Our colleague, friend, and long-standing SSIB member, Sue Ritter was diagnosed with stage 4 ovarian cancer in 2015. She passed away on March 14th, 2021. During her illness Sue maintained her typical grace, charm, and hard work. She did not want to be defined by her illness, and few of her colleagues were aware of the battle she was waging. Rather, Sue continued to engage in her studies and to enjoy time with family, including her husband Bob, sons Josh, Lincoln, and their families, including her four grandchildren.

Sue completed her PhD in physiological psychology at Bryn Mawr College in 1973 and accepted a position at Wyeth Laboratories in suburban Philadelphia where she continued investigating the role of mesencephalic catecholamine cell groups and their rostral projections in reward behavior with Larry Stein. Sue’s interest in defining roles for caudal brainstem catecholamine cell groups and their projections in the control of regulatory behavior and physiology would be a dominant focus of her science throughout her career. In 1974 Sue accepted a tenure track Assistant Professorship at Washington State University in the Department of Veterinary Pharmacology and Physiology, College of Veterinary Medicine where she would spend her entire academic career. During her time at WSU Sue witnessed and fostered the development of a strong group of neuroscience scholars, centered in what would become the Department of Integrative Physiology and Neuroscience. Together with former department chairman, Charles Barnes, Sue was instrumental in instituting WSU’s neuroscience baccalaureate degree program in 1999. She and Bob taught the foundation course for that program continuously until 2016.

Sue’s scholarship focused like a laser on crucial problems in regulatory neuroscience including, identifying the compensatory response effector circuits that, when engaged by the detection of insufficient energy, trigger a range of behavioral, autonomic, neuroendocrine responses, often referred to as counterregulatory responses (CRR). These CRR collectively and redundantly serve to increase available energy to sustain organ systems, especially the brain. The elicited CRR thereby compensate for a detected energy deficit. These weighty research questions had engaged many creative minds in the history of regulatory physiology beginning with C. Bernard and W. Cannon. And Sue was joined in her interests by contemporaries such as Y. Oomura, B. Levin, B. Thorens, E. Scharrer, W. Langhans, A. Watts, H. Grill and others. While some focused on peripheral detection of glucose deficits and others focused on CNS detectors; there is support for contributions from each of these. Sue was taken with the idea that by reducing central glucose metabolism, inducing cytoglucopenia with non-metabolizable glucose analogues like 2, deoxy-D-glucose or 5, thio-glucose, applied regionally or in a site-specific fashion one could derive the location of relevant detectors and the effectors that drive CRRs.

While historically the question of where within the brain the detectors and compensatory effector circuits resided focused initially on hypothalamic nuclei owing to Oomura’s electrophysiologic work (Oomura et al., 1974) and the zeitgeist more generally, Sue’s data, along with results from Grill and colleagues, were critical in establishing the caudal brainstem as a critical glucose detecting area. More specifically, her work established the essential role of hindbrain catecholamine neurons and their rostral, as well as caudal, connections in the activation of CRRs, including compensatory feeding, sympathoadrenal elevation of plasma glucose, and corticosterone secretion. Sue and her colleagues applied a range of complementary strategies including, careful mapping of central sites positive for eliciting feeding, glycemic, and corticosterone responses following intraparenchymal infusion of 5TG into a range of hindbrain and hypothalamic sites; c-Fos immunohistochemistry as a marker of cellular activation to determine which subpopulations of catecholamine neurons are activated by the induced cytoglucopenia; targeted application of a toxin – anti-dopamine beta-hydroxylase saporin (DSAP) - that binds to DBH and is selectively internalized by norepinephrine and epinephrine neurons; gene silencing, and TH-Cre targeted chemogenetic analysis of the CNO-driven effects of A1/C1 neuron excitation.

Sue and her colleagues found that injection sites that were effective for eliciting CRRs were concentrated in or near hindbrain catecholamine cell groups and, when combined with cytoglucopenia-driven c-Fos histochemistry, they showed that subpopulations of these neurons were most prevalent in the ventrolateral medulla, compared to the dorsomedial medulla (S. Ritter, Llewellyn-Smith, & Dinh, 1998). When injected into a catecholamine axon terminal area, DSAP is retrogradely transported to the cell body selectively destroying the DBH-positive neurons innervating the injection site. DSAP injections into the paraventricular hypothalamic nucleus (PVH), which receives dense innervation by hindbrain catecholamine neurons, destroyed the majority of rostrally-projecting DBH neurons in both the dorsal and ventral medulla and abolished the feeding response to insulin-induced hypoglycemia as well as systemic 2DG injections (S. Ritter, Bugarith, & Dinh, 2001). PVH DSAP injections also eliminated 2DG-induced increased corticosterone secretion (S. Ritter, Watts, Dinh, Sanchez-Watts, & Pedrow, 2003). By contrast, DSAP injections into the thoracic spinal cord, sites where preganglionic sympathetic neurons receive terminal innervation from catecholamine neurons in the rostral ventrolateral medulla, destroyed a different population of these neurons, the majority of which were C1 neurons in the rostral ventrolateral medulla. This treatment eliminated cytoglucopenia-induced activation of the adrenal medulla (the absence of c-Fos expression compared to controls), reduced adrenal epinephrine secretion, and eliminated the blood glucose response to 2DG (S. Ritter et al., 2001). It was notable that spinal DSAP injections had no direct effect on cytoglucopenia-evoked feeding or corticosterone secretion. Results obtained from DSAP injected rats using 2DG-induced cytoglucopenia were replicated using insulin-induced hypoglycemia (S. Ritter et al., 2001; S. Ritter et al., 2003).

Recent chemogenetic results from Sue’s lab showed that the catecholamine neurons mediating the sympathoadrenal glucose response are distributed in rostral half of C1 while those mediating feeding and corticosterone responses are concentrated more caudally in C1 and A1/C1. Sue and colleagues also observed that the glucose response required activation of two adjacent sites in the ventrolateral medulla, while feeding and corticosterone response appeared to require only one site. Sue collaborated with Rick Rogers and Gerlinda Hermann to show cytoglucopenia-induced activation of both astrocytes and neurons in the dorsomedial medulla, suggesting a role for astrocytes in activation of CRR circuitry (Rogers, McDougal, S. Ritter, Qualls-Creekmore, & Hermann, 2018). Sue’s work on the neural mediation of CRRs was also informed by the potentially lethal clinical phenomena observed in some diabetics called hypoglycemia associated autonomic failure (HAAF) wherein repeated bouts of marked hypoglycemia result in lesser efficacy of CRRs in response to subsequent hypoglycemic occurrences. She examined the effect of repeated chemogenetic activation of CA neurons in the A1/C1 cell group on elicitation and magnitude of feeding, corticosterone secretion, and respiratory quotient and gathered data implicating a functional impairment in A1/C1 in HAAF biology (Li, Wang, & Ritter, 2020). While much of Sue’s research focused on responses to glucose deficit, her lab also made a number of important discoveries in related areas. For example, in a series of studies utilizing pharmacological genetic tools Sue and her group produced evidence that feeding in response to fatty acid analogues, which was previously attributed to inhibition of lipid metabolism, actually was mediated by G-protein-coupled receptors that bind fatty acids (Li, Wiater, Wang, Wank and Ritter, 2016). These raised a re-awareness that energy substrates not only are monitored via there intracellular metabolism, but may serve as ligands at membrane bound receptors as well.

Sue’s research was continuously funded by NIH R01 and other grants since 1974. She mentored 11 PhDs, 5 postdocs, 3 research scientists and numerous veterinary and undergraduate students. Sue was a member of the SSIB Board of Directors and also served on several of its committees. Sue received a variety of awards and honors including two Fogarty Senior International Fellowships, Pfizer and Sahlin Awards for Excellence in Research. She was elevated to Regents Professor at WSU, and was elected to the Washington State Academy of Sciences, and was serving on its board of directors at the time of her death. Sue was active in community service, including on committees and on the board of directors for Palouse Habitat for Humanity. Sue was a creative, generative and generous as a scientist, mentor and friend. Her contributions to our field were important and rigorous. She will be greatly missed and fondly remembered by family, friends and colleagues..

 

Written by:
Harvey J. Grill and James H. Peters