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Principal Investigator: Jason H. Mateika
Organization: JOHN D DINGELL VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Sleep disordered breathing (SDB) affects 4-9% of the general population and up to 60 % of the Veteran
population. There is also a high prevalence of sleep disordered breathing in patients with subacute and chronic
spinal cord injury (SCI), and the frequency of SCI is approximately 3 times greater in the Veteran population.
Close to 90 % of individuals with cervical SCI demonstrate central sleep apnea (CSA). The presence of CSA is
often accompanied by cardiovascular disease and hypertension. A common underlying mechanism could be
responsible for this coupling. An intriguing possibility is that reductions in central nervous system serotonin,
and/or modifications in serotonin receptor sub-types, that might underlie mental health disorders (e.g. post-
traumatic stress disorder), or be altered in response to SCI, could be responsible for the coupling of central sleep
apnea and heart failure. Thus, our general hypothesis is that depletion of serotonin, induced either genetically
or because of SCI, causes increases in the severity of CSA (i.e. frequency and duration of events). This increase
is coupled to increased sympathetic outflow and ultimately heart failure that manifests with age. To test this
general hypothesis, we will explore in Aim 1a if SCI in young and elderly tryptophan hydroxylase 2 wild type
(TPH2+/+) and knock-out (TPH2-/-) mice leads to more frequent and prolonged apneic events coupled to reduced
arousal and chemoreflex responses to hypoxia and hypercapnia. Aim 1b will explore if modifications in central
nervous system serotonin or its receptor sub-types induced genetically or via spinal cord injury also leads to
increased sympathetic outflow and left ventricular hypertrophy with conserved ejection fraction in young male
mice. We propose that with age these modifications will ultimately lead to heart failure characterized by a reduced
ejection fraction. Lastly, we will determine if treatment with a selective serotonin re-uptake inhibitor (i.e.
paroxetine) will lead to reductions in the number and duration of apneic events along with reductions in lumbar
sympathetic nerve activity and left ventricular hypertrophy coupled to an increase in ejection fraction.The findings
from this proposal will be a significant step toward determining if modulation of serotonin in the central nervous
system is an important mechanistic link between CSA and heart failure in SCI Veterans. The findings will also
provide the rationale to therapeutically modulate serotonin levels to mitigate centrally modulated apneic events
and cardiac dysfunction in intact or SCI Veterans.
Terms: <5-HT><5-HT Receptors><5-HT pathway><5-HT system><5-HT-2A Gene><5-HT2A><5-Hydroxytryptamine><5-Hydroxytryptamine (Serotonin) Receptor 2A Gene><5-Hydroxytryptamine Receptor 2A><5-Hydroxytryptamine Receptor 2A Gene><5-Hydroxytryptamine Receptors><5HT><Affect><Age><Air Movements><Apnea><Arousal><Brain Stem><Brainstem><Breathing><CNS Nervous System><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Central Alveolar Hypoventilation><Central Apnea><Central Nervous System><Central Sleep Apnea><Central Sleep Apnea Syndrome><Central Sleep-Disordered Breathing><Central Sleep-Disordered Breathings><Cervical Injury><Cervical spinal cord injury><Chronic><Classification><Coupled><Coupling><Cranial Nerve XII><Diagnosis><Disease><Disorder><Dysfunction><EFRAC><Echocardiogram><Echocardiography><Ejection Fraction><Elderly><Enteramine><Event><Frequencies><Functional disorder><General Population><General Public><Genetic><Geometry><HTR2><HTR2 Gene><HTR2A><HTR2A gene><Heart Vascular><Heart failure><High Prevalence><Hippophaine><Hypercapnia><Hypertension><Hypoglossal Nerve><Hypoglossal nerve structure><Hypoxia><Hypoxic><Incidence><Individual><KO mice><Knock-out Mice><Knockout Mice><LVEF><Lead><Left><Left Ventricular Ejection Fraction><Left Ventricular Function><Left Ventricular Hypertrophy><Link><Measures><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modification><Motor Cell><Motor Neurons><Murine><Mus><Myocardial depression><Myocardial dysfunction><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurologic><Neurological><Neurons><Null Mouse><Obstructive Sleep Apnea><Ondine Syndrome><Outcome><Oxygen Deficiency><PTSD><Paroxetine><Patients><Pb element><Phrenic Nerve><Physiologic><Physiological><Physiopathology><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Psychiatric Disease><Psychiatric Disorder><Receptor Protein><Reflex><Reflex action><Respiratory Aspiration><Respiratory Inspiration><Respiratory Muscles><Role><SSRI><SSRIs><Screening procedure><Selective Serotonin Reuptake Inhibitor><Selective serotonin re-uptake inhibitor><Sensory><Serotonergic System><Serotonin><Serotonin 5-HT-2 Receptor Gene><Serotonin 5-HT-2A Receptor><Severities><Sleep Apnea><Sleep Apnea Syndromes><Sleep Fragmentations><Sleep Hypopnea><Sleep-Disordered Breathing><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Structure of phrenic nerve><Sympathetic Nervous System><Syndrome, Sleep Apnea, Obstructive><Systematics><TPH2><Testing><Therapeutic><Time><Transthoracic Echocardiography><Traumatic Myelopathy><Twelfth Cranial Nerve><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Ventilatory Muscles><Veterans><Wild Type Mouse><Withdrawal><advanced age><ages><air flow><airflow><airway muscle><carbon dioxide retention><cardiac dysfunction><cardiac failure><cardiac function><cardiovascular disorder><circadian><circulatory system><constriction><elevated carbon dioxide><function of the heart><genioglossus><genioglossus muscle><geriatric><heart dysfunction><heart function><heart sonography><heavy metal Pb><heavy metal lead><high blood pressure><hypercarbia><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><increased level Carbon dioxide><inspiration><male><mental illness><military veteran><motoneuron><mouse model><murine model><neuronal><pathophysiology><post-trauma stress disorder><posttrauma stress disorder><prevent><preventing><psychiatric illness><psychological disorder><receptor><respiratory><response><screening tools><senior citizen><serotonergic pathway><serotonin pathway><serotonin receptor><serotonin reuptake inhibitor><serotonin system><sleep-related breathing disorder><social role><traumatic neurosis><tryptophan hydroxylase 2><veteran population><wildtype mouse>