Decoding Neural Metabolic Markers From the Carotid Sinus Nerve in a Type 2 Diabetes Model

Recent studies showed that the carotid sinus nerve (CSN) and the sympathetic nervous system (SNS) are overactivated in type 2 diabetes and that restoring the correct CSN neural activity can re-establish the proper metabolism. However, a robust characterization of the relationship between CSN and SNS neural activities and metabolism in type 2 diabetes is still missing. Here, we investigated the relationship between neural activity of CSN and SNS in control rats and in rats with diet-induced type 2 diabetes and the animal condition during metabolic challenges. We found that the diabetic condition can be discriminated on the basis of CSN and SNS neural activities due to a high-frequency shift in both spectra. This shift is suppressed in the SNS in case of CSN denervation, confirming the role of CSN in driving sympathetic overactivation in type 2 diabetes. Interestingly, the Inter-Burst-Intervals (IBIs) calculated from CSN bursts strongly correlate with perturbations in glycaemia levels. This finding, held for both control and diabetic rats, indicates the possibility of detecting metabolic information from neural recordings even in pathological conditions. Our results suggest that CSN activity could serve as a marker to monitor glycaemic alterations and, therefore, it could be used for closed-loop control of CSN neuromodulation. This paves the way to the development of novel and effective bioelectronic therapies for type 2 diabetes.

[1]  Maria P. Guarino,et al.  Carotid Body Denervation Prevents the Development of Insulin Resistance and Hypertension Induced by Hypercaloric Diets , 2013, Diabetes.

[2]  Theodoros P. Zanos,et al.  Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity , 2018, Proceedings of the National Academy of Sciences.

[3]  H. Forster,et al.  The role of the carotid chemoreceptors in the control of breathing during exercise. , 1994, Medicine and science in sports and exercise.

[4]  P. Fadel,et al.  Insulin increases ventilation during euglycemia in humans. , 2018, American journal of physiology. Regulatory, integrative and comparative physiology.

[5]  Hans-Peter Kriegel,et al.  A Density-Based Algorithm for Discovering Clusters in Large Spatial Databases with Noise , 1996, KDD.

[6]  J. Dixon,et al.  Sympathetic nervous activation in obesity and the metabolic syndrome--causes, consequences and therapeutic implications. , 2010, Pharmacology & therapeutics.

[7]  A. Thorp,et al.  Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome , 2015, Journal of diabetes research.

[8]  J. Paton,et al.  The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases , 2013, Hypertension.

[9]  H. Forster,et al.  Hyperpnea of exercise at various PIO2 in normal and carotid body-denervated ponies. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[10]  Stanislav Herwik,et al.  A Wireless Multi-Channel Recording System for Freely Behaving Mice and Rats , 2011, PloS one.

[11]  R. Fonseca-Pinto,et al.  Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver , 2016, Diabetologia.

[12]  A. Dahan,et al.  Plasticity of Central Chemoreceptors: Effect of Bilateral Carotid Body Resection on Central CO2 Sensitivity , 2007, PLoS medicine.

[13]  Jaakko Astola,et al.  Generalized Hampel Filters , 2016, EURASIP J. Adv. Signal Process..

[14]  Constancio González,et al.  Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats , 2011, British Journal of Nutrition.

[15]  D. Wasserman,et al.  Evidence that carotid bodies play an important role in glucoregulation in vivo. , 2000, Diabetes.

[16]  Beat Kleiner,et al.  Graphical Methods for Data Analysis , 1983 .

[17]  Cristian Sevcencu,et al.  An Intraneural Electrode for Bioelectronic Medicines for Treatment of Hypertension , 2018, Neuromodulation : journal of the International Neuromodulation Society.

[18]  Theodore W. Berger,et al.  Chronic multi-region recording from the rat hippocampus in vivo with a flexible Parylene-based multi-electrode array , 2017, 2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[19]  Johannes J. Struijk,et al.  A Respiratory Marker Derived From Left Vagus Nerve Signals Recorded With Implantable Cuff Electrodes , 2018, Neuromodulation : journal of the International Neuromodulation Society.

[20]  Brian Litt,et al.  Drug discovery: A jump-start for electroceuticals , 2013, Nature.

[21]  P. Kumar,et al.  Indirect sensing of insulin‐induced hypoglycaemia by the carotid body in the rat , 2004, The Journal of physiology.

[22]  Erkki Oja,et al.  Independent Component Analysis , 2001 .

[23]  Sara Reardon,et al.  Electroceuticals spark interest , 2014, Nature.

[24]  Constancio González,et al.  Carotid body chemoreceptors: from natural stimuli to sensory discharges. , 1994, Physiological reviews.

[25]  Blair D. Johnson,et al.  Role of the carotid body chemoreceptors in glucose homeostasis and thermoregulation in humans , 2018, The Journal of physiology.

[26]  Silvestro Micera,et al.  High frequency shift in Carotid Sinus Nerve and Sympathetic Nerve activity in Type 2 Diabetic Rat Model* , 2019, 2019 9th International IEEE/EMBS Conference on Neural Engineering (NER).

[27]  Victor Pikov,et al.  Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes , 2018, Diabetologia.

[28]  Maria P. Guarino,et al.  Carotid body, insulin, and metabolic diseases: unraveling the links , 2014, Front. Physiol..

[29]  Cristian Sevcencu,et al.  A neural blood pressure marker for bioelectronic medicines for treatment of hypertension. , 2017, Biosensors & bioelectronics.

[30]  J. Dempsey,et al.  Do carotid chemoreceptors inhibit the hyperventilatory response to heavy exercise? , 1994, Canadian journal of applied physiology = Revue canadienne de physiologie appliquee.

[31]  C. Stecco,et al.  The Carotid Sinus Nerve—Structure, Function, and Clinical Implications , 2019, Anatomical record.

[32]  P. Matafome,et al.  Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats , 2019, Nutrients.

[33]  R. Oostenveld,et al.  Nonparametric statistical testing of EEG- and MEG-data , 2007, Journal of Neuroscience Methods.

[34]  J. Marshall,et al.  Peripheral chemoreceptors and cardiovascular regulation. , 1994, Physiological reviews.

[35]  Silvia V Conde,et al.  Carotid body: a metabolic sensor implicated in insulin resistance. , 2018, Physiological genomics.

[36]  R. Iturriaga.  Translating carotid body function into clinical medicine , 2017, The Journal of physiology.

[37]  J. Karemaker,et al.  Denervation of Carotid Baro‐ and Chemoreceptors in Humans , 2003, The Journal of physiology.

[38]  Stéphane Mallat,et al.  A Theory for Multiresolution Signal Decomposition: The Wavelet Representation , 1989, IEEE Trans. Pattern Anal. Mach. Intell..

[39]  G. Dibona.  Sympathetic nervous system and hypertension. , 2013, Hypertension.

[40]  K. Patel,et al.  Role of Chemoreceptor Activation in Hemodynamic Responses to Electrical Stimulation of the Carotid Sinus in Conscious Rats , 2015, Hypertension.

[41]  S. Malpas.  Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. , 2010, Physiological Reviews.