Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice

Abstract

Both normal aging and dementia are associated with dysregulation of the biological clock, which contributes to disrupted circadian organization of physiology and behavior. Diminished circadian organization in conjunction with the loss of cholinergic input to the cortex likely contributes to impaired cognition and behavior. One especially notable and relatively common circadian disturbance among the aged is "sundowning syndrome," which is characterized by exacerbated anxiety, agitation, locomotor activity, and delirium during the hours before bedtime. Sundowning has been reported in both dementia patients and cognitively intact elderly individuals living in institutions; however, little is known about temporal patterns in anxiety and agitation, and the neurobiological basis of these rhythms remains unspecified. In the present study, we explored the diurnal pattern of anxiety-like behavior in aged and amyloid precursor protein (APP) transgenic mice. We then attempted to treat the observed behavioral disturbances in the aged mice using chronic nightly melatonin treatment. Finally, we tested the hypothesis that time-of-day differences in acetylcholinesterase and choline acetyltransferase expression and general neuronal activation (i.e., c-Fos expression) coincide with the behavioral symptoms. Our results show a temporal pattern of anxiety-like behavior that emerges in elderly mice. This behavioral pattern coincides with elevated locomotor activity relative to adult mice near the end of the dark phase, and with time-dependent changes in basal forebrain acetylcholinesterase expression. Transgenic APP mice show a similar behavioral phenomenon that is not observed among agematched wild-type mice. These results may have useful applications to the study and treatment of age-and dementia-related circadian behavioral disturbances, namely, sundowning syndrome.Alzheimer's disease | cholinesterase | nucleus basalis of Meynert | behavioral and psychological signs and symptoms of dementia B oth normal aging and dementia are associated with disturbances in the biological clock that contribute to dramatic circadian disorganization, including the sleep-wake cycle, body temperature rhythm, and daily patterns of hormone release (1). Generally, aging is associated with reduced amplitudes among these daily rhythms; the most severe changes are associated with Alzheimer's disease (AD) (2). Circadian disorders affect more than 80% of individuals over age 65 (3) because of several converging factors; loss of neurons in the suprachiasmatic nucleus, decreased melatonin and melatonin receptor sensitivity, and minimal zeitgebers because of lifestyle all contribute to circadian dysfunction (1, 4).Normal aging and dementia are also associated with impairments in cognition and behavior, in part caused by loss of cholinergic input to the cortex (5). In particular, parts of the basal forebrain, most notably the nucleus basalis of Meynert (NBM), undergo degenerative changes, such as down-regulation of choline acetyltransferase (ChAT) activity (the r...

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…76 That may also explain why not every single AD patient has anxiety disorder as seen in different types of APP-related AD animal models. [24][25][26]77 However, several recent studies indicate that 3XTg AD mice show significant anxiety. 29,30 Thus, we speculate that tauopathies may play a more important role in inducing mental disorder than b-amyloid during the course of AD.…”

“…22,23 In the AD-related APP or APP/PS1 models, some show anxiety, 24,25 others do not, [26][27][28] whereas the 3XTg mice, which overexpress tau and APP/PS1, show significant anxiety behaviors, 29,30 suggesting a more intimate connection between tau and anxiety. In transgenic mice with conditional expression of N-terminal tau in nesting-positive cells, the anxiety behavior was also shown, 31 which provides direct evidence supporting the role of tau in anxiety.…”

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…In a further study on APP23 mice, activity in the second half of the active phase is increased (61), and this might be analogous to sundowning in AD patients, which also occurs in the second half of the active phase. In the APP mouse there are alterations in the temporal organization of anxiety-like symptoms that emerge when compared with age-matched control subjects (62) and again suggest that such changes might be important for understanding circadian influences on sundowning.…”

Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases

“…The majority of animal studies evaluating the effects of melatonin on AD model animals have outcomes of interest other than sleep or circadian disorders, although sundowning has been shown not to be decreased by 4 weeks of melatonin administration in an AD animal model [47]. In AD models evaluating disease pathology, data for a beneficial effect of melatonin are more encouraging.…”