Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats
Introduction
Diabetes mellitus (DM) is a common metabolic disorder with neurological complications in the peripheral and central nervous systems [1]. Diabetic polyneuropathy (DPN) is the most common form of neuropathy that occurs in up to 50% of diabetic patients leading to sensory, motor, and/or autonomic dysfunction [2], [3]. DM also contributes to central nervous system neurodegenerative processes, including brain atrophy and cognitive decline [4]. Recent studies have revealed that DM can accelerate age-related cognitive decline and is a risk factor for both vascular dementia and Alzheimer's disease (AD) [5], [6]. The common cognitive dysfunctions identified in DM patients include mental and motor slowing, worsened executive functioning such as planning, problem-solving and working memory [7]. Functional neuroimaging studies have provided important insights into the neural mechanisms associated with cognitive decline in type 2 DM patients. It has been shown that type 2 DM patients exhibited gray matter atrophy in the hippocampus, amygdala, prefrontal and parietal cortex, and reduced integrity of cerebral white matter [8], [9], [10], [11]. However, the therapeutic interventions for preventing and/or ameliorating cognitive dysfunction in DM patients remain undefined.
Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique providing a focal polarity-specific direct current electric field, either anodal or cathodal, through the skull to modulate brain function [12]. Over the past decade, tDCS has been increasingly used in clinical trials to improve motor dysfunction caused by stroke or Parkinson's disease, and cognitive performances in patients with neuropsychiatric disorders such as schizophrenia, depression, epilepsy and AD [13], [14], [15], [16], [17]. Besides these potential clinical benefits, tDCS has been shown to improve declarative and working memory capacity in healthy subjects [18], [19], [20]. Animal studies have reported similar beneficial effects of tDCS on visuospatial working memory training and skill learning in normal rats [21], spatial memory in rats with traumatic brain injury [22], and object recognition test in a genetic rat model of attention-deficit/hyperactivity disorder [23]. Furthermore, electrophysiological experiments have also shown that tDCS can induce a sustained response in the form of a long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity in the human motor cortex [24]. Given that LTP- and LTD-like plasticity are considered to be the cellular correlates of learning and memory [25], tDCS might be an attractive method to overcome learning- and memory-related deficits associated with cognitive decline in DM patients. Indeed, our recent study has demonstrated that anodal tDCS over the dorsolateral prefrontal cortex can improve visuospatial working memory performance in patients with concomitant DPN and mild cognitive impairment [26]. However, it remains unclear how tDCS produces its effect. The present study was designed to study the cellular mechanisms underlying the effect of tDCS on cognitive decline in streptozotocin (STZ)-induced diabetic rats. Because repeated sessions of tDCS may have cumulative effects associated with greater magnitude and duration of effects [27], repeated tDCS protocol was used. We hypothesized that repeated anodal tDCS over the medial prefrontal cortex (mPFC) may alter expression profiles of molecules importantly involved in maintaining synaptic structure and function, to improve spatial working memory performance in STZ-induced diabetic rats. Because decreased brain-derived neurotrophic factor (BDNF) levels have been associated with the cognitive decline in STZ-induced diabetic rats [28], we examined the role of BDNF in mediating the effects of tDCS.
Section snippets
Animals
Eight-week-old male Sprague-Dawley rats (280–300 g; n = 130) were used. Hyperglycemia was induced by a single tail vein injection of STZ (50 mg/kg; Sigma-Aldrich, St. Louis, MO) dissolved in freshly prepared 0.05 M citrate buffer (pH 4.5) [29]. Control rats received an equivalent volume of citrate buffer. The rats were randomly assigned to the conditions of STZ or citrate buffer injection and were housed two per cage. The plasma glucose was sampled from the tail vein before and 1 week after STZ
Repeated applications of prefrontal tDCS improve spatial working memory performance in STZ-induced diabetic rats
Assessment of cognitive function was carried out by investigating performance in the DNMT, a powerful behavioral task for evaluating spatial working memory in rodents [38]. STZ treatment induced a significant increase in the levels of plasma glucose compared with vehicle-treated group (p < 0.001; Fig. 1A). The experimental setup for the tDCS treatment is depicted in Fig. 1B. STZ-induced diabetic rats exhibited impaired performance in the DNMT task, as confirmed by a two-way repeated measure
Discussion
Our previous findings demonstrated that anodal tDCS over the dorsolateral prefrontal cortex can improve visuospatial working memory performance in DM patients who suffer from both DPN and mild cognitive impairment [26]. Extending these clinical observations, our current results provide additional insight into the mechanistic basis for understanding how tDCS elicits improvement in DM-related cognitive dysfunction. We confirmed that STZ-induced diabetic rats exhibited significant deficits in
Conclusions
Our findings demonstrate that repeated anodal tDCS over the mPFC is effective to improve spatial working memory performance in STZ-induced diabetic rats, presumably resulting in augmented synaptic and structural plasticity that requires BDNF secretion and transcription/translation of NMDARs in mPFC layer V pyramidal neurons, which are essential for cognitive performance, especially memory formation [60]. These plastic changes may be the mechanism by which repeated tDCS application improves
Funding
This work was supported by research grants from the Ministry of Science and Technology (104-2314-B-006-006; 105-2628-B-006-009-MY2 and 106-2321-B-006-018) and National Cheng Kung University Hospital (NCKUH-10307016; NCKUH-10408016 and NCKUH-10507024), Taiwan.
Competing interests
The authors declare no competing interests.
Acknowledgments
We thank Dr. Ying-Zu Huang and Dr. Chi-Hung Juan for valuable discussion and suggestions.
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