Biology subjects

Totty, M.

Publications and source records attributed to Totty, M..

5 recordsLinked to original sources

bioRxiv2026

Cortistatin neurons in the prelimbic cortex regulate seizure susceptibility in female mice via BDNF-TrkB signaling

The risk of developing psychiatric disorders, particularly stress-related disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), is increased threefold in patients with epilepsy. While this increased risk may arise as a consequence of living with epilepsy, shared neurobiological mechanisms, particularly dysregulation of GABAergic signaling, may also contribute. To investigate this link, we investigated the function of GABAergic neurons co-expressing the neuropeptide cortistatin (CST), which has anticonvulsant effects and is implicated in both MDD and PTSD. Targeting CST+ neurons in the prelimbic cortex (PrL), a rodent brain region that is functionally and anatomically similar to the human dorsal anterior cingulate cortex (dACC), we found that ablating CST+ neurons disrupts context-dependent fear renewal, causes spontaneous convulsive seizures, dramatically increases susceptibility to chemically-induced seizures, and increases anxiety-like phenotypes following stressors. We further show that repeated chemogenetic inhibition of CST+ neurons increases the rate of seizure kindling in female mice, and that disruption of brain derived neurotrophic factor signaling in CST+ neurons phenocopies the effects of acute inhibition. These data support the hypothesis that epilepsy and stress-related psychiatric disorders potentially share common neurobiological mechanisms, and that loss of CST+ neuron function may be a critical feature underlying fear dysregulation and cortical hyperexcitability. HighlightsO_LILoss of prelimbic CST+ neurons disrupts fear renewal, causes anxiety-like symptoms, and induces spontaneous seizures. C_LIO_LIInhibition of prelimbic CST+ by chemogenetics or BDNF inhibition by TrkB increases seizure susceptibility in females only. C_LIO_LICST+ neurons represent a subset of primarily SST and PVALB expressing GABAergic neurons. C_LI

neuroscience↗

bioRxiv2025

Orchestrating Spatial Transcriptomics Analysis with Bioconductor

Spatial transcriptomics technologies provide spatially-resolved measurements of gene expression through assays that can either target selected genes or capture transcriptome-wide expression profiles. The complexity and variability of these technologies and their associated data necessitate multi-step workflows integrating diverse computational methods and software packages. We provide a freely accessible, open-source, continuously updated and tested online book containing reproducible code examples, datasets, and discussion about data analysis workflows for spatial omics data using Bioconductor in R, including interoperability with Python.

bioinformatics↗

bioRxiv2025

Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord

Spinal cord injury (SCI) results in significant neurological deficits, with no currently available curative therapies. Neural progenitor cell (NPC) transplantation has emerged as a promising approach for neural repair, as graft-derived neurons (GDNs) can integrate into the host spinal cord and support axon regeneration. However, the mechanisms underlying functional recovery remain poorly understood. In this study, we investigate the synaptic integration of NPC-derived neurons into locomotor circuits, the projection patterns of distinct neuronal subtypes, and their potential to modulate motor circuit activity. Using transsynaptic tracing in a mouse thoracic contusion SCI model, we found that NPC-derived neurons form synaptic connections with host locomotor circuits, albeit at low frequencies. Furthermore, we mapped the axon projections of V0C and V2a interneurons, revealing distinct termination patterns within host spinal cord laminae. To assess functional integration, we employed chemogenetic activation of GDNs, which induced muscle activity in a subset of transplanted animals. However, NPC transplantation alone did not significantly improve locomotor recovery, highlighting a key challenge in the field. Our findings suggest that while GDNs can integrate into host circuits and modulate motor activity, synaptic connectivity remains a limiting factor in functional recovery. Future studies should focus on enhancing graft-host connectivity and optimizing transplantation strategies to maximize therapeutic benefits for SCI.

neuroscience↗

bioRxiv2025

Associative coding of conditioned fear in the thalamic nucleus reuniens in rodents and humans

The nucleus reuniens (RE) is a midline thalamic structure interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Recent work in both rodents and humans implicates the RE in the adaptive regulation of emotional memories, including the suppression of learned fear. However, the neural correlates of aversive learning in the RE of rodents and humans remains unclear. To address this, we recorded RE activity in humans (BOLD fMRI) and rats (fiber photometry) during Pavlovian fear conditioning and extinction. In both rats and humans, we found that conditioned stimulus (CS)-evoked activity in RE reflects the associative value of the CS. In rats, we additionally found that spontaneous neural activity in RE tracks defensive freezing and shows anticipatory increases in calcium activity that precede the termination of freezing behavior. Single-unit recordings in rats confirmed that individual RE neurons index both the associative value of the CS and defensive behavior transitions. Moreover, distinct neuronal ensembles in the RE encode fear versus extinction memories. These findings suggest a conserved role of the RE across species in modulating defensive states and emotional memory processes, providing a foundation for future translational research on fear-related disorders.

neuroscience↗

bioRxiv2022

Sex differences in the immediate extinction deficit and renewal of extinguished fear in rats

Extinction learning is central to exposure-based behavioral therapies for reducing fear and anxiety in humans. However, patients with fear and anxiety disorders are often resistant to extinction. Moreover, trauma and stress-related disorders are highly prone to relapse and are twice as likely to occur in females compared to males, suggesting that females may be more susceptible to extinction deficits and fear relapse phenomena. In this report, we tested this hypothesis by examining sex differences in a stress-induced extinction learning impairment, the immediate extinction deficit (IED), and renewal, a common form of fear relapse. In contrast to our hypothesis, there were no sex differences in the magnitude of the immediate extinction deficit in two different rat strains (Long-Evans and Wistar). However, we did observe a sex difference in the renewal of fear when the extinguished conditioned stimulus was presented outside the extinction context. Male Wistar rats exhibited significantly greater renewal than female rats, a sex difference that has previously been reported after appetitive extinction. Collectively, these data reveal that stress-induced extinction impairments are similar in male and female rats, though the context-dependence of extinction is more pronounced in males.

animal behavior and cognition↗