Biology subjects

Rodger, J.

Publications and source records attributed to Rodger, J..

12 recordsLinked to original sources

bioRxiv2026

Chronic subthreshold intermittent theta burst stimulation promotes structural axon initial segment plasticity in cortical neurons

Repetitive transcranial magnetic stimulation (rTMS) is used widely in neuroscience to study and alter neural plasticity. The cellular mechanisms underlying the effect of rTMS on the brain remain unclear but is primarily thought to act via activity-dependent synaptic plasticity mechanisms. Here we investigated whether chronic repetitive magnetic stimulation in vitro and in vivo can induce another form of activity-dependent neural plasticity, axon initial segment (AIS) plasticity. Cortical neurons isolated from postnatal wild-type mice were stimulated with 6 hours of sham, repetitive magnetic stimulation in the form of intermittent theta-burst stimulation (iTBS), or 15 mM potassium chloride, with changes to AIS location and length measured +0 hours and +24 hours post-stimulation. In addition, adult transgenic mice expressing green fluorescent protein at the AIS received daily sham or iTBS over the primary motor cortices for 7 consecutive days and processed for microscopy 3 hours after the last stimulation. Analysis of neurons stimulated in vitro showed that chronic iTBS caused bidirectional and time-dependent shifts to the AIS position relative to the soma and a delayed shortening of the AIS length at +24 hours. In the adult mice, 7 consecutive days of daily iTBS decreased AIS lengths in layers 2/3 and 5 pyramidal neurons. Our findings provide in vitro and in vivo evidence that rTMS induces neuronal plasticity outside of the synapse, which may contribute to the long-lasting effect of rTMS on the brain with repeated stimulation protocols.

neuroscience↗

bioRxiv2026

Sex-Dependent Effects of Chronic Stress During Adolescence on Cognitive Bias and Functional Connectome in Young Adult Rats

Negative cognitive biases in depression are more pronounced in females than in males. This sex difference emerges during adolescence, a sensitive developmental stage when chronic stress exposure increases the risk of depression in adulthood. Neuroimaging studies in adult depression suggest that sex differences in negative bias are associated with aberrant functional connectivity. However, the neurobiology linking adolescent stress to sex-specific cognitive bias and resting-state network reorganization in adults remains poorly understood. The study aimed to investigate the longitudinal effects of chronic restraint stress (CRS) during adolescence on cognitive bias and functional connectome in emerging adulthood. 28 Wistar rats (sex-balanced; aged five weeks on arrival) were trained on a judgment bias task with distinct tactile cues signaling differential rewards. Bias was quantified from responses to ambiguous probe trials. Following training, animals were randomly and equally assigned to CRS or control groups (sex-balanced). Offline resting-state functional MRI scans were conducted at adolescent baseline (pre-CRS) and again in adulthood (post-CRS), followed by probe trials to assess neural and behavioral changes. Behaviors were analyzed using linear mixed-effects models, and network connectivity was assessed using Network-Based R-Statistics. Both behavioral and network analyses identified sex-dependent differences in change from baseline to post-CRS. Specifically, females showed a greater tendency toward negative bias than males. Network analysis suggested female-specific reorganization within a subnetwork, spanning brainstem, limbic, striatal, insula, parahippocampal, orbitofrontal, and retrosplenial regions. These results highlight the translational importance of considering sex and distributed network organization when modelling how adolescent stress may shape later vulnerability to depression.

animal behavior and cognition↗

bioRxiv2025

Identifying Neuroimaging Biomarkers of Resilience and Vulnerability to Chronic Stress in An Animal Model: An Exploratory Analysis

Stress is a main contributor to mood disorders, with individuals displaying great heterogeneity in response to stressful life events and adversity. Identifying biomarkers of vulnerability and resilience to stress would facilitate a prevention-based approach to mental illness that benefits individuals and reduces healthcare costs. The present study adopted a multivariate machine-learning approach to track neuroimaging biomarkers predictive of resilience and vulnerability following a chronic restraint stress (CRS) model. 96 male Sprague-Dawley rats underwent two sessions of MRI and behavioral tests, before and after CRS. Resilience and vulnerability to CRS were assessed with elevated plus maze and forced swimming tests. Hierarchical clustering was applied to construct brain networks. Partial correlation was used to compute network connectivity. Repeated nested cross validation with a support vector machine was employed to identify rs-fMRI biomarkers predictive of resilience and vulnerability following CRS. No strong group effect size of behavioral changes following CRS was observed within the same animals, suggesting the presence of resilient and vulnerable subgroups. Although the average model performance was modest (area under the receiver operating characteristic curve: 0.3 ~ 0.67), baseline functional connectivity across cerebellum, brainstem, striatum, prefrontal and salience-orbitofrontal regions, as well as functional alteration across hippocampus, striatum, prefrontal regions, auditory thalamus, cerebellum, inferior colliculi and brainstem were identified as stable features. The present study is the first to identify connectome-based neuroimaging biomarkers predictive of resilience and vulnerability using an animal model. The results may provide insights into neuroimaging biomarkers to aid diagnosis and prevention of mood disorders in humans.

neuroscience↗

bioRxiv2024

Translational modelling of low and medium intensity transcranial magnetic stimulation from rodents to humans

BackgroundRodent models using subthreshold intensities of transcranial magnetic stimulation (TMS) have provided insight into the biological mechanisms of TMS but often differ from human studies in the intensity of the electric field (E-field) induced in the brain. ObjectiveTo develop a finite element method model as a guide for translation between low and medium intensity TMS rodent studies and high intensity TMS studies in humans. MethodsFEM models using three head models (mouse, rat, and human), and eight TMS coils were developed to simulate the magnetic flux density (B-field) and E-field values induced by three intensities. ResultsIn the mouse brain, maximum B-fields ranged from 0.00675 T to 0.936 T and maximum E-field of 0.231 V/m to 60.40 V/m E-field. In the rat brains maximum B-fields ranged from of 0.00696 T to 0.567 T and maximum E-fields of 0.144 V/m to 97.2 V/m. In the human brain, the S90 Standard coil could be used to induce a maximum B-field of 0.643 T and E-field of 241 V/m, while the MC-B70 coil induced 0.564 T B-field and 220 V/m E-field. ConclusionsWe have developed a novel FEM modelling tool that can help guide the replication of rodent studies using low intensity E-fields to human studies using commercial TMS coils. Modelling limitations include lack of data on dielectric values and CSF volumes for rodents and simplification of tissue geometry impacting E-field distribution, methods for mitigating these issues are discussed. A range of additional cross-species factors affecting the translation of E-fields were identified that will aid TMS E-field modelling in both humans and rodents. We present data that describes to what extent translation of brain region-specific E-field values from rodents to humans is possible and detail requirements for future improvement. A graphical abstract of the translational modelling pipeline from this study is provided below (Figure A.1). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/591424v1_figA1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@5aa978org.highwire.dtl.DTLVardef@2c2128org.highwire.dtl.DTLVardef@13507c1org.highwire.dtl.DTLVardef@9044d6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure A.1:C_FLOATNO A translational modelling pipeline describing the use of structural imaging data for FEM modelling purposes and the comparison of brain region-specific rodent and human LI-rTMS E-field values. C_FIG HighlightsO_LIClinical translation of rodent TMS studies is challenging due to the differences in coil and brain size and shape between rodents and humans. C_LIO_LIWe have built a FEM model for the accurate replication of TMS-derived E-fields validated in rodent models in multiple brain regions in humans. C_LIO_LIThis model is useful in designing stimulation parameters for humans based on rodent studies. C_LIO_LIThis model is a critical part of a translational pipeline for evidence based TMS. C_LI

neuroscience↗

bioRxiv2024

Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfr-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Multiple consecutive daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre- existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing [~]471{micro}m more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs and increased the number of surviving OLs that contributed to remyelination in the corpus callosum (CC). As LI-rTMS can non-invasively promote remyelination by modifying the behaviour of new and surviving OLs, it may be suitable as an adjunct intervention to enhance remyelination in people with MS.

neuroscience↗

bioRxiv2022

Dissecting the functional contributions of different neuronal subtypes in the dorsal striatum to perseverative behaviour in ephrin-A2/A5-/- mice

Overreliance on habit is linked with disorders such as drug addiction and obsessive-compulsive disorder and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and reduce relapse or accelerated shift towards habit formation. Here we studied the brains of ephrin-A2A5-/- mice, which previously showed perseverative behaviour in progressive-ratio tasks, associated with low cellular activity in nucleus accumbens. We investigated if rTMS treatment had altered the hierarchical recruitment of brain regions from ventral to dorsal striatum associated with abnormal habit formation in these mice. Brain sections of mice that underwent progressive-ratio tasks with and without low intensity rTMS (LI-rTMS) were taken from a previous study. We take advantage of the previous characterisation of perseverative behaviour to investigate the contribution of different neuronal subtypes and striatal regions. Striatal regions were stained for neuronal activation with c-Fos and for medium spiny neurons with DARPP32. Qualitative analysis was carried out for other neuronal subtypes in the striatum - GABAergic, parvalbumin-expressing and cholinergic interneurons. Contrary to our hypothesis, we found neuronal activity in ephrin-A2A5-/- mice still reflected goal-directed behaviour. However, we saw that the dorsolateral striatum contributed more to total striatal activity in untreated ephrin-A2/A5-/- mice. This supported our hypothesis that ephrin-A2/A5-/- mice have greater c-Fos activity in habit-associated striatal regions. LI-rTMS in ephrin-A2A5-/- mice also appeared to delay the shift from goal-directed to habitual behaviour as suggested by increased activation in dorsomedial striatum and nucleus accumbens.

neuroscience↗

bioRxiv2022

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated activity

BackgroundRepetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS; however, the influence of sub-action potential threshold (low-intensity; LI-) rTMS on neuronal activity is largely unknown. HypothesisWe investigated whether LI-rTMS modulates neuronal activity and functional connectivity. We also specifically assessed modulation of parvalbumin interneuron activity. MethodsWe conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos/parvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. ResultsLI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. ConclusionLI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation. Highlights- Low-intensity rTMS increases brain-wide anti-correlated functional connectivity - Acute excitatory LI-rTMS modulates cortical and subcortical neuronal activity - Decreased parvalbumin interneuron activity may promote anti-correlated activity - Striatum and amygdala show prominent modulation with LI-rTMS

neuroscience↗

bioRxiv2022

Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that can alter neural activity and induce neural plasticity that outlasts the period of stimulation. While SMS is typically delivered for short periods (e.g., 10 minutes) to alter corticospinal excitability or motor behaviours, the plasticity mechanisms that can be induced with longer periods of stimulation have not been explored. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity as a homeostatic mechanism to counteract chronic changes in neuronal activity. Therefore, we investigated whether the chronic application of SMS would induce structural AIS plasticity in cortical neurons. SMS (0.5 Tesla in intensity) was delivered to postnatally derived mouse primary cortical neurons consisting of mainly inhibitory neurons, for 6 or 48 hours beginning from 7 days in vitro (DIV7). AIS structural plasticity (length and starting distance from the soma) was quantified immediately after and 24 hours post-stimulation. Following 6 hours of stimulation, we observed an immediate decrease in median AIS length compared to control, that persisted to 24 hours post stimulation. In addition, there was a distal shift in the AIS start position relative to the soma that was only observed 24 hours after the 6-hour stimulation. Following 48 hours of stimulation, we observed an immediate shortening of AIS length and a distal shift in AIS start position relative to the soma, however only the distal shift in AIS start position persisted to 24 hours post-stimulation. Our findings provide the foundation to expand the use of SMS to more chronic applications as a method to study or promote AIS plasticity non-invasively.

neuroscience↗

bioRxiv2022

Magnetic Temporal Interference for Noninvasive Focal Brain Stimulation

Non-invasive stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has a poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference of two high-frequency magnetic fields generated by two electromagnetic solenoids. To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems.

bioengineering↗

bioRxiv2021

Low intensity repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 Tesla), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. ObjectiveTo assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. MethodsLongitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). ResultsWe found strong evidence (BF>10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. ConclusionThese findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

neuroscience↗

bioRxiv2020

Validation of chronic restraint stress model in rats for the study of depression using longitudinal multimodal MR imaging

Prior research suggests that the neurobiological underpinnings of depression include disruptions in functional connectivity, neurometabolite levels, and hippocampal volume. This study examined the validity of a chronic restraint stress (CRS) paradigm in male Sprague Dawley rats for the study of depression using longitudinal behavioural tests and multiple 9.4 T MRI modalities (resting-state functional MRI, proton magnetic resonance spectroscopy, and volumetric studies). In the CRS protocol, rats were placed in individual transparent tubes for 2.5 h daily over 13 days. Elevated plus-maze test (EPM) and forced swim test (FST) confirmed the presence of anxiety-like and depression-like behaviours respectively post-restraint. Brain changes were also detected by MR. The rs-fMRI data revealed hypoconnectivity within the salience and interoceptive networks and hyperconnectivity of several brain regions to the cingulate cortex. The 1H-MRS data revealed decreased sensorimotor cortical glutamate, glutamine and combined glutamate-glutamine levels. Volumetric analysis of T2-weighted images revealed decreased hippocampal volume, which was also correlated with salience network connectivity. Depression-like behaviours were correlated with salience and interoceptive network connectivity, glutamate and combined glutamate-glutamine levels and hippocampal volume. Anxiety-like behaviours were correlated with both hippocampus connectivity and interoceptive network connectivity. The present findings identify significant changes in brain connectivity, neurometabolites and structure that are correlated with abnormal behaviour in CRS rats. Importantly, these changes parallel those found in human depression, suggesting that the CRS rodent model has utility for translational studies and novel intervention development for depression.

neuroscience↗

bioRxiv2019

Myelin and nodal plasticity modulate action potential conduction in the adult mouse brain

Central nervous system myelination increases action potential conduction velocity, however, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials, and facilitate information processing within cortical and associative circuits. Here, we show that mature myelin remains plastic in the adult mouse brain and can undergo subtle structural modifications to influence action potential arrival times. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and tunes conduction velocity to increase the synchronicity of action potential transit.

neuroscience↗