Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

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Acute physiological stressors such as fluctuations in blood pressure (Madden, Stocker, & Sved, 2006), blood glucose (Ritter, Li, Wang, & Dinh, 2011), blood gases (Guyenet, 2000), blood volume (Krukoff, MacTavis, Harris, & Jhamandas, 1995), or inflammation (Dayas, Buller, Crane, Xu, & Day, 2001) evoke homeostatic reflexes mediated by central autonomic pathways that include neurons in the ventrolateral medulla oblongata (VLM) (Card et al., 2006; Guyenet et al., 2013). Neurons in the VLM have widespread projections including to the hypothalamus and spinal cord, that mediate multiple actions such as via the paraventricular‐adrenal axis (and other hormonal effectors) and sympathetic outflows respectively. A proportion of both catecholaminergic and noncatecholaminergic VLM neurons are activated (denoted by the presence of c‐Fos protein) following hypotensive (Burman, Sartor, Verberne, & Llewellyn‐Smith, 2004; Stornetta, Schreihofer, Pelaez, Sevigny, & Guyenet, 2001; Stornetta, Sevigny, & Guyenet, 2002), hypertensive (Chan & Sawchenko, 1994; Graham, Hoffman, & Sved, 1995), glucoprivic (Parker, Kumar, Lonergan, & Goodchild, 2015; Ritter, Llewellyn‐Smith, & Dinh, 1998), inflammatory (Dayas et al., 2001) as well as hypoxic and hypercapnic stimuli (Haxhiu, Yung, Erokwu, & Cherniack, 1996; Spirovski, Li, & Pilowsky, 2012). Catecholaminergic VLM neurons are required to mediate appropriate responses to individual stressors as demonstrated by selective lesion studies: destruction of spinally projecting catecholaminergic VLM neurons attenuates baroreceptor and chemoreceptor reflex function (Madden et al., 2006; Schreihofer & Guyenet, 2000) and adrenaline release following 2‐deoxy‐D‐glucose (2DG) evoked glucoprivation (Ritter, Bugarith, & Dinh, 2001) while destruction of catecholaminergic VLM neurons that project to the hypothalamus decreases plasma vasopressin and oxytocin levels evoked in response to hydralazine (HDZ: Madden et al., 2006) and eliminates feeding responses and corticotrophin releasing factor (CRF) release in response to glucoprivation (Ritter et al., 2001). Spinally projecting catecholaminergic VLM neurons that respond to 2DG are differentiated from VLM sympathetic premotor neurons that regulate vasomotor tone by their lack of barosensitivity and relative scarcity (Verberne & Sartor, 2010) and these neurons appear to differentially innervate subsets of sympathetic preganglionic neurons (SPN) that respond to 2DG or hypotension, but not both (Morrison & Cao, 2000). Furthermore, a neurochemical code discriminating functionally distinct SPN is indicated, since glucose responsive SPN include all prepro‐enkephalin (PPE) containing neurons projecting to the adrenal gland (Parker et al., 2013). Together these data suggest that distinct subpopulations of VLM neurons respond to hypotensive and glucoprivic stimuli.
VLM neurons are neurochemically heterogeneous, expressing mRNA for a range of neurochemicals including: vesicular glutamate transporter 2, PPE (Parker et al., 2015; Stornetta et al., 2001), neuropeptide Y (NPY) (Parker et al., 2015; Stornetta, Akey, & Guyenet, 1999), cocaine and amphetamine‐regulated transcript (CART) (Parker et al., 2015), pituitary adenylate cyclase‐activating polypeptide (PACAP) (Farnham, Li, Goodchild, & Pilowsky, 2008), substance P (preprotachykinin, PPT) (Li, Goodchild, Seyedabadi, & Pilowsky, 2005), and prepro‐galanin (Spirovski et al., 2012) indicating that multiple neurochemicals exist within the region (Stornetta, 2009). Our key goal is to determine whether neurochemical codes can be identified to distinguish functionally discrete subsets of neurons in the ventrolateral medulla.
The first aim of this study was to characterize the neurochemical code of neurons within the VLM that respond to HDZ administration. As barosensitive neurons within the rostral VLM (RVLM) that would be activated following HDZ are not sensitive to glucoprivation, at least when recorded electrophysiologically (Verberne & Sartor, 2010) and independent pathways to target organs are proposed, we hypothesized that discrete subsets of neurochemically defined VLM neurons activated by each physiological stimulus could be discriminated.
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