Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D. D uring the recent two decades, the epidemic of type 2 diabetes (T2D) has reached an explosive scale in the United States and many other developed countries. The risk factors for the development of T2D include a group of prognostic disorders known collectively as insulin resistance syndrome, which manifests frequently in the form of glucose intolerance, insulin resistance, dyslipidemia, and blood pressure (BP) increase in association with aging and obesity. As broadly documented in the literature (1-7), all of these disorders are characterized by the existence of stress and inflammatory molecules in the circulation and various tissues. Although it is still poorly understood how all these pathophysiological changes are etiologically connected, a variety of intracellular stresses have been proposed as primary pathogenic factors (8, 9). These advances have included the recent understanding on endoplasmic reticulum (ER) stress (10-12), a set of intracellular molecular responses when the ER fails to adapt to various physiological or pathological conditions that challenge the normal functions of ER. Under diabetes-prone environmental changes, induction of ER stress was reported to occur in insulin-secreting pancreatic β-cells (13-15) and various insulin-responsive peripheral tissues (16-18), which together cause the compromised regulation of glucose homeostasis by insulin. Most recently, chronic ER stress was revealed to occur in the hypothalamus under conditions of nutritional excess and cause hypothalamic hormonal (leptin and insulin) defects that promote feeding and weight gain (19,20). Such effects of chronic brain ER stress are predicted to incur long-term pathological changes that contribute to T2D in a manner which is secondary to weight gain and obesity (19,20).The central nervo...

The present study investigated the effect of trans-spinal direct current (tsDC) on the firing rate, pattern, and amplitude of spontaneous activity of the tibial nerve and on the magnitude of cortically elicited triceps surae (TS) muscle contractions. The effect of combined tsDC and repetitive cortical electrical stimulation (rCES) on the amplitude of cortically elicited TS twitches was also investigated. Stimulation was applied by two disk electrodes (0.79 cm(2)): one was located subcutaneously over the vertebral column (T(10)-L(1)) and was used to deliver anodal DC (a-tsDC) or cathodal DC (c-tsDC) (density range: ± 0.64 to ± 38.2 A/m(2)), whereas the other was located subcutaneously on the lateral aspect of the abdomen and served as a reference. While the application of a-tsDC significantly increased the spike frequency and amplitude of spontaneous discharges compared with c-tsDC, c-tsDC made the spontaneous discharges more rhythmic. Cortically elicited TS twitches were depressed during a-tsDC and potentiated after termination. Conversely, cortically elicited TS twitches were enhanced during c-tsDC and depressed after termination. While combined a-tsDC and rCES produced similar effects as a-tsDC alone, combined c-tsDC and rCES showed the greatest increase in cortically elicited TS twitches. tsDC appears to be a powerful neurostimulation tool that can differentially modulate spinal cord excitability and corticospinal transmission.

Trans-spinal direct current (tsDC) stimulation is a modulator of spinal excitability and can influence cortically elicited muscle contraction in a polarity-dependent fashion. When combined with low-frequency repetitive cortical stimulation, cathodal tsDC [tsDC(-)] produces a long-term facilitation of cortically elicited muscle actions. We investigated the ability of this combined stimulation paradigm to facilitate cortically elicited muscle actions in spinal cord-injured and noninjured animals. The effect of tsDC-applied alone or in combination with repetitive spinal stimulation (rSS) on the release of the glutamate analog, D-2,3-(3)H-aspartate (D-Asp), from spinal cord preparations in vitro-was also tested. In noninjured animals, tsDC (-2 mA) reproducibly potentiated cortically elicited contractions of contralateral and ipsilateral muscles tested at various levels of baseline muscle contraction forces. Cortically elicited muscle responses in animals with contusive and hemisectioned spinal cord injuries (SCIs) were similarly potentiated. The combined paradigm of stimulation caused long-lasting potentiation of cortically elicited bilateral muscle contraction in injured and noninjured animals. Additional analysis suggests that at higher baseline forces, tsDC(-) application does not increase the rising slope of the muscle contraction but causes repeated firing of the same motor units. Both cathodal and anodal stimulations induced a significant increase of D-Asp release in vitro. The effect of the combined paradigm of stimulation (tsDC and rSS) on the concentration of extracellular D-Asp was polarity dependent. These results indicate that tsDC can powerfully modulate the responsiveness of spinal cord neurons. The results obtained from the in vitro preparation suggest that the changes in neuronal excitability were correlated with an increased concentration of extracellular glutamate. The combined paradigm of stimulation, used in our experiments, could be noninvasively applied to restore motor control in humans with SCI.