Neuronal Network Activation Induced by Forniceal Deep Brain Stimulation in Mice

Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry mechanisms remain unknown. This study we explored the neural network circuits involved in forniceal DBS treatment. Methods: We used acute forniceal DBS-induced expression of c-Fos, an activity-dependent neuronal marker, to map the brain structures functionally connected to the fornix. We also evaluated the mouse behavior of locomotion, anxiety, and fear memory after acute forniceal DBS treatment. Results: Acute forniceal DBS induces robust activation of multiple structures in the limbic system. DBS-induced neuronal activation extends beyond hippocampal formation and includes brain structures not directly innervated by the fornix. Conclusions: Acute forniceal DBS activates multiple limbic structures associated with emotion and memory. The neural circuits revealed here help elucidate the neural network effect and pave the way for further research on the mechanism by which forniceal DBS induces benefits on cognitive impairments.