Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway

Ssu-Ju Li; Yu-Chun Lo; Hsin-Yi Tseng; Sheng-Huang Lin; Chao-Hung Kuo; Ting-Chieh Chen; Ching-Wen Chang; Yao-Wen Liang; Yi-Chen Lin; Chih-Yu Wang; Tsai-Yu Cho; Mu-Hua Wang; Ching-Te Chen; You-Yin Chen

doi:10.1016/j.ynstr.2023.100566

Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway

Neurobiol Stress. 2023 Aug 22:26:100566. doi: 10.1016/j.ynstr.2023.100566. eCollection 2023 Sep.

Authors

Ssu-Ju Li¹, Yu-Chun Lo², Hsin-Yi Tseng³, Sheng-Huang Lin^{4

5}, Chao-Hung Kuo⁶, Ting-Chieh Chen¹, Ching-Wen Chang^{1

7}, Yao-Wen Liang¹, Yi-Chen Lin¹, Chih-Yu Wang¹, Tsai-Yu Cho¹, Mu-Hua Wang¹, Ching-Te Chen⁸, You-Yin Chen^{1

2}

Affiliations

¹ Department of Biomedical Engineering, National Yang Ming Chiao Tung University, No.155, Sec. 2, Linong St., Taipei, 112304, Taiwan, ROC.
² The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, No. 250 Wu-Xing St., Taipei, 11031, Taiwan, ROC.
³ The Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 11031, Taiwan, ROC.
⁴ Department of Neurology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 707, Sec. 3, Zhongyang Rd., Hualien, 97002, Taiwan, ROC.
⁵ Department of Neurology, School of Medicine, Tzu Chi University, No. 701, Sec. 3, Zhongyang Rd., Hualien, 97004, Taiwan, ROC.
⁶ Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei, 11217, Taiwan, ROC.
⁷ Institute of Biomedical Sciences, Academia Sinica, No. 128, Sec. 2, Academia Rd., Taipei, 115024, Taiwan.
⁸ Abbott Medical Taiwan Co, 5/F No. 407, Ruei-Guang Rd., Taipei, 11492, Taiwan, ROC.

Abstract

Major depressive disorder (MDD), a common psychiatric condition, adversely affects patients' moods and quality of life. Despite the development of various treatments, many patients with MDD remain vulnerable and inadequately controlled. Since anhedonia is a feature of depression and there is evidence of leading to metabolic disorder, deep brain stimulation (DBS) to the nucleus accumbens (NAc) might be promising in modulating the dopaminergic pathway. To determine whether NAc-DBS alters glucose metabolism via mitochondrial alteration and neurogenesis and whether these changes increase neural plasticity that improves behavioral functions in a chronic social defeat stress (CSDS) mouse model. The Lab-designed MR-compatible neural probes were implanted in the bilateral NAc of C57BL/6 mice with and without CSDS, followed by DBS or sham stimulation. All animals underwent open-field and sucrose preference testing, and brain resting-state functional MRI analysis. Meanwhile, we checked the placement of neural probes in each mouse by T2 images. By confirming the placement location, mice with incorrect probe placement (the negative control group) showed no significant therapeutic effects in behavioral performance and functional connectivity (FC) after receiving electrical stimulation and were excluded from further analysis. Western blotting, seahorse metabolic analysis, and electron microscopy were further applied for the investigation of NAc-DBS. We found NAc-DBS restored emotional deficits in CSDS-subjected mice. Concurrent with behavioral amelioration, the CSDS DBS-on group exhibited enhanced FC in the dopaminergic pathway with increased expression of BDNF- and NeuN-positive cells increased dopamine D1 receptor, dopamine D2 receptors, and TH in the medial prefrontal cortex, NAc, ventral hippocampus, ventral tegmental area, and amygdala. Increased pAMPK/total AMPK and PGC-1α levels, functions of oxidative phosphorylation, and mitochondrial biogenesis were also observed after NAc-DBS treatment. Our findings demonstrate that NAc-DBS can promote BDNF expression, which alters FC and metabolic profile in the dopaminergic pathway, suggesting a potential strategy for ameliorating emotional processes in individuals with MDD.

Keywords: Deep brain stimulation; Depression; Dopaminergic pathway; Functional connectivity (FC); Mitochondrial biogenesis; Nucleus accumbens.