A significant number of patients with Alzheimer's disease (AD) manifest depressive symptoms. This comorbid condition is exceptionally detrimental to quality of life in these individuals. The etiology and central pathways affected in these disorders is a subject of intense investigation. Although animal models of depression have been available for some time, only recently has a double transgenic mouse (dtg) model of AD been developed. Preliminary results indicate a significant loss of noradrenergic cells in the locus coeruleus (LC) of these mice. Noradrenergic pathways are also implicated in depressive behavior. Moreover, LC projection to the paraventricular nucleus (PVN) of the hypothalamus may play an important role in regulation of the hypothalamic-pituitary adrenal axis. This axis, driven by corticotropin-releasing hormone (CRH) and vasopressin (VP) containing cells in the PVN is impaired in both AD and depression. A major goal of this proposal is to investigate depressive characteristics in these mice. Moreover, synaptic connectivity between noradrenergic nerve terminals and PVN cells containing CRH and VP will be investigated at both light and electron microscopic (EM) level. It is hypothesized that: 1) the double transgenic mice will manifest depressive behavior; 2) the depressive symptoms will be exaggerated in the aged dtg mice; 3) a reduced number of CRH and VP containing neurons will be observed in the PVN of dtg mice; 4) a reduced number of synaptic contacts between noradrenergic terminals and CRH and VP containing neurons of PVN will be obtained in dtg mice. Young, adult and old dtg mice and their wild type control will be used. Porsolt forced swim test and tail suspension tests will be used to evaluate depressive characteristics. Immunocytochemistry combined with stereology will be applied to quantify specific cell number and synapses at both light and EM levels. Results from these studies will enhance our understanding of circuits that might be involved in concomitant expression of depression and AD. Such knowledge can lead to better interventions in this devastating comorbid condition.
