Voluntary Exercise During Puberty Enhances Spatial Memory Through Synaptic and Structural Plasticity in Hippocampal Dentate Gyrus and CA3 Regions

The hippocampus is essential for encoding, storing, and retrieving memories. It comprises adjacent cortical regions: the dentate gyrus (DG), CA3, CA2, and CA1. In the DG, new memories are distinguished from the older ones, such as for spatial and contextual representation, while the CA3, recurrent synaptic connections are formed which appear necessary for pattern completion and memory recall. Synaptic plasticity which is the ability of synapses to strengthen or weaken over time is the main mechanism underlying learning and memory. Previous studies have shown that physical exercise can enhance hippocampal neurogenesis and cognitive function in adult rodents, however, the effects of voluntary, self-initiated exercise during puberty have not been thoroughly investigated. To this end, new study published in Cerebral Cortex and led by Professor Wei Meng from the Jiangxi Science and Technology Normal University and conducted Changjian Wan, Xueqing Song, Zhuyu Zhang, Wenxiang Hu, Yanhua Chen, Wei Sun, Zhibin Liu, and Songhua Wang, investigated how voluntary exercise during puberty influences spatial memory and the underlying neural mechanisms. They focused on a 4-week voluntary wheel running (VWR) exercise protocol in developing mice (30 days of age) where they examined carefully the changes in synaptic transmission, receptor expression, and dendritic spine density in different hippocampal subregions to identify the pathways through which early-life exercise can enhance cognitive function.

The researchers used Kunming mice which is a well-established model to study learning and memory. They divided the mice into four groups: male control, male exercise, female control, and female exercise. The exercise groups had access to running wheels in their cages which allowed them to engage in VWR for a period of 30 days. In contrast, the control groups had locked wheels which prevented them from running. They designed the protocol to simulate self-initiated physical activity during a critical developmental period. Moreover, they assessed the effects of VWR on spatial memory using the Y-maze test to evaluated spatial working memory and reference memory. The Y-maze consists of three arms, and mice naturally explore new arms which reflect the working memory capability. The researchers measured spontaneous alternation (the tendency to explore new arms) and novel arm exploration (a measure of reference memory). They found the Y-maze experiments has significant improvements in spatial memory for both male and female mice in the exercise groups with the exercise groups has higher spontaneous alternation rates and spent more time exploring the novel arm compared to their control counterparts which indicate that voluntary exercise during development enhances spatial working memory and reference memory in mice.

Furthermore, the team performed whole-cell patch-clamp recordings on hippocampal brain slices to investigate the synaptic mechanisms underlying these behavioral improvements. The whole-cell patch-clamp technique measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) and provide valuable information on the synaptic activity at the cellular level. The authors found that VWR significantly increased both mEPSCs and mIPSCs in the DG and CA3 neurons of the hippocampus, but not in CA1 neurons which suggests that voluntary exercise enhances synaptic transmission specifically in the DG and CA3 regions that are critical for spatial memory. Moreover, the increase in mEPSCs indicates enhanced excitatory synaptic activity, while the increase in mIPSCs reflects heightened inhibitory synaptic transmission which suggests a balanced enhancement of synaptic inputs.

The researchers also performed immunofluorescence analysis to examine the expression levels of key synaptic receptors NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptors and the α1 subunit of gamma-aminobutyric acid type A (GABAA) receptors and found an increase in the expression of NR2A, NR2B, and α1GABAA receptors in the DG and CA3 regions but not in CA1 region of mice that underwent VWR, compared to control mice.  They also performed Golgi staining to visualize dendritic spines and observed an increase in dendritic spine density in the DG and CA3 regions but not CA1 region of mice that engaged in VWR, compared to control mice. According to the authors, higher dendritic spine density in the DG and CA3 regions means enhanced synaptic connectivity and structural plasticity, which ultimately enhance spatial memory in the exercised mice. In conclusion, Professor Wei Meng and his team provided valuable data on the neuroplastic changes that occur in the specific hippocampal regions in puberty during voluntary exercise. The new research recommend encouraging voluntary physical activity during puberty which can have lasting positive effects on cognitive function.  Moreover, this has practical implications for educational policies and childhood development programs to advocate for the integration of regular physical exercise into school curricula and daily routines for adolescents. Furthermore, the findings can guide the development of targeted interventions for cognitive enhancement for rehabilitation programs in children with developmental disorders or cognitive impairments.