Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens.

Hojin Shin,Hoon-Ki Min,Hyun-U Cho,Sang-Yoon Lee,Dong Pyo Jang,Yoonbae Oh,Kendall H Lee,In Young Kim

doi:10.3389/fnins.2019.01109

Abstract

The Papez circuit, including the fornix white matter bundle, is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression. We previously reported a large-animal study of deep brain stimulation (DBS) in the fornix that found stimulation-induced hemodynamic responses in both the medial limbic and corticolimbic circuits on functional resonance imaging (fMRI) and evoked dopamine responses in the nucleus accumbens (NAc), as measured by fast-scan cyclic voltammetry (FSCV). The effects of DBS on the fornix are challenging to analyze, given its structural complexity and connection to multiple neuronal networks. In this study, we extend our earlier work to a rodent model wherein we characterize regional brain activity changes resulting from fornix stimulation using fludeoxyglucose (18F-FDG) micro positron emission tomography (PET) and monitor neurochemical changes using FSCV with pharmacological confirmation. Both global functional changes and local changes were measured in a rodent model of fornix DBS. Functional brain activity was measured by micro-PET, and the neurochemical changes in local areas were monitored by FSCV. Micro-PET images revealed increased glucose metabolism within the medial limbic and corticolimbic circuits. Neurotransmitter efflux induced by fornix DBS was monitored at NAc by FSCV and identified by specific neurotransmitter reuptake inhibitors. We found a significant increase in the metabolic activity in several key regions of the medial limbic circuits and dopamine efflux in the NAc following fornix stimulation. These results suggest that electrical stimulation of the fornix modulates the activity of brain memory circuits, including the hippocampus and NAc within the dopaminergic pathway.

Highlights

The Papez circuit is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression (Rajmohan and Mohandas, 2007)
In a largeanimal functional magnetic resonance imaging study, we previously demonstrated that fornix deep brain stimulation (DBS) elicits functional interactions between the medial limbic and mesocorticolimbic circuits and partially regulates major excitatory input into and through the nucleus accumbens (NAc) (Ross et al, 2016)
In targeting the fornix, we avoided the medial forebrain bundle, which contains direct dopaminergic fibers from the ventral tegmental area (VTA), and histology confirmed that the stimulation electrode was not in close proximity to the mfb

Summary

Introduction

The Papez circuit is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression (Rajmohan and Mohandas, 2007). In dementia patients, memory decline has been shown to correlate with the dysfunction of intrinsic connectivity between the hippocampus, PFC, and striatum (Greicius et al, 2004; Buckner et al, 2005; Zhou and Seeley, 2014) These findings highlight the importance of studying the interaction between the medial limbic and mesocorticolimbic circuits (Ito et al, 2008; Mikell et al, 2009; Kahn and Shohamy, 2013; Bagot et al, 2015). A clinical trial investigating deep brain stimulation (DBS) of limbic circuitry as a treatment for morbid obesity resulted in unexpected effects on specific memory functions, evoking detailed autobiographical memories, and enhancing performance on associative memory tasks (Hamani et al, 2008) Based on this finding, DBS was applied to the fornix to address the memory dysfunction associated with dementia in a small cohort of patients with Alzheimer’s disease (AD) (Laxton et al, 2010; Fontaine et al, 2013; Holroyd et al, 2015; Lozano et al, 2016; Ponce et al, 2016). The results of the clinical trial were favorable, we do not fully understand the mechanism by which electrically stimulating the fornix bundle affects memory function, nor its broader effects on other circuits with which the fornix bundle interacts (Vann, 2013; Ross et al, 2016)

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