bioRxiv Science⌕ Search

Biology subjects

Schinder, A. F.

Publications and source records attributed to Schinder, A. F..

3 recordsLinked to original sources

The dentate gyrus provides flexibility for efficient spatial navigation

The hippocampus plays a critical role in spatial navigation and declarative memory. The dentate gyrus is the neurogenic region of the hippocampal formation and it has long been implicated in the fine separation of similar contexts or close object locations. However, it is unclear how an accurate discrimination could be beneficial to a goal-guided behavior in a changing environment. Therefore, we used chemogenetic inhibition to study the role of the dentate gyrus in a goal-guided spatial navigation paradigm over a familiar but dynamic crossword maze. Mice were challenged to localize a novel reward location from alternative pathways in two versions of the task with particular configurations in each experimental day. In the simple task, the two optimal paths to the goal shared some segments in their trajectory. In a more complex task, optimal trajectories demanded completely different directions to the reward location. Overall, mice with chemogenetic inhibition of the dentate gyrus were able to learn all the routes regardless the complexity of the task, similarly to control animals. However, after having solved a first route in the complex task, mice with dentate gyrus inhibition displayed an impairment to efficiently navigate over the alternate path. Our results demonstrate a role of the dentate gyrus in cognitive flexibility required to reach a goal in a changing familiar environment.

animal behavior and cognition↗

Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus

The adult hippocampus generates new granule cells (aGCs) that exhibit distinct functional capabilities along development, conveying a unique form of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like neural stem cells (RGL) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to follow newborn aGCs along differentiation using single-nuclei RNA sequencing (snRNA-seq). Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple sequential immature stages bearing increasing levels of effector genes supporting growth, excitability and synaptogenesis. Remarkably, four discrete cellular states were defined by the expression of distinct sets of transcription factors (TFs): quiescent neural stem cells, proliferative progenitors, postmitotic immature aGCs, and mature aGCs. The transition from immature to mature aCGs involved a transcriptional switch that shutdown molecular cascades promoting cell growth, such as the SoxC family of TFs, to activate programs controlling neuronal homeostasis. Indeed, aGCs overexpressing Sox4 or Sox11 remained stalled at the immature state. Our results unveil precise molecular mechanisms driving adult neural stem cells through the pathway of neuronal differentiation.

neuroscience↗

Unique potential of immature adult-born neurons for the remodeling of CA3 spatial maps

Mammalian hippocampal circuits undergo extensive remodeling through adult neurogenesis. While this process has been widely studied, the specific contribution of adult-born granule cells (aGCs) to spatial operations in the hippocampus remains unknown. Here we show that optogenetic activation of 4-week-old (young) aGCs in free-foraging mice produces a non- reversible reconfiguration of spatial maps in proximal CA3, while rarely evoking neural activity. Stimulation of the same neuronal cohort on subsequent days recruits CA3 neurons with increased efficacy but fails to induce further remapping. In contrast, stimulation of 8- week-old (mature) aGCs can reliably activate CA3 cells but produce no alterations in spatial maps. Our results reveal a unique role of young aGCs in remodeling CA3 representations, a potential that can be depleted and is lost with maturation. This ability could contribute to generate orthogonalized downstream codes supporting pattern separation.

neuroscience↗