Deep brain stimulation in midline thalamic region facilitates synaptic transmission and short-term memory in a mouse model of Alzheimer’s disease

Abstract

Based on evidence suggesting that deep brain stimulation (DBS) may promote certain cognitive processes, we have been interested in developing DBS as a means of mitigating memory and learning impairments in Alzheimer’s disease (AD). In this study we used an animal model of AD (TgCRND8 mice) to determine the effects of high-frequency stimulation (HFS) on non-amyloidogenic α-secretase activity and DBS in short-term memory. We tested our hypothesis using hippocampal slices (in vitro studies) from TgCRND8 mice to evaluate whether HFS increases α-secretase activity (non-amyloidogenic pathway) in the CA1 region. In a second set of experiments, we performed in vivo studies to evaluate whether DBS in midline thalamic region re-establishes hippocampal dependent short-term memory in TgCRND8 mice. The results showed that application of HFS to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a 2-fold increase of non-amyloidogenic α-secretase activity, in comparison to low frequency stimulated controls from TgCRND8 mice. In the in vivo studies, DBS treatment facilitated acquisition of object recognition memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in the CA1 region of hippocampus in a mouse model of AD.

Limbic Neuromodulation

“…55 DBS treatment has also been shown to facilitate acquisition of object-recognition memory in rats in comparison with the baseline. 55 Stone and colleagues 56 took this idea one step further and showed that stimulation of the entorhinal cortex in rats influences cognitive function via activity-dependent regulation of hippocampal neurogenesis. Acute stimulation of entorhinal cortex transiently promoted proliferation in the dentate gyrus.…”

Current Status of Deep Brain Stimulation for Alzheimer's Disease: From Chance Observation to Clinical Trials

“…Of note, the memory enhancement emerged gradually and was specific to hippocampal-dependent memory (Xia et al 2017). Thalamic DBS has also been shown to improve hippocampal-dependent short-term memory in the Tg transgenic mouse as well (Arrieta-Cruz et al 2010). Interestingly, a rodent study comparing EC, thalamic, and forniceal DBS showed that EC and forniceal DBS improved hippocampal-dependent memory more robustly than thalamic DBS.…”

“…The EC and thalamus have also been posited as potential DBS targets (Arrieta-Cruz et al 2010). EC DBS has also been shown to improve behavior in AD rodent models.…”

Assessment of Potential Targets for Deep Brain Stimulation in Patients With Alzheimer’s Disease

“…Various rodent models have been used to demonstrate the efficacy of DBS in modulating the memory circuits and enhancing the neurogenesis [ 13 , 14 ]. Hamani et al [ 14 ] showed that DBS of the anterior thalamic region in corticosterone-treated rats improved performance and enhanced hippocampal neurogenesis 1 month following stimulation.…”

“…Decreased glucose uptake in thalamus/hippocampal region was observed following bilateral lesioning of anterior thalamic nuclei. Another animal study using TgCRND8 mice demonstrated that DBS (high frequency) of the midline thalamic region enhanced short-term memory in the CA1 region of hippocampus and also increased the non-amyloidogenic α-secretase activity [ 13 ]. These promising results instigated researchers for the clinical trials of DBS for modulating the memory circuits.…”