High-Intensity Interval Training-Induced Hippocampal Molecular Changes Associated with Improvement in Anxiety-like Behavior but Not Cognitive Function in Rats with Type 2 Diabetes

Abstract

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80-100% of V_Max, 4-10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

Keywords: anxiety-like behaviors; beta-amyloid; exercise; learning and memory; tau protein; type 2 diabetes.

Figure 1

The procedure timeline of the study.

Figure 2

Fasting blood glucose before starting the intervention (month 0), after diabetes induction (2 months of high-fat diet and STZ injection) (month 2), and 48 h after the last training session (month 4) for all groups. Each bar represents mean ± SEM (n = 7 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise. FBG: Fasting blood glucose. * shows a significant difference between DM and DM+EX with other groups.

Figure 3

The effects of HIIT on the %open arm time (%OAT ((A), and %open arm entry (%OAE) (B) of rats exposed to high-fat diet and STZ in the elevated plus maze (EPM). Significant differences: ** p < 0.01, *** p < 0.001 as compared to the control group, ^# p < 0.05 as compared to the DM group. Each bar represents mean ± SEM (n = 7 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise.

Figure 4

The effects of HIIT on the inner zone distance (A), inner zone frequency (B), inner zone time (C), rearing (D), and grooming (E) of rats exposed to high-fat diet and STZ in the open field test (OFT). Significant differences: * p < 0.05 as compared to the control group. ^## p < 0.01 compared to DM group. Each bar represents mean ± SEM (n = 7 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise.

Figure 5

The effects of HIIT on step-through latency time in shuttle box test of rats exposed to high-fat diet and STZ. Each bar represents mean ± SEM (n = 7 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise.

Figure 6

The effects of HIIT on time spent in each block (learning) (A) and time spent in the target quadrant (memory) (B) of rats exposed to high-fat diet and STZ in the Morris water maze (MWM). Each bar represents mean ± SEM (n = 7 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise.

Figure 7

The effects of HIIT on tau (A) and Aβ (B) protein levels in the hippocampus of rats exposed to high-fat diet and STZ in the passive avoidance test (PAT). * p < 0.05 as compared to the control group, ^# p < 0.05 as compared to the DM group. Each bar represents mean ± SEM (n = 5 in each group). Groups: C, control; C+EX, control + exercise; DM, diabetes mellitus (type 2); DM+EX, diabetes mellitus (type 2) + exercise.