Biology subjects

Ralston, J. D.

Publications and source records attributed to Ralston, J. D..

6 recordsLinked to original sources

bioRxiv2026

Divergent co-transmission by a predictive motor circuit modulates auditory processing.

During behavior, an animals movements often stimulate its own sensory receptors. For instance, whether during flight or the production of courtship song, when flies beat their wings they cause mechanosensory disturbances that activate primary auditory neurons in the antennae. However, flight and courtship occur under very different behavioral contexts and temporal-scales. As a consequence, the nervous system contains predictive motor circuits that modify sensory processing in anticipation of self-induced (re-afferent) stimulation. However, it is unclear how information about planned movements can be used to effectively tune specialized sensory processing circuits. Here we describe a predictive motor circuit that releases two transmitters to differentially modify auditory neurons that process sound under different behavioral contexts. In Drosophila, two metathoracic ascending histamine neurons (MtAHNs) become active prior to wing movement and project to the primary auditory network. We found that the MtAHNs co-transmit the neuropeptide Dh44 and histamine, and each suppresses the activity of auditory neurons that are integrated into distinct networks that support escape and courtship, respectively. Additionally, Dh44 has a greater impact on male auditory neurons and suppression by Dh44 occurs over a longer time course than histamine. Disrupting either histamine synthesis or neuropeptide release by the MtAHNs reduces courtship success with an increase in cessation during the wing extension step. Consistent with a role in auditory processing of courtship cues, Dh44 cotransmission is present in Drosophila species that have an auditory component to their courtship displays, but is absent in species that use either purely visual courtship or lack apparent courtship behavior. Finally, the projections of the MtAHNs into auditory centers were missing in snow flies, which are wingless. Our results indicate that divergent cotransmission by predictive motor circuits may represent an efficient means to differentially modulate sensory subnetworks impacted by reafferent feedback.

neuroscience↗

bioRxiv2025

Connectivity of serotonin neurons reveals a constrained inhibitory subnetwork within the olfactory system.

Inhibitory local interneurons (LNs) play an essential role in sensory processing by refining stimulus representations via a diverse collection of mechanisms. The morphological and physiological traits of individual LN types, as well as their connectivity within sensory networks, enable each LN type to support different computations such as lateral inhibition or gain control and are therefore ideal targets for modulatory neurons to have widespread impacts on network activity. In this study, we combined detailed connectivity analyses, serotonin receptor expression, neurophysiology, and computational modeling to demonstrate the functional impact of serotonin on a constrained LN network in the olfactory system of Drosophila. This subnetwork is composed of three LN types and we describe each of their distinctive morphology, connectivity, biophysical properties and odor response properties. We demonstrate that each LN type expresses different combinations of serotonin receptors and that serotonin differentially impacts the excitability of each LN type. Finally, by applying these serotonin induced changes in excitability to a computational model that simulates the impact of inhibition exerted by each LN-type, we predict a role for serotonin in adjusting the dynamic range of antennal lobe output neurons and in noise reduction in odor representations. Thus, a single modulatory system can differentially impact LN types that subserve distinct roles within the olfactory system. Significance StatementInhibitory interneurons refine information processing within sensory networks by enforcing distinct local computations. They are therefore ideal targets for modulatory neurons to efficiently alter sensory processing by up- or downregulating the computations each interneuron class subserves. We identify an interconnected network of three interneuron types in the olfactory system of Drosophila that receive a large amount of serotonergic synaptic input. Each interneuron type differs in their biophysical and response properties and serotonin differentially impacts their excitability. Finally, using a computational model, we predict that the combined effects of serotonin on these inhibitory neurons enables noise reduction in the olfactory system. Thus, modulation of individual cell types collectively adjusts distinct network computations to enable flexible sensory coding.

neuroscience↗

bioRxiv2024

Free water elimination tractometry for aging brains

Tractometry of diffusion-weighted magnetic resonance imaging (dMRI) non-invasively quantifies tissue properties of brain connections. It is widely used in aging studies but could be less reliable in aging brains due to increased white matter free water. We demonstrate that computational free water elimination (FWE) increases reliability and accuracy of tractometry in a large (n = 339) cohort of older adults (66 - 103 y.o.). We found substantial (up to [~]37%) improvements in reliability in a split-half comparison at every stage of the pipeline: estimation of voxel-level fiber orientation distribution functions, delineation of major pathway trajectories, and assessment of tissue properties along the pathways. FWE also improves inferences from tractometry, producing more accurate cross-validated predictions of clinician Fazekas scores. By sub-sampling a multi-b-value dataset, we demonstrated that these findings generalize to both single-b-value data, which is important for many datasets where only one b-value may be available. Overall, the results highlight the importance of accounting for free water in tractometry studies, especially in aging brains. We provide opensource software for free-water elimination that can be applied to a wide range of clinical and research datasets (https://github.com/nrdg/fwe).

neuroscience↗

bioRxiv2023

Stimulus-Specific Modulation is Enabled by Differential Serotonin Receptor Expression

Neural networks must be able to flexibly process information under different conditions. To this end, networks frequently rely on uniform expression of modulatory receptors by distinct classes of neurons to fine tune the computations supported by each neuronal class. In this study, we explore the consequences of heterogeneous, rather than uniform, serotonin (5-HT) receptor expression within a cell class for olfactory processing in Drosophila melanogaster. Here, we demonstrate that two distinct populations of olfactory output neurons (projection neurons, PNs) display heterogeneous receptor co-expression of all 5-HT receptors. Moreover, the PN populations that express distinct 5-HT receptors innervate different combinations of glomeruli, implying that the effects of 5-HT on these PNs may vary with their odor tuning. Furthermore, connectomic analyses reveal that PN subsets with different receptor profiles have little convergence upon downstream synaptic partners. Finally, 5-HT differentially modulates the odor-evoked responses of PNs with distinct receptor expression profiles and odor tuning. Overall, this implies that heterogeneous modulatory receptor expression enables differential tuning of activity within a neuronal class depending on the odor scene to which individual neurons respond.

neuroscience↗

bioRxiv2023

Organization of an Ascending Circuit that Conveys Flight Motor State

Natural behaviors are a coordinated symphony of motor acts which drive self-induced or reafferent sensory activation. Single sensors only signal presence and magnitude of a sensory cue; they cannot disambiguate exafferent (externally-induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to make appropriate decisions and initiate adaptive behavioral outcomes. This is mediated by predictive motor signaling mechanisms, which emanate from motor control pathways to sensory processing pathways, but how predictive motor signaling circuits function at the cellular and synaptic level is poorly understood. We use a variety of techniques, including connectomics from both male and female electron microscopy volumes, transcriptomics, neuroanatomical, physiological and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs), which putatively provide predictive motor signals to several sensory and motor neuropil. Both AHN pairs receive input primarily from an overlapping population of descending neurons, many of which drive wing motor output. The two AHN pairs target almost exclusively non-overlapping downstream neural networks including those that process visual, auditory and mechanosensory information as well as networks coordinating wing, haltere, and leg motor output. These results support the conclusion that the AHN pairs multi-task, integrating a large amount of common input, then tile their output in the brain, providing predictive motor signals to non-overlapping sensory networks affecting motor control both directly and indirectly.

neuroscience↗

bioRxiv2021

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

The recent rise in mutational variants of SARS-CoV-2, especially with changes in the Spike protein, is of significant concern due to the potential ability for these mutations to increase viral infectivity, virulence and/or ability to escape protective antibodies. Here, we investigated genetic variations in a 414-583 amino acid region of the Spike protein, partially encompassing the ACE2 receptor-binding domain (RBD), across a subset of 570 nasopharyngeal samples isolated between April 2020 and February 2021, from Washington, California, Arizona, Colorado, Minnesota and Illinois. We found that samples isolated since November have an increased number of amino acid mutations in the region, with L452R being the dominant mutation. This mutation is associated with a recently discovered CAL.20C viral variant from clade 20C, lineage B.1.429, that since November-December 2020 is associated with multiple outbreaks and is undergoing massive expansion across California. In some samples, however, we found a distinct L452R-carrying variant of the virus that, upon detailed analysis of the GISAID database genomes, is also circulating primarily in California, but emerged even more recently. The newly identified variant derives from the clade 20A (lineage B.1.232) and is named CAL.20A. We also found that the SARS-CoV-2 strain that caused the only recorded case of infection in an ape - gorillas in the San Diego Zoo, reported in January 2021 - is CAL.20A. In contrast to CAL.20C that carries two additional to L452R mutations in the Spike protein, L452R is the only mutation found in CAL.20A. According to the phylogenetic analysis, however, emergence of CAL.20C was also specifically triggered by acquisition of the L452R mutation. Further analysis of GISAID-deposited genomes revealed that several independent L452R-carrying lineages have recently emerged across the globe, with over 90% of the isolates reported between December 2020 - February 2021. Taken together, these results indicate that the L452R mutation alone is of significant adaptive value to SARS-CoV-2 and, apparently, the positive selection for this mutation became particularly strong only recently, possibly reflecting viral adaptation to the containment measures or increasing population immunity. While the functional impact of L452R has not yet been extensively evaluated, leucine-452 is positioned in the receptor-binding motif of RBD, in the interface of direct contact with the ACE2 receptor. Its replacement with arginine is predicted to result in both a much stronger binding to the receptor and escape from neutralizing antibodies. If true, this in turn might lead to significantly increased infectivity of the L452R variants, warranting their close surveillance and in-depth functional studies.

microbiology↗