Deficiencies in choroidal blood flow (ChBF) have long been suggested to underlie age-related retinal decline, and cause the outer retinal abnormalities that set the stage for AMD, given the necessary risk-conferring genes. Nonetheless, experimental evidence that this is the case has been lacking. We have been investigating the parasympathetic control of ChBF. We have found that the vasodilatory parasympathetic facial nerve input to choroid from the pterygopalatine ganglion appears to maintain high ChBF during low systemic blood pressure. We have found that this adaptive reflex, which we term ChBF baroregulation, is impaired by age, and when impaired by experimental manipulations in animal models leads to ChBF insufficiency and declines in retinal function. The studies proposed here will build on these findings and experimentally determine if impaired ChBF baroregulation leads to the types of outer retinal pathologies that characterize aging and/or early (i.e. dry) AMD.
Three Aims will be pursued, all in rats. In the first Aim, we will determine the basic neural mechanisms by which ChBF baroregulation is mediated. These studies will provide basis for determining the defects that cause dysfunction of ChBF baroregulation, and identify points of intervention that might allow restoration of normal ChBF control. Our particular goal is to determine how blood pressure signals from the thoracic aorta via the aortic depressor nerve (ADN) regulate ChBF by their input to the nucleus of the solitary tract (NTS) and its output to the parasympathetic part of the facial nucleus (the superior salivatory nucleus, SSN), which project to the vasodilatory neurons of the pterygopalatine ganglion, which themselves innervate choroidal blood vessels. To this end, we will use imaging of circuit connectivity and pharmacological approaches to determine if SSN- projecting NTS neurons are excitatory and receive input from inhibitory ADN-receptive NTS neurons. In our second Aim, we will characterize by functional and morphological means the outer retinal abnormalities caused by long-term disturbance in ChBF baroregulation. We will be particularly interested in determining if the outer retina pathologies include those observed in aging, such as sub-RPE basal laminar deposits and photoreceptor loss, and/or those seen early in AMD, such as sub-RPE basal linear deposits, RPE and photoreceptor loss, and outer retinal waste accumulation (cholesterol, and proteins with advanced glycation end-product or peroxidized lipid adducts). Since light history is an AMD risk factor, we will also determine if impaired ChBF baroregulation exacerbates photoreceptor light damage. In the third Aim, we will determine if age-related choroidal baroregulatory impairments are associated with outer retinal dysfunction and pathology. Our studies may suggest choroidal baroregulation impairment as underlying age-related retinal decline, and as an AMD risk factor. This would suggest testing of choroidal baroregulation to assess AMD risk, and recommend drugs that boost ChBF as therapies.
Our studies will determine how the brain uses low blood pressure signals to maintain high blood flow in the choroidal layer of the eye, so the outer retina receives the nutrients it needs to remain healthy and function properly. We will also determine if impairment of this function underlies the retinal decline that occurs with aging, and explains why aging is the major risk factor for AMD. Our studies may lead to use testing of blood pressure regulation of choroidal blood flow as an AMD risk assessment, as well as lead to use of drugs that normalize neural control of choroidal blood flow to slow AMD onset and progression.
|Reiner, Anton; Fitzgerald, Malinda E C; Del Mar, Nobel et al. (2018) Neural control of choroidal blood flow. Prog Retin Eye Res 64:96-130|
|Li, Chunyan; Fitzgerald, Malinda E C; Del Mar, Nobel et al. (2018) Defective Choroidal Blood Flow Baroregulation and Retinal Dysfunction and Pathology Following Sympathetic Denervation of Choroid. Invest Ophthalmol Vis Sci 59:5032-5044|
|Li, Chunyan; Fitzgerald, Malinda E C; Del Mar, Nobel et al. (2016) Disinhibition of neurons of the nucleus of solitary tract that project to the superior salivatory nucleus causes choroidal vasodilation: Implications for mechanisms underlying choroidal baroregulation. Neurosci Lett 633:106-111|
|Li, Chunyan; Fitzgerald, Malinda E C; Del Mar, Nobel et al. (2015) The identification and neurochemical characterization of central neurons that target parasympathetic preganglionic neurons involved in the regulation of choroidal blood flow in the rat eye using pseudorabies virus, immunolabeling and conventional pathway Front Neuroanat 9:65|
|Reiner, Anton; Heldt, Scott A; Presley, Chaela S et al. (2015) Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int J Mol Sci 16:758-87|
|Toledo, Claudio A B; Reiner, Anton; Patel, Reena S et al. (2011) Immunohistochemical localization of AMPA-type glutamate receptor subunits in the nucleus of the Edinger-Westphal in embryonic chick. Neurosci Lett 498:199-203|
|Reiner, Anton; Del Mar, Nobel; Zagvazdin, Yuri et al. (2011) Age-related impairment in choroidal blood flow compensation for arterial blood pressure fluctuation in pigeons. Invest Ophthalmol Vis Sci 52:7238-47|
|Kozicz, Tamás; Bittencourt, Jackson C; May, Paul J et al. (2011) The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 519:1413-34|
|Reiner, Anton; Li, Chunyan; Del Mar, Nobel et al. (2010) Choroidal blood flow compensation in rats for arterial blood pressure decreases is neuronal nitric oxide-dependent but compensation for arterial blood pressure increases is not. Exp Eye Res 90:734-41|
|Li, Chunyan; Fitzgerald, Malinda E C; Ledoux, Mark S et al. (2010) Projections from the hypothalamic paraventricular nucleus and the nucleus of the solitary tract to prechoroidal neurons in the superior salivatory nucleus: Pathways controlling rodent choroidal blood flow. Brain Res 1358:123-39|
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