A cellular basis for neurogenic orthostatic hypotension

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 DESCRIPTION (provided by applicant): In humans, orthostatic hypotension (OH) is defined as a fall in blood pressure of at least 20/10 (systolic/diastolic) mmHg within three minutes of standing or during head-up tilt. It occurs in a wide variety of medical conditions, including neurologic disorders. Neurogenic OH is common in patients with dizziness, vertigo, brainstem lesions, and diseases such as multiple system atrophy and Parkinson's disease. Clinical studies indicate that one cause of neurogenic OH may be vestibular system hypofunction, particularly involving vestibulo-sympathetic reflex pathways. Support for this derives from numerous studies in humans and experimental animals that provide clear evidence for a functional link between the vestibular system and blood pressure control. Both vestibular system disorders (e.g. balance) and OH are more prevalent and severe in the elderly. This exploratory project uses an aged rat model to study one putative cellular alteration underlying OH. Pituitary adenylate cyclase-activating peptide (PACAP) is a neuromodulator involved in a wide range of physiological functions including cardiovascular control and neuroprotection. Recent preliminary studies indicate that PACAP is normally present in rat vestibular neurons, and that this expression is severely altered in aged animals with behavioral signs of OH. The present proposal seeks to determine, in both sexes, whether OH in aged rats is associated with degeneration of PACAP-containing neurons of the vestibulo-sympathetic reflex pathway. Aim 1 is to assess blood pressure changes in young-adult and aged male and female rats in response to sinusoidal galvanic vestibular stimulation and nose-up tilt, both of which activate the vestibulo- sympathetic reflex. We hypothesize that blood pressure will decrease in most aged rats, but few young-adults, establishing a rodent model of orthostatic hypotension. Aim 2 is to compare FluoroJade C labeling, which identifies degenerating neurons, in PACAP-positive vestibulo-sympathetic reflex projection neurons in tissue from the physiologically characterized rats studied in Aim 1. The retrograde tracer FluoroGold will be used to identify the projections, and cFos labeling will be used to verify that the neurons are activated by the stimulus. We hypothesize that OH correlates with degeneration of PACAP-containing vestibular neurons of the vestibulo-sympathetic reflex pathway. If successful, this project will provide the foundation for a comprehensive study addressing the cellular bases for the decline in vestibulo-sympathetic function in the elderly.