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  • In fact changes in mitochondrial dynamics directly affects


    In fact, changes in mitochondrial dynamics directly affects many things including cellular metabolism [127], mitochondrial mass and turnover [128], mitochondrial transport, and calcium buffering [129]. Nigrostriatal DA neurons seem to have a preferential susceptibility to loss of Mfn2 when compared to VTA DA neurons [130]. Although a specific mitochondrial fusion or fission protein has not been implicated in classic PD, recent data suggest that impaired mitochondrial fusion due to mutations in Opa1 cause parkinsonism in the absence of clinically significant optic atrophy [131]. Furthermore, it is well known that α-synuclein and MPTP cause fragmentation of mitochondria [132]. Taken together, these studies support the notion that interventions to increase mitochondrial fusion are crucial to re-establish proper SN DA neuronal function and avoid neurodegeneration, as demonstrated in [133], [134]. Moreover, Rappold and colleagues [134] suggest that increased mitochondrial fusion not only can be a strategy to prevent neurodegeneration but also can be used to restore proper function of remaining cells, as impairment in mitochondrial dynamics also disrupts synaptic release of dopamine. Spared TH+ cells in PD patients and animal models of PD after establishment of Parkisonism could benefit from mitochondrial fusion inducing agents to re-establish proper synaptic dopamine release and thus ameliorate the symptoms of PD. Finally, disruption of cellular metabolism is a key feature of PD, with both α-synuclein and PD-related neurotoxins such as MPTP acting as disruptors [135], [136]. Bioenergetic failure produced by these and other factors may also contribute to the degeneration of vulnerable neurons, such as SN DA cells. Dopamine neurons of the SN are particularly vulnerable to energy failure because of their substantial energy demands. Neurons in general consume a huge amount of energy in order to maintain the ionic gradient across their plasma membrane. SN DA neurons have long unmyelinated itk inhibitor and extensive arborization making their energy demands especially high [137], [138]. Furthermore, they exhibit pacemaking activity that maintains basal DA tone across an expansive region, increasing their energy demands even further [139]. Neurons do not store glycogen so they are especially sensitive to fluctuations in energy demand and reliant on neighboring astrocytes to provide nutrients [140]. Unfortunately, SN DA neurons have relatively few surrounding astrocytes to provide supplementary energy [140]. Thus, the nigrostriatal DA system is probably the most vulnerable neuronal population to compromised bioenergetic status [141], becoming very sensitive to changes in mitochondrial dynamics that impact oxidative capacity and cellular bioenergetics.
    Author contribution
    Introduction The vagus nerve, one of the cranial nerves, conveys signals from the gastrointestinal tract to the central nervous system (CNS). The appetite-stimulating hormone ghrelin, a 28–amino acid peptide, is produced in gastric endocrine cells [1]. Two forms of ghrelin exist, n-octanoylated ghrelin and desacyl-ghrelin. The ghrelin receptor (also known as the growth hormone secretagogue receptor, GHSR) is produced in nodose ganglion neurons and transferred to the stomach via axons [2]. The ghrelin signal is transmitted to the nucleus tractus solitarii (NTS) in the medulla oblongata via the vagus afferent nerve, and then relayed to hypothalamic neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) [3]. A previous report demonstrated that GHSR restoration in the hindbrain is not sufficient to induce ghrelin-stimulated food intake in GHSR-null mice [4]. However, this study did not investigate the ghrelin signaling via the vagal afferent nerve. In the current study, we studied peripheral ghrelin signaling via the vagus nerve in GHSR-null mice and in GHSR/Phox2b mice, which express GHSR only in the nodose ganglion neurons. Restoration of GHSR expression in nodose ganglion neurons rescued low fasting blood glucose levels in GHSR-null mice. Intraperitoneal administration of ghrelin elevated blood glucose levels, but did not induce food intake or growth hormone release in GHSR/Phox2b mice. GHSR-positive neurons in the nodose ganglion were less abundant in GHSR/Phox2b mice than in wild-type mice. Our results suggest that GHSR neurons expressed in the nodose ganglion play a critical role in gastric-derived ghrelin signaling.