Aerobic exercise improves cognitive flexibility and modulates regional volume changes in a rat model of autism

Abstract

Gestational exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD). Rodents exposed to VPA in utero display common features of ASD, including volumetric dysregulation in higher-order cognitive regions like the medial prefrontal cortex (mPFC), the anterior cingulate cortex (ACC), and the hippocampus. Exercise has been shown in elderly populations to boost cognition and to buffer against brain volume losses with age. This study employed an adolescent treadmill exercise intervention to facilitate cognitive flexibility and regional brain volume regulation in rats exposed to VPA during gestation. It was found that exercise improved performance on extra-dimensional shifts of attention on a set-shifting task, which is indicative of improved cognitive flexibility. Exercise decreased frontal cortex volume in females, whereas in males exercise increased the ventral hippocampus. These findings suggest that aerobic exercise may be an effective intervention to counteract the altered development of prefrontal and hippocampal regions often observed in ASD.

Keywords: ASD; Adolescence; Anterior cingulate; Brain volume; Cerebellum; Hippocampus; VPA.

Fig. 1.

Timeline of behavioral events. (Left panel) Rats were injected at gestational day 12 with saline or VPA. Rats were tested on rotarod at P28 and then began treadmill training at P40 for 4 weeks. Rats were tested on rotarod a second time and performed the attentional set-shifting task. A second rotarod test was conducted at P60. (Right panel) An example brain with regions segmented, red (medial prefrontal cortex), yellow and blue (motor cortex), orange (caudate), light green and aqua (hippocampus), pink, purple and dark blue (cerebellar regions). (Created in part in Biorender.com).

Fig. 2.

Female (left) and Male (right) set-shifting performance on ID4 and ED phases. Exercise improved VPA female performance on the ID4 phase, fewer trials to criterion is better (p < 0.05). Exercise improved ED performance in control and VPA females (p < 0.05). Exercise impaired control and VPA male performance on ID4 phase (p < 0.05), but improved performance on the ED phase (p < 0.05), with fewer trials to criterion after exercise (dark orange and black bars are lower than grey and light orange bars).

Fig. 3.

Rotarod performance. All rats stayed on the rotarod longer on trial 2 compared to trial 1 (*p < 0.05), meaning rats did better on the second attempt. There was also an effect of condition (*p < 0.05) where control rats stayed on the rod longer than VPA rats.

Fig. 4.

Normalized volume for female ACC (left), motor cortex (middle), and PCC (right). Exercise decreased ACC volume for control and VPA females (p < 0.05), decreased VPA motor cortex volumes (p < 0.05), and increased control female PCC volumes (p < 0.05).

Fig. 5.

Normalized volume for female (left) and male (right) left amygdala. VPA sedentary females had enlarged left amygdala compared to control sedentary animals (p < 0.05). Exercise increased left amygdala volume in controls only (p < 0.05), whereas there were no changes in VPA animals. VPA males did not show enlargements, suggesting that there may be subtle sex differences in VPA animals within the left amygdala.

Fig. 6.

Normalized volume of female left dorsal hippocampus (left) and right dorsal hippocampus (right). Exercise increased left dorsal hippocampal volumes for control females (p < 0.05). Sedentary and VPA females had larger left dorsal hippocampi compared to sedentary controls (p < 0.05). Exercise increased right dorsal hippocampus for control females. After exercise, VPA females had volume similar to control exercised females suggesting exercise was modulating the overgrowth observed in sedentary females.

Fig. 7.

Normalized volume of male left ventral hippocampus. Exercise increased left ventral hippocampus of VPA males (p < 0.05).

Fig. 8.

Female mPFC and performance on ED phase. There was an interaction between condition and volume where control females with larger volumes were impaired on the ED phase and VPA females with smaller volumes were impaired (p < 0.05).

Fig. 9.

Female left dorsal hippocampus and ED phase There was an effect of left dorsal hippocampus volume on ED performance where control and VPA females with larger volumes performed better (p < 0.05).

Fig. 10.

Female left crus I and ED phase. There was an interaction between condition and left crus I volume on ED performance where control females with larger volumes performed worse and VPA females with larger volumes performed better (p < 0.05).

Fig. 11.

Male left crus I and total trials across the task. There was an effect of left crus I volume on total trials where, for both control and VPA males, larger left crus I was associated with better overall task performance (p < 0.05).

Fig. 12.

Male right dorsal hippocampus and total trials across the task. There was interaction between right dorsal hippocampus and condition for total trials. Control males with smaller volumes performed better across the task, whereas VPA males with larger volumes performed better across the task (p < 0.05).