209-LB: Evidence Thathypothalamic Glucoregulatory Neurons Sense and Respond to Changes of Glycemia in Conscious, Free-Living Mice

Abstract

The brain’s capacity to normalize the defended blood glucose level in diabetic animals is now well established. We hypothesized that for this to occur, the brain, like the pancreas, must detect and respond to changes in circulating glucose, but whether and how this occurs remains unknown. To identify specific neuronal subsets that are responsive to changes in glycemia in conscious, free-living mice, we combined continuous arterial glucose monitoring (CGM) with fiber photometry (FP) to measure the calcium activity of neurons located in the hypothalamic ventromedial nucleus that express the peptide, Pacap (VMHPacap neurons) . CGM and FP data from each of six mice were obtained during both a 1-h baseline monitoring period (without access to food) and over a 2-h intervention period in which the blood glucose (BG) level was elevated by either chow or a high-sucrose meal consumption, or by IP glucose injection. Cross-correlation analysis revealed that following a 60-80 s delay, interventions that raise the BG level are reliably associated with significantly reduced VMHPacap neuron activity (p < 0.01) . Interestingly, levels of BG and VMHPacapneuron calcium activity were also significantly correlated under baseline conditions (i.e., in the absence of any intervention) , but unlike what occurs following an intervention, these two variables were positively correlated with a ∼25 min offset, suggestive of an oscillatory pattern. We conclude that after a short delay, physiological stimuli that raise the BG level are coupled to reduced activity of VMHPacap neurons in vivo. In the basal state, levels of these two variables are positivity correlated in a delayed manner suggestive of an oscillatory control mechanism. These findings identify hypothalamic glucoregulatory neurons that are capable of sensing and responding to changes of glycemia in conscious, free-living mice. Disclosure J. D. Deem: None. A. Kumar: None. J. M. Scarlett: None. G. J. Morton: Research Support; Novo Nordisk A/S. M. W. Schwartz: None. D. Tingley: None. A. Bjerregaard: Employee; Novo Nordisk. C. L. Faber: None. T. P. Doan: None. B. N. Phan: None. Z. Nasir: None. B. Wu: None. M. K. Hwang: None. Funding NIDDK:P30 DK035816 K01 DK126793 R01 DK124238 R01 DK83042 NIDA:P30 DA048736; Novo Nordisk Research Agreement:CMS-431104