Jaeschke-Angi, L. | Search bioRxiv

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↗