of biophysical properties and connectivity patterns within individual networks can predict their response to opioids, and we show how modulation of these network features can make breathing more susceptible or resistant to the effects of opioids.

neuroscience↗

bioRxiv2022

Latent neural population dynamics underlying normal breathing, opioid induced respiratory depression, and gasping

Breathing is vital and must be concurrently robust and flexible. This rhythmic behavior is generated and maintained within a rostro-caudally aligned set of medullary nuclei called the Ventral Respiratory Column (VRC). The rhythmic properties of individual VRC nuclei are well known, yet technical challenges have limited the interrogation of the entire VRC population simultaneously. Here, we characterize over 13,000 VRC units using high-density electrophysiology, opto-tagging, and histological reconstruction. Population dynamics analysis reveals interactions between inspiratory and expiratory dynamical states give rise to a low-dimensional, elliptical neural manifold. The structure of this manifold is robust and maintained even during opioid-induced respiratory depression (OIRD). However, during severe hypoxia-induced gasping, the low-dimensional dynamics of the VRC reconfigure from rotational to all-or-none, ballistic efforts.

neuroscience↗

bioRxiv2021

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm generating network

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the -opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBotzinger Complex (preB[o]tC). To unravel the cellular- and network-level consequences of MOR activation in the preBotC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBotC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act together to make the normally robust inspiratory-rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

neuroscience↗

bioRxiv2019

Continuous, multidimensional coding of 3D complex tactile stimuli by primary sensory neurons of the vibrissal system

To reveal the full representational capabilities of sensory neurons, it is essential to observe their responses to complex stimuli. In the rodent vibrissal system, mechanical information at the whisker base drives responses of primary sensory neurons in the trigeminal ganglion (Vg). Studies of how Vg neurons encode stimulus properties are typically limited to 2D analyses and restricted stimulus sets. Here we record from Vg neurons during 3D stimulation while quantifying the complete 3D whisker shape and mechanics. Results show that individual Vg neurons simultaneously represent multiple mechanical features of the stimulus, do not preferentially encode principal components of the stimuli, and represent continuous and tiled variations of all available mechanical information. As a population, the neurons span a continuum of rapid and slow adaptation properties; a binary distinction between these adaptation classes is oversimplified. These results contrast with proposed codes in which Vg neurons segregate into functional classes.

neuroscience↗

bioRxiv2019

WHISKiT Physics: A three-dimensional mechanical model of the rat vibrissal array

Rodents tactually explore the environment using ~62 whiskers (vibrissae), regularly arranged in arrays on both sides of the face. The rat vibrissal system is one of the most commonly used models to study how the brain encodes and processes somatosensory information. To date, however, researchers have been unable to quantify the mechanosensory input at the base of each whisker, because the field lacks accurate models of three-dimensional whisker dynamics. To close this gap, we developed WHISKiT Physics, a simulation framework that incorporates realistic morphology of the full rat whisker array to predict time-varying mechanical signals for all whiskers. The dynamics of single whiskers were optimized based on experimental data, and then validated against free tip oscillations and the dynamic response to collision. The model is then extrapolated to include all whiskers in the array, taking into account each whiskers individual geometry. Simulations of first mode resonances across the array approximately match previous experimental results and fall well within the range expected from biological variability. Finally, we use WHISKiT Physics to simulate mechanical signals across the array during three distinct behavioral conditions: passive whisker stimulation, active whisking against two pegs, and active whisking in a natural environment. The results demonstrate that the simulation system can be used to predict input signals during a variety of behaviors, something that would be difficult or impossible in the biological animal. In all behavioral conditions, interactions between array morphology and individual whisker geometry shape the tactile input to the whisker system.

neuroscience↗