Biology subjects

Todd, A.

Publications and source records attributed to Todd, A..

10 recordsLinked to original sources

bioRxiv2026

Spatial segregation and multi-scale space-use adjustments to socio-ecological variables in western gorillas

Background: Identifying the mechanisms that shape space-use dynamics and the scale at which they operate can provide insights into the socio-ecology of numerous animal species. This is crucial for addressing both applied (e.g., conservation) and theoretical questions (e.g., the coexistence or segregation of individuals). Yet, longitudinal views of the space-use dynamics are generally rare. Taking advantage of a long-term movement dataset (up to 8 years) on five habituated groups of wild western gorillas (Gorilla gorilla) in Central Africa, we investigated the dynamics of their space use in relation to the socio-ecological variables from everyday movement to home range shifts. Methods: We looked at which temporal scale their ranging movements are stationary to highlight the dynamics of home range settling and shifts. We also studied how daily space use is shaped by (i) foraging and intra-group constraints (i.e., diet, group size, presence of offspring), and by (ii) inter-group competition (direct or indirect), quantifying static and dynamic interactions in neighbouring group-dyads. Results: Gorilla groups shifted the centre of their home range 0.17 times per year by a distance larger than the mean home range radius. Movements within the home range were highly dependent on the group composition and the ecological features (with larger daily-travelled distances in the high-fruit season compared to the low-fruit season). The presence of dependent infants affected the daily-travel distance: the larger their number, the smaller the daily-travel distance. Furthermore, the frequently visited sites of the home range were also used the longest, but their locations differed seasonally, suggesting space use flexibility. Although there was little overlap between the home ranges of neighbouring groups, these groups did not seem to avoid each other more than expected at random. They could even venture into, and slept in, the central part of the home range of a neighbouring group. Conclusion: Our study suggests that spatial segregation should be the simple consequence of avoidance of depleted areas rather than of territorial behaviour. It shows how socio-ecological constraints may shape the space-use patterns at different scales in a non-territorial species, and questions the role of cognition in space-use dynamics.

ecology↗

bioRxiv2026

Neurons in the lateral spinal nucleus give rise to the spinotectal component of the anterolateral system in the mouse

The anterolateral system (ALS) originates from neurons in various regions of the spinal cord and conveys somatosensory information related to pain, skin temperature and itch to several brain targets. One component of the ALS is the spinotectal tract, which projects to the superior colliculus (SC) and is thought to underlie directed movements of the head towards a painful stimulus. Using anterograde and retrograde tracing, we demonstrate that the input from the spinal enlargements to the SC originates predominantly from neurons in the lateral spinal nucleus (LSN), many of which express calbindin. This input, which mainly targets the caudal and lateral parts of the SC, is somatotopically organised, and is associated with the clusters of Pitx2-expressing neurons that have been identified in previous studies. Since activation of Pitx2 neurons drives directed head movements, input from LSN neurons to the Pitx2 cells is likely to be a critical component of orientation and attention towards a noxious stimuli. We also provide evidence that spinotectal LSN cells receive excitatory synaptic input from neurons in superficial dorsal horn that express substance P or the gastrin-releasing peptide receptor (GRPR). Since GRPR neurons are strongly implicated in itch, our findings raise the possibility that the SC has a role in coordinating movements in response to pruritic stimuli.

neuroscience↗

bioRxiv2026

Chronic lower limb pain is not associated with a loss of inhibitory neurons in the human lumbar spinal dorsal horn

The spinal dorsal horn is the primary processing site of nociceptive sensory input from the periphery. Excitatory spinal interneurons releasing glutamate can amplify this information before it is sent to the brain, whereas inhibitory neurons releasing GABA and/or glycine can suppress the outflow of nociceptive signals. An imbalance favoring excitation is thought to underlie certain aspects of chronic pain. Although rodent studies have identified spinal mechanisms underlying hyperalgesia and allodynia, little is known about the anatomical changes associated with chronic pain in the human spinal cord, a gap in knowledge we sought to address in this study. Using immunohistochemistry and in situ hybridization on lumbar spinal cord tissue recovered from organ donors, we characterized neuronal size and density across the human dorsal horn and confirmed the presence of the human equivalent of the lateral spinal nucleus in many individuals. Chronic lower limb pain was not associated with changes in neuronal density in the dorsal horn. Likewise, the ratio of excitatory (SLC17A6+) to inhibitory (PAX2+) neurons remained consistent across laminae for age, sex and chronic pain state, providing no evidence for selective loss of inhibitory neurons with chronic pain in humans. We found no differences in the size or density of the postsynaptic markers Homer1 and gephyrin between groups, suggesting glutamatergic and GABAergic postsynaptic sites remain structurally stable. These findings provide a thorough evaluation of cellular anatomy of the human dorsal horn and form a foundation for future studies investigating neuronal changes that may contribute to chronic pain in humans.

neuroscience↗

bioRxiv2025

Ultra-high-field fMRI reveals layer-specific responses in the human spinal cord

Developments in functional magnetic resonance imaging (fMRI) at ultra-high field (UHF) now allow for insights into human brain function at mesoscopic scale. However, similar progress has not been achieved for the human spinal cord, despite its importance for reciprocal brain-body communication. Here, we therefore integrate substantial methodological improvements that enable previously unattainable high-resolution UHF spinal fMRI. Using a heat-pain paradigm in healthy volunteers, we investigate fMRI responses in the dorsal horn: we characterize their spatial pattern, establish their robustness and demonstrate that they can be reliably observed even for individual participants. Most importantly, we uncover two physiologically relevant spinal response components - phasic and tonic heat responses - that map differentially onto superficial and deep layers of the dorsal horn. Taken together, our novel UHF fMRI approach allows for differentiating responses across fundamental spinal processing units and will enable insights into human spinal cord function at mesoscopic scale in health and disease.

neuroscience↗

bioRxiv2025

Glutamatergic and GABAergic synapses in the human spinal dorsal horn revealed with immunohistochemistry

Primary afferent neurons detect sensory stimuli in the periphery and transmit this information to the dorsal horn of the spinal cord, where it is extensively processed by excitatory and inhibitory spinal controls before being sent to higher brain centres. Immunohistochemical analysis of the synaptic architecture of these spinal circuits has been notoriously difficult in formaldehyde-fixed tissue and often requires antigen retrieval techniques to reveal antigen binding epitopes. To avoid the damage this harsh treatment can induce, studies have used antibodies raised against scaffolding proteins Homer1 and gephyrin, which anchor glutamate and GABA receptors to the membrane, respectively, to identify synaptic associations in rodent spinal cord underlying pain and itch transmission. In contrast, few studies have attempted to visualise spinal cord synapses in the human, partly due to a lack of high-quality tissue with low postmortem intervals. In this study, we reveal both excitatory and inhibitory synapses at a high resolution in human lumbar spinal cord tissue using antibodies to Homer1 and gephyrin and show that the basic organisation of these proteins within the dorsal horn is similar to that seen in the rodent. We show these postsynaptic markers are highly colocalised with glutamate and GABA receptor subunits and are in close apposition to presynaptic markers, confirming their specificity. Finally, we use Homer1-immunolabelling to demonstrate that primary afferents can form complex synaptic arrangements in human. We conclude that these antibodies can be used as reliable tools for the study of the human CNS and we have used them to reveal insight into the microanatomy of somatosensory connections in the human spinal cord that can be expanded upon in future studies.

neuroscience↗

bioRxiv2025

Expression of Tacr1 and Gpr83 by spinal projection neurons

Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that [~]60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that [~]90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1CreERT2 and Gpr83CreERT2 mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that [~]90% of ALS neurons in SDH express Tacr1, with 40-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.

neuroscience↗

bioRxiv2025

Mineralocorticoid Receptor Antagonism Reduces Atrial Arrhythmias Post-Cardiac Surgery and Attenuates Atrial Stress Responses to Cardioplegic Arrest

BackgroundNew postoperative atrial fibrillation (POAF) occurs in about 40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We examined the impact of preoperative MRA use on POAF and also examine the atrial cell type impacted by MRA treatment during cold cardiac preservation. MethodsRetrospective study of 19,042 patients who underwent cardiac surgery at Mayo Clinic in Minnesota, and performed 1:3 propensity matching to obtain 298 patients on preoperative MRA matched to 894 who were not. We also separately matched patients using preoperative diuretics. Single-nuclei RNA sequencing (snRNA-seq) examined MRAs effects on different atrial cell types in canrenone (water soluble MRA) treated human donor hearts undergoing cold preservation followed by ex-vivo reperfusion and compared gene expression to the atria of patients with AF. ResultsPropensity matched preoperative MRA group had less new onset POAF (19.8% vs 31.5%, P<0.001). To account for the possibility that preoperative diuretic use and volume reduction may impact POAF, we propensity matched 298 preop diuretic users that included MRA use to another 894 patients who used a non-MRA diuretic preoperatively. Those who used preoperative MRA similarly had a lower incidence of POAF (19.8% vs 33.2%, P<0.001). No survival difference was present between the propensity matched groups that used preoperative diuretics (P=0.079). Preoperative MRA use also reduced the development of paroxysmal and chronic AF at 6 years of follow up. From our snRNA-seq data, we identified a subpopulation of atrial cardiomyocytes (CM2) that had high MR expression where canrenone suppressed the increase in MR target gene expression associated with cold preservation-reperfusion. These MR targets were conversely elevated in patients with chronic AF. Canrenone also suppressed other cardiac preservation associated genes that show elevated expression in atrial macrophages and pericytes from chronic AF atria. ConclusionsOur studies show that preoperative MRA use is associated with 40% reduction in POAF as well as lowering long standing AF development by about 41%. Our cold cadiac preservation-reperfusion model showed that canrenone reduced expression of MR target genes associated with chronic AF, particular in cardiomyocytes with important roles in electrical conduction. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study shows that preoperative use of mineralocorticoid receptors antagonists (MRA) is associated with a reduced incidence of new onset perioperative atrial fibrillation after cardiac surgery utilizing cardiopulmonary bypass. C_LIO_LIWe show that preoperative MRA use is associated with a lower incidence of developing more chronic paroxymal or sustained atrial fibrillation. C_LIO_LIAddition of canrenone, a clinically utilized water soluble MRA, to cardioplegia solution used during cardiac preservation can attenuate atrial inflammatory reponses and reduce signaling through molecular pathways that promote atrial fibrillation. C_LI What are the clinical implications?O_LIPerioperative use of MRAs may be considered to reduce early postoperative atrial fibrillation as well as lowering the risk of developing more chronic atrial arrhythmias. C_LIO_LIThese findings support pursuing a clinical trial to determine the impact of MRA use on atrial arrhythmias following cardiac surgery in the setting of cardiopulmonary bypass with cold cardiac preservation. C_LI

molecular biology↗

bioRxiv2024

Equity in Action: A Four-Year journey towards Gender Parity and Racial Diversity in Biochemistry Hiring

Recruitment of faculty members in academic departments shapes the department for decades in both research and teaching arenas. Having a diverse department is beneficial for undergraduate and graduate students as representation of underrepresented minority groups in the professoriate can inspire a greater diversity of students to pursue higher levels of education or research-focused careers. Increased diversity benefits research directly as diverse teams have been shown to have better ideas and outcomes. In 2020, our department had lower gender diversity than would be expected based on the pool of PhD students and post-doctoral fellows in Canada. Therefore, we altered our hiring process, primarily by redacting applications, for recruitment into entry-level tenure-track faculty positions. With this change in process, female hires increased from 17% in the previous ten years (5 hires) to 80% in the subsequent four years (5 hires) with no substantial change in hiring of racially diverse individuals (50% to 40%). Overall, combined with retirements, the percentage of female faculty in the department went from 25% to 50% and the percentage of racialized faculty went from 38% to 44%. The new hires have met or exceeded expectations of success with respect to grant funding and are on track to meet or exceed expectations for other metrics of success. Thus, our intervention was very successful in increasing the diversity of our department within a short timeframe. We believe that our experience could provide other departments with a template for making substantive change, even in the absence of internal expertise in the area. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/617211v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@164c310org.highwire.dtl.DTLVardef@42585borg.highwire.dtl.DTLVardef@1b6f6eaorg.highwire.dtl.DTLVardef@10ca067_HPS_FORMAT_FIGEXP M_FIG C_FIG

scientific communication and education↗

bioRxiv2023

Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify 3 clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 & ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons. Significance StatementThe anterolateral system (ALS) is a major ascending pathway from the spinal cord that underlies perception of pain, itch and skin temperature. It is therefore an important target for the development of new treatments for chronic pain. Our understanding of this system has been hampered by the considerable diversity of its constituent cells. Here we dissect the complex heterogeneity of these cells by using high-resolution RNA sequencing. We reveal five distinct types of ALS neurons, which are differentially distributed within the spinal cord, and probably represent functional populations. Our data provide novel insights into the molecular architecture of the ALS, and will be important for future studies to define the roles of different ALS cell types in sensory processing.

neuroscience↗

bioRxiv2020

Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells

Diabetic patients taking metformin have lower risk for Mycobacterium tuberculosis (Mtb) infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence. However, a detailed mechanistic understanding of metformins protective immunological benefits on host resistance to TB is lacking. In this study, using mass cytometry we show that metformin treatment expands memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy and diabetic humans. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from CXCR3-/- mice did not exhibit metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhanced immunogenicity and protective efficacy against Mtb challenge. Collectively, our results demonstrate an important role of CD8+ T cells in metformin-derived host metabolic-fitness towards Mtb infection.

immunology↗