Frequency- and circuit- specific effects of septohippocampal deep brain stimulation in mice as measured by functional ultrasound imaging

Deep brain stimulation (DBS) has shown remarkable success in treating neurological and psychiatric disorders such as Parkinson’s disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. Despite this success, the underlying mechanism of action remains unknown. DBS is now being explored as a means to improve cognition and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e. schizophrenia). While most DBS treatments for movement disorders require continuous stimulation, there is evidence that intermittent stimulation in cognitive and psychiatric conditions may have persisting effects beyond the period of stimulation. This suggests that the effects of DBS on brain activity last beyond the time of its acute electrical effects, necessitating a broader exploration of how neuromodulation alters brain networks. In this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice. Imaging from a sagittal plane across a variety of brain regions, we find that MSN theta-frequency (7.7Hz) DBS had a larger effect on hippocampal cerebral blood volume (CBV) after stimulation offset. This was observed following an intraperitoneal (i.p.) injection of either saline vehicle or MK-801 (1 mg/kg). This effect was not present using standard high frequency DBS stimulation parameters (i.e. gamma [100Hz]). These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in manner that continues beyond the period of electrical stimulation. Significance Statement Deep brain stimulation (DBS) is a well-established treatment for neurological and neuropsychiatric diseases, yet it’s mechanism of action remains unknown. We recently demonstrated that medial septal nucleus (MSN) DBS improves spatial memory in rodents treated with the NMDA antagonist MK-801, a drug known to mimic cognitive impairment in schizophrenia. Here we utilize functional ultrasound imaging (fUSI) in mice to visualize the effects of MSN DBS on cerebral blood volume (CBV) following saline or MK-801 administration. We find that theta frequency-specific (7.7Hz) MSN DBS restored MK-801-induced CBV reductions within the septohippocampal circuit (i.e., hippocampus) after stimulation offset. These results demonstrate that MSN stimulation drives circuit-specific neurovascular activity and may ultimately improve cognitive function in diseases with NMDA hypofunction, such as schizophrenia. ### Competing Interest Statement The authors have declared no competing interest.