A longitudinal, multi-parametric functional MRI study to determine age-related changes in the rodent brain

Abstract

As the population ages, the incidence of age-related neurological diseases and cognitive decline increases. To further understand disease-related changes in brain function it is advantageous to examine brain activity changes in healthy aging rodent models to permit mechanistic investigation. Here, we examine the suitability, in rodents, of using a novel, minimally invasive anaesthesia protocol in combination with a functional MRI protocol to assess alterations in neuronal activity due to physiological aging. 11 Wistar Han female rats were studied at 7, 9, 12, 15 and 18 months of age. Under an intravenous infusion of propofol, animals underwent functional magnetic resonance imaging (fMRI) and functional magnetic resonance spectroscopy (fMRS) with forepaw stimulation to quantify neurotransmitter activity, and resting cerebral blood flow (CBF) quantification using arterial spin labelling (ASL) to study changes in neurovascular coupling over time. Animals showed a significant decrease in size of the active region with age (P ​< ​0.05). fMRS results showed a significant decrease in glutamate change with stimulation (ΔGlu) with age (P ​< ​0.05), and ΔGlu became negative from 12 months onwards. Global CBF remained constant for the duration of the study. This study shows age related changes in the blood oxygen level dependent (BOLD) response in rodents that correlate with those seen in humans. The results also suggest that a reduction in synaptic glutamate turnover with age may underlie the reduction in the BOLD response, while CBF is preserved.

Keywords: Aging; Imaging; Preclinical models; fMRI; fMRS.

Fig. 1

Individual rat weights at 7, 9, 12, 15 and 18 months (n ​= ​11).

Fig. 2

Oxygen saturation (A), Breathing rate (B) at the start and end of the period on room air, and Temperature (C) at the start and end of scanning, in 7 months old and 18 months old animals (∗P ​= ​0.05, ∗∗∗P ​= ​0.001). Data is displayed as mean ​± ​SD, n ​= ​8 and 7 respectively.

Fig. 3

Example images displaying S1FL activation in a representative rat at 7 months (A), 9 months (B), 12 months (C), 15 months (D) and 18 months. All analysis was performed with a z threshold of 2.3 and cluster P threshold of 0.01.

Fig. 4

Effect of age on various aspects of the BOLD signal including the maximum BOLD signal change in S1FL (A), the mean BOLD signal change of all active voxels in S1FL (B), and the number of active voxels in S1FL (C). There was a significant decrease in the number of active voxels with age (∗P ​= ​0.05, between various times points). Data is displayed as mean ​± ​SD, n ​= ​8, 8, 8, 10, and 7 ​at 7, 9, 12, 15 and 18 months respectively.

Fig. 5

(A) Bar graph showing time to peak of BOLD signal at all time points. Data is displayed as mean ​± ​SD, n ​= ​8, 8, 8, 10, and 7 ​at 7, 9, 12, 15 and 18 months respectively. (B–F) Average time series plots of BOLD signal at each time point, taken from the voxel with the highest z statistic. n ​= ​8, 8, 8, 10, and 7 ​at 7, 9, 12, 15 and 18 months respectively.

Fig. 6

Effect of age on glutamate change in S1FL with forepaw stimulation. There was a significant decrease in the glutamate signal change with increasing age (∗P ​= ​0.05, between various times points). Data is displayed as mean ​± ​SD, n ​= ​8, 10, 9, 11, and 4 ​at 7, 9, 12, 15 and 18 months respectively.

Fig. 7

Effect of age on intensity of NAA (A) and Inositol (B) levels with age in the somatosensory cortex. Both NAA and Inositol levels significantly decreased with increasing age (∗P ​= ​0.05, between various times points). Data is displayed as mean ​± ​SD, n ​= ​8, 10, 9, 11, and 4 ​at 7, 9, 12, 15 and 18 months respectively.

Fig. 8

The effect of age on resting CBF at bregma. There were no significant differences in resting CBF at bregma at any of the time points measured. Data is displayed as mean ​± ​SD, n ​= ​11 ​at all time points apart from n ​= ​10 ​at 18 months.