Abstract
Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer’s disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.
Highlights
Increased human longevity has magnified the negative impact that aging can have on cognitive integrity in older individuals (Foster et al, 2017)
Compared to the aged sham group, the distance ratio was significantly increased in the 5 Hz Repetitive transcranial magnetic stimulation (rTMS) group (P < 0.05, Figure 1B), and the time of platform crossing was significantly increased in the 5 Hz and 25 Hz rTMS groups (P < 0.05, Figure 1C)
Age-related cognitive impairment is considered a pre-symptomatic phase of dementia, which may take decades to evolve (Allison et al, 2016)
Summary
Increased human longevity has magnified the negative impact that aging can have on cognitive integrity in older individuals (Foster et al, 2017). Normal aging is associated with declining cognitive function, which may result from changes in hippocampus circuits (Vanguilder and Freeman, 2011). Hippocampal-functional dependent learning and memory capabilities are vulnerable during brain aging (Gray and Barnes, 2015), and these involve attention, working memory, and episodic memory (Rosenzweig and Barnes, 2003). It is well accepted that synaptic plasticity in the normal aging process is still reserved in the hippocampus and provides opportunities for potential interventions in prodromal stages before dementia. Delivering electrical stimuli to excite or inhibit the brain can affect neuron activity so as to play different roles in neural modulation by adjusting stimulation parameters such as frequency and intensity (Houdayer et al, 2008). High-frequency stimulation (HF-rTMS) is considered to evoke neural excitability (Medina and Túnez, 2013). Some neuroscientific studies have shown that HF-rTMS (e.g., 10 Hz, 15 Hz, or 20 Hz) applied over the left dorsolateral prefrontal cortex (DLPFC) with a motor threshold within a range of 80%–110% was likely to bring out significant cognitive improvement in adult patients or healthy volunteers (Cattaneo and Silvanto, 2008)
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