Abstract
The progression of amyloid plaques and neurofibrillary tangles in different brain areas is associated with the effects of Alzheimer’s disease (AD). In addition to cognitive impairment, circadian alterations in locomotor activity have also been detected, but they have not been characterized in a jet lag protocol. Therefore, the present study aimed to compare 3xTg-AD and non-transgenic mice in changes of 24 h cycles of spontaneous locomotor activity in a jet lag protocol, in an environment without a running wheel, at 3 different states of neuronal damage: early, intermediate and advanced (3, 8 and 13 months, respectively). The 3xTg-AD mice at 3 months presented differences in phase angle and acrophase, and differentially increased activity after advances more than after delays. At 13 months, a shortening of the free-running period in constant darkness was also noted. 3xTg-AD mice showed a significant increase (123%) in global activity at 8 to 13 months and in nighttime activity (153%) at 13 months. In the advance protocol (ADV), 3xTg-AD mice displayed a significant increase in global activity (171%) at 8 and 13 months. The differences in masking effect were evident at 8 months. To assess a possible retinal dysfunction that could interfere with photic entrainment as part of the neurodegenerative process, we compared electroretinogram recordings. The results showed early deterioration in the retinal response to light flashes in mesopic conditions, observed in the B-wave latency and amplitude. Thus, our study presents new behavioral and pathological characteristics of 3xTg-AD mice and reveals the usefulness of non-invasive tools in early diagnosis.
Highlights
It is currently estimated that 44 million people worldwide have dementia
ELECTRORETINOGRAM ANALYSIS We explored if the functional retinal response was progressively affected in the 3xTg-Alzheimer’s disease (AD) mice at 3, 8 and 13 Mo, which correspond to early, intermediate and advanced states of neurodegeneration
CIRCADIAN DISTURBANCES IN 3XTG-AD MICE The results indicated that 3xTg-AD mice at 13 Mo increased total locomotor activity and photophase activity after LD advance
Summary
It is currently estimated that 44 million people worldwide have dementia. Of these, 60–80% are due to Alzheimer’s disease (AD) [1, 2]. Its photic entrainment (effect of light on the regulation of internal biological rhythms) starts in the intrinsically photosensitive retinal ganglion cells (ipRGCs) that send information through the retinohypothalamic tract (RHT) and release glutamate and PACAP to neurons and glia within the SCN [10] This information influences clock genes, which control all aspects of physiological activities and are involved in generating and maintaining circadian rhythms by means of two transcriptional activation/repression loops: a positive one controlled by Clock and Bmal genes and a negative one controlled by Per and Cry. The chemical and electrical coupling between SCN neurons influences neuroendocrine and behavioral outputs that affect virtually all tissues within the organism (peripheral oscillators). This process of resynchronization, associated with various metabolic, physiological and behavioral changes, and with a deficit in cognitive processes such as attention, memory and reaction times, is known as jet lag [13,14,15,16]
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