Regulation of neurons in the dorsal motor nucleus of the vagus by SIRT1

Abstract

Neurons in the dorsal motor nucleus of the vagus (DMV) play a critical role in the regulation of autonomic functions. Previous studies indicated that central activation of sirtuin 1 (SIRT1) has beneficial effects on homeostasis, most likely via modulation of the autonomic output. Sirtuins are NAD+-dependent deacetylases and have been associated with longevity. SIRT1 is one of the best-characterized sirtuins expressed in mammals, and may be involved in the regulation of metabolism. Resveratrol, a SIRT1 activator reduced hyperglycemia likely through activation of vagal output; however, the cellular mechanisms of action have not been determined. In this study, whole-cell patch-clamp electrophysiology on acute brainstem slices was used to test the hypothesis that activation of SIRT1 with resveratrol enhances neurotransmission in DMV neurons. Application of resveratrol increased the frequency of spontaneous excitatory postsynaptic currents (sEPSC). This effect was KATP channel-dependent and was prevented with pre-application of SIRT1 inhibitor, EX527. Resveratrol also increased miniature EPSC (mEPSC) frequency without change in amplitude. Furthermore, our data demonstrated that resveratrol regulates excitatory neurotransmission in a PI3 kinase-dependent manner, since wortmannin, a PI3K inhibitor prevented the increase of mEPSC frequency caused by resveratrol. In conclusion, our data demonstrate that resveratrol via SIRT1 increases excitatory neurotransmission to DMV neurons. These observations suggest that activation of SIRT1 may regulate the function of subdiaphragmatic organs through controlling the activity of parasympathetic DMV neurons.

Inflammatory Stress Induced by Intraperitoneal Injection of LPS Increases Phoenixin Expression and Activity in Distinct Rat Brain Nuclei

“…The DMN is located near the mNTS [ 23 ] and is highly interconnected with it [ 41 ]. Its parasympathetic neurons [ 42 ] influence several aspects, such as energy homeostasis as well as food intake and digestion [ 43 ]. Its function is controlled by several brain areas, including the hypothalamus [ 42 ].…”

“…Its parasympathetic neurons [ 42 ] influence several aspects, such as energy homeostasis as well as food intake and digestion [ 43 ]. Its function is controlled by several brain areas, including the hypothalamus [ 42 ]. Interestingly, phoenixin was previously shown to exert anti-inflammatory neuroprotective effects which relied on SIRT-1 [ 32 ], a protein also involved in the function of the DMN in energy homeostasis [ 42 ], regulating glucose by reducing diet-induced hyperglycemia [ 44 ] and increasing peripheral insulin sensitivity [ 45 ] while also playing a role in maintaining body weight [ 46 ].…”

“…Its function is controlled by several brain areas, including the hypothalamus [ 42 ]. Interestingly, phoenixin was previously shown to exert anti-inflammatory neuroprotective effects which relied on SIRT-1 [ 32 ], a protein also involved in the function of the DMN in energy homeostasis [ 42 ], regulating glucose by reducing diet-induced hyperglycemia [ 44 ] and increasing peripheral insulin sensitivity [ 45 ] while also playing a role in maintaining body weight [ 46 ]. Intestinal inflammation, on the other hand, was shown to lead to a decrease in afferent neurons to the DMN and decrease its function [ 47 ].…”

Central control of autonomic functions in health and disease

“…The dorsal motor nucleus of the vagus (DMV) is positioned downstream to vagal afferents and receives viscerosensory information via the NTS. In the original work of Jiang and Zsombok ( 2014 ), the role of a Sirtuin in the DMV in regulating energy homeostasis is investigated. The authors show that SIRT1 modulates excitatory inputs to DMV motor neurons, which relies on potassium channel modulation to increase glutamate release from presynaptic terminals.…”

Central control of autonomic functions in health and disease

“…In the original work of Jiang and Zsombok (2014), the role of a Sirtuin in the DMV in regulating energy homeostasis is investigated. The authors show that SIRT1 modulates excitatory inputs to DMV motor neurons, which relies on potassium channel modulation to increase glutamate release from presynaptic terminals.…”