Mora, S. A. R. | Search bioRxiv

bioRxiv2025

A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is unknown. We developed a novel mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS) - the first rapid-acting rTMS antidepressant protocol - reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projecting neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. Similarly, aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Finally, chemogenetic inhibition of dmPFC IT neurons during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.

neuroscience↗

bioRxiv2024

A developmental brain-wide screen identifies retrosplenial cortex as a key player in the emergence of persistent memory

Memories formed early in life are short-lived while those formed later persist. Recent work revealed that infant memories are stored in a latent state. But why they fail to be retrieved is poorly understood. Here we investigated brain-wide circuit mechanisms underlying infantile amnesia. We performed a screen that combined contextual fear conditioning, activity-dependent neuronal tagging at different postnatal ages, tissue clearing and light sheet microscopy. We observed striking developmental changes in regional activity patterns between infant, juvenile, and adult mice, including changes in the retrosplenial cortex (RSP) that aligned with the emergence of persistent memory. We then performed a series of targeted investigations of RSP structure and function across development. Chronic chemogenetic reactivation of tagged RSP ensembles during the week after learning enhanced memory in adults and juveniles, but not in infants. However, after 33 days, reactivating infant-tagged RSP ensembles recovered forgotten memories. Changes in the developmental functions of RSP memory ensembles were accompanied by changes in dendritic spine density and the likelihood that those ensembles could be reactivated by contextual cues. These studies show that RSP ensembles store latent infant memories, reveal the time course of RSP functional maturation, and suggest that immature RSP functional networks contribute to infantile amnesia.

neuroscience↗