Ting-Chieh Chen1, Yu-Chun Lo2, Szu-Yi Chou2, Ssu-Ju Li1, Ting-Chun Lin1, Ching-Wen Chang1, Yin-Chieh Liu1, Hsin-Tzu Lu1, and You-Yin Chen1,2
1Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan, 2Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
Synopsis
Cognitive
dysfunctions were demonstrated to be associated with the metabolic syndrome
(MetS), which could be treated with deep brain stimulation (DBS) of nucleus
accumbens (NAc) by altering brain circuitss and facilitating synapse plasticity.
However, NAc-DBS for memory-related cognitive function has yet to be
investigated. Diffusion MRI, resting-state
functional MRI, and behavioral test were applied in this study. We found restoration
of the microstructure, increased functional connectivity, and an improvement in
cognitive behaviors after NAc-DBS in the MetS models, C-C motif ligand
5/Regulated-on-Activation-Normal-T-cell-Expressed-and-Secreted knockout mice.
Introduction
Cognitive
dysfunctions were associated with the metabolic syndrome (MetS)1. MetS and altered
mitochondria dynamics were correlated with the neurodegenerative progresses2. The dopaminergic
pathways were sensitive to glucose metabolism in the whole brain3, which was mainly
composed of the mesolimbic and the mesocortical pathways4. The mesolimbic pathway
transmitted dopamine from the ventral tegmental area (VTA) to the limbic system
via the nucleus accumbens (NAc), integrating the signals from limbic and
cortical regions5. Besides, the
mesocortical pathway transmitted dopamine from the VTA to the downstream
regions, the prefrontal cortex (PFC)5. NAc was responsible
for cognitive functions, including reward functions, executive functions, and
long-term memory6-8 , and played a crucial role
in the dopaminergic system. Deep brain stimulation (DBS) targeting NAc demonstrated
increased dopamine efflux with antidepressant-like behavior by altering
mitochondrial function in the energy metabolism9. However, NAc-DBS for
memory-related cognitive function has yet to be investigated. In this study, we
applied NAc-DBS treatment, resting-state functional MRI (rsfMRI), diffusion tensor imaging
(DTI), and behavioral test to the C-C motif ligand 5 (CCL5)/Regulated-on-Activation-Normal-T-cell-Expressed-and-Secreted
(RANTES) knockout (KO) mice, the MetS model10. We hypothesized that
DBS of the NAc may restore the functional connectivity (FC) and the white
matter (WM) integrity at dopaminergic pathways, which thereby improves
cognitive functions.Methods
Male
adult C57BL/6 mice, which were used as healthy controls, and male adult CCL5/RANTES
KO mice (Jackson Laboratory Inc.; MGI:2180195; Bar Harbor, ME, USA) (weight 25
± 5 g), which were used as MetS models in the study, were housed in the animal
facility under 12:12-h light/dark cycle with controlled temperature at 22 ±
2°C. To investigate the NAc-DBS therapeutic effect on the MetS mice, the
animals were divided into three groups: (1) healthy controls (N = 5) (2) CCL5/RANTES KO sham controls
(N = 5) (3) CCL5/RANTES KO DBS group
(N = 5). All mice were implanted with
MR-compatible neural probes into the bilateral NAc (AP: + 1.1 mm, ML: ± 1.1 mm,
DV: − 4.0 mm) in week 10. The bilateral NAc-DBS (frequency:130 Hz; pulse width
60 μs; intensity 200 μA) was applied consecutively for 30 minutes to
CCL5/RANTES KO DBS group per day in week 13 (Figure 1). Novel object recognition (NOR) test was conducted to
evaluate long-term recognition memory in week 12 (pre-DBS) and week 13
(post-DBS), respectively11, and a preference index
(PI) was calculated as the memory performance. Whole brain images were acquired
from a 7 Tesla Bruker MRI scanner (Bruker Biospec 70/30 USR, Ettlingen,
Germany) in week 14. The rsfMRIs were acquired using gradient-echo planar
imaging (GE-EPI) sequence (TR / TE = 2,000 / 20 ms, FOV = 20 × 20 mm2,
matrix size = 80 × 80, bandwidth = 200 kHz, 14 coronal slices, and thickness =
0.5 mm). DTIs were acquired by the DTI EPI Spin-Echo sequence (TR / TE = 3750 /
0.4 ms, FOV = 20 × 20 mm2, matrix size = 50 × 50). Regions of
interest (ROIs) were selected according to the Allen mouse brain atlas12, including medial
prefrontal cortex (mPFC), NAc, hippocampus (HIPP), and VTA (Figure 2A). FC was calculated through the FMRIB Software Library
v5.0 (FSL 5.0; http://www.fmrib.ox.ac.uk/fsl) and the analysis of functional
neuroimages (AFNI) software (http://afni.nimh.nih.gov/afni), then normalized to
the baseline (healthy controls). DTI analysis was performed by DSI Studio
(http://dsi-studio.labsolver.org), and the fractional anisotropy (FA) values
were averaged within each ROI. For the visualization of FC, significant
connections were identified by using a one sample t test (FDR-corrected p < 0.05 thresholds with the minimum
cluster size of 200 voxels). The Kruskal-Wallis test (p < 0.05) was conducted to compare FC values, FA values and the
PI of NOR among the three groups. A post-hoc analysis with Dunn’s test (p < 0.05) was performed to elucidate
the within-group difference. Results
A
week after the CCL5/RANTES KO mice received NAc-DBS, increased FC was observed
in the VTA and in downstream region among mPFC, NAc and HIPP (Figure 2B & 2C). FA values in the HIPP and
VTA also exhibited significant increase in the CCL5/RANTES KO DBS group compared
to the sham controls (Figure 3).
Moreover, PI in CCL5/RANTES KO DBS group was increased to the baseline,
suggesting that NAc-DBS could ameliorate the cognitive impairment in
CCL5/RANTES KO mice (Figure 4).Discussion
FC between the dopaminergic pathways was
enhanced after NAc-DBS in the CCL5/RANTES KO mice. Dopamine neurons played a
fundamental role in motivational and memory processes for the ability to
modulate synaptic transmission and plasticity13,
14. Additionally,
decreased FA values were assumed to result from degradation in myelinated
fibers14. Therefore,
cognitive abnormality was restored to the baseline after NAc-DBS in the
CCL5/RANTES KO mice due to increased FC and FA values in dopaminergic regions
and HIPP.Conclusion
The
findings implied that NAc-DBS could alter the WM in the dopaminergic pathways
and strengthen the memory-related cognitive behavior, and suggested that the
NAc-DBS may be a potential therapeutic intervention for memory disabilities in
MetS models.Acknowledgements
No acknowledgement found.References
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