Original ArticleRapid Modulation of Protein Expression in the Rat Hippocampus Following Deep Brain Stimulation of the Fornix
Introduction
Deep brain stimulation (DBS) refers to the therapeutic delivery of electrical current through implanted electrodes in precisely targeted areas of the brain. It is estimated that over 100,000 patients worldwide have been implanted with DBS systems, with the rate of annual accrual increasing [1]. DBS has proven to be remarkably effective in treating a range of neurological disorders including Parkinson's disease (PD), essential tremor, dystonia and is currently being evaluated in pain and psychiatric illness [2], [3], [4], [5], [6]. Recently, the potential beneficial effects of DBS have been reported for memory enhancement in rodents [7], [8], [9], [10] and humans [11], [12], [13], [14] and thus has implications for therapeutic applications.
The fornix, a white matter tract bundle, is the predominant efferent projection from the hippocampus to the septal regions and mammillary bodies [15]. Another major component of the fornix is the axonal projections from the septal area to the hippocampus. The fornix constitutes an integral part of the classical circuit of Papez, a major pathway of the limbic system, primarily involved in memory function [16]. Lesions of the fornix in experimental animals and humans are known to produce memory deficits [17], [18], [19]. Moreover, it was shown in a rat model of dementia that bilateral DBS of the forniceal region reversed the memory impairing effects of scopolamine in the object location task [10].
In 2008, our group reported on a 50-year-old man with morbid obesity treated with bilateral DBS targeting the fornix/hypothalamic area demonstrated certain aspects of memory [11]. On the basis of this case-observation, we initiated a phase I study in patients with Alzheimer's disease (AD) investigating the safety of DBS targeting the limbic system as a potential treatment of dementia/cognitive impairment [12]. These patients showed increased cortical glucose metabolism contrary to the expected longitudinal decline generally seen in AD patients [20], [21]. In addition, two of these six patients showed growth of the hippocampus, contrary to the expected progressive atrophy that is characteristic of AD [22], suggesting that forniceal DBS may have neurotrophic effects. These studies have led to increased interest in the possibility of DBS for neurodegenerative disorders and fornix DBS is currently being investigated for its potential in treating AD in a double blind, sham stimulation controlled multicenter trial involving 42 patients (ClinicalTrials.gov Identifier: NCT01608061).
These observations in patients are complemented by experiments in laboratory animals that have shown stimulation of limbic structures, e.g. entorhinal cortex (EC) or anterior nucleus of the thalamus (ANT), modulate hippocampus-dependent memory and neurogenesis [8], [9], [23], [24]. Recent work has also demonstrated that DBS at other targets, including the subthalamic nucleus (STN), the ventromedial prefrontal cortex (vmPFC) and the cerebellum, modulates gene and protein expression [25], [26], [27], [28]. However, the mechanisms of action of DBS in general and for forniceal stimulation in particular remain unknown.
In the present study, we investigated the effects of fornix DBS on the modulation of protein expression in the rat hippocampus at different time-points following high frequency fornix stimulation for 1 h. We analyzed the expression of selected proteins within 3 broad categories: 1) proteins known to be involved in AD including tau, phosphorylated tau (ptau), amyloid precursor protein (APP) as well as 2) the trophic factors brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) and 3) synaptic markers of long-term potentiation and plasticity, namely synaptophysin and growth associated protein 43 (GAP-43). We also studied the effect of fornix stimulation on the expression of cFos and selected heat shock proteins as markers of neurophysiologic activity and stress.
Section snippets
Materials and methods
A summary of our experimental design and timeline is outlined in Fig. 1.
Results
We investigated both AD-related and candidate proteins whose levels of expression after DBS could be predicted to change.
Discussion
Our study shows that 1 h of DBS of the fornix area modulates protein expression in the hippocampus, a connected remote area. Acute DBS in the forniceal area increases trophic factors including BDNF and VEGF (Fig. 5) and the synaptic markers GAP-43, synaptophysin and α-synuclein (Fig. 6). Notably, these increases occurred within 2.5 h after the initiation of the fornix stimulation and returned to control levels by 5 h. No changes were found in APP, tau, ptau (Fig. 4), GDNF and chaperone proteins.
Conclusion
We have shown that 1 h of fornix DBS activated the hippocampus and led to an increase in neurotrophic factors as well as markers of synaptic plasticity, which are all known to play crucial roles in memory functions. Changes in the expression of these proteins could possibly contribute to the improvement of memory after fornix stimulation in animal models [10] or patients [11], [12], [14].
The increased neurogenesis and improved memory performance in animals undergoing Papez circuit DBS [8], [9],
Acknowledgments
We wish to thank Roger Raymond for his excellent histological help.
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This study was funded by the Weston Foundation.