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. 2024 Mar 15:18:1372315.
doi: 10.3389/fnins.2024.1372315. eCollection 2024.

Theta-frequency medial septal nucleus deep brain stimulation increases neurovascular activity in MK-801-treated mice

Lindsey M Crown #  1 , Kofi A Agyeman #  2 , Wooseong Choi #  3 , Nancy Zepeda  3 , Ege Iseri  2 , Pooyan Pahlavan  2 , Steven J Siegel  1 , Charles Liu #  3   4   5   6 , Vasileios Christopoulos #  2   4   7 , Darrin J Lee #  1   2   3   4   5   6
Affiliations

Theta-frequency medial septal nucleus deep brain stimulation increases neurovascular activity in MK-801-treated mice

Lindsey M Crown et al. Front Neurosci. .

Abstract

Introduction: Deep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks.

Methods: 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.

Results: Imaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters [i.e., gamma (100 Hz)].

Discussion: These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation.

Keywords: MK-801; deep brain stimulation; functional ultrasound imaging; hippocampus; medial septal nucleus; schizophrenia; theta.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Experimental setup and fUSI recording protocol. (A) Schematic illustration of connectivity between the MSN and ROIs. Arrowheads represent axonal projections to and/or from MSN. (B) Experimental set-up showing the anesthetized mouse in a stereotaxic frame under the Iconeus One motorized probe mount. DBS stimulating electrodes were implanted on the left hemisphere and a sagittal plane of the right hemisphere was imaged. (C) Diagram of the protocol for the 60 min of continuous fUSI acquisition. After 5 min, saline or 1.0 mg/kg MK-801 was injected. After a total of 45 min of either theta, gamma, or no stimulation was applied for 5 min followed by 10 more minutes of recording.
Figure 2
Figure 2
Example of histological mapping of electrode placement in the MSN. (A) Representative Nissl stain of the mouse brain with lesion indicating the electrode placement (B) Annotation of the MSN from the Allen Reference Atlas shows the MSN in approximately the same position as the lesion in A.
Figure 3
Figure 3
Functional ultrasound imaging of the mouse brain. (A) 3D mouse brain model with fUSI probe positioning (white bar). (B) Power Doppler-based vascular maps in a sagittal plane (max-min normalized relative scale). (C) ROIs – hippocampus (HPF), medial prefrontal cortex (mPFC), hypothalamus (HYT), thalamus (TLM), pallidum (PDM), and striatum (STM), superimposed onto a mean grayscale fUSI vascular map of the sagittal mouse brain.
Figure 4
Figure 4
pD signal change (i.e., ΔCBV) in ROIs prior to stimulation onset in saline- and MK-801-treated animals. Curves show for (A) hippocampus, (B) hypothalamus, (C) mPFC, (D) pallidum, (E) striatum, and (F) thalamus after saline (blue) and 1.0 mg/kg MK-801 (red) injection. The radar chart shows that MK-801-induced decreases in CBV in all ROIs more than saline over the last 2 min (38–40 min post injection).
Figure 5
Figure 5
DBS effects on pD signal during and post stimulation onset in saline-treated animals. (A–F) Temporal course (theta [orange], gamma [blue], no-stimulation [black]) of mean pD signal change (i.e., ΔCBV) relative to baseline for the (A) hippocampus, (B) hypothalamus, (C) mPFC, (D) pallidum, (E) striatum, and (F) thalamus regions in the saline-treated animals. (G,H) Radar charts illustrate the mean %pD change during and post stimulation for theta-, gamma-, and no-stimulation animals in the ROIs investigated. Means were calculated using the last 2 min of pD signals acquired during (3rd – 5th minute after stimulation offset) and post (8th – 10th minute after stimulation offset) stimulation, respectively, across animals in each stimulation category.
Figure 6
Figure 6
DBS effects on pD signal during and post stimulation onset in MK-801 treated mice. (A–F) Temporal course [theta (red), gamma (blue), no-stimulation (black)] of mean pD signal change (i.e., ΔCBV) relative to baseline for (A) hippocampus, (B) hypothalamus, (C) mPFC, (D) pallidum, (E) striatum, and (F) thalamus regions in the MK-801 drug injected mice. (G,H) Radar charts present the mean percentage ΔCBVs during and after stimulation for theta [red], gamma [blue], and no-stimulation [dark gray] animals in the ROIs investigated. Means were calculated utilizing the last 2 min of pD signal during and post stimulation.
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