Neurobiology of Aging 27 (2006) 1848–1858 Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments O. George a,b,∗ , A. Parducz c , D. Dupret a,b , M. Kharouby a,b , M. Le Moal a,b , P.V. Piazza a,b , W. Mayo a,b a INSERM, U588, Bordeaux, F-33077 France b Universit´ e de Bordeaux II, Institut Fran¸ cois Magendie, F-33077 France c Laboratory of Molecular Neurobiology, Instituteof Biophysics, Biological Research Center, 6701 Szeged, Hungary Received 3 June 2005; received in revised form 7 October 2005; accepted 18 October 2005 Available online 28 November 2005 Abstract In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGF-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies. © 2005 Elsevier Inc. All rights reserved. Keywords: Aging; Memory; Sleep; Cholinergic; Pedunculopontine; Growth factor 1. Introduction Human aging is associated with impairments of episodic memories that range from mild to severe deficits [24,51]. Pathophysiological origins of severe deficits, like Alzheimer’s disease, have been largely investigated, but lit- tle is known on the origins of mild deficits, like age-associated memory impairments (AAMI) which occurs in 22 to 56% of the aged [14,30,53–55]. Several observations suggest that age-related alterations of the sleep/wake circadian rhythm could play a primary role in AAMI. Firstly, memories impaired in AAMI are processed during non-REM sleep and REM sleep [65]. Sec- ∗ Corresponding author. Tel.: +33 5 57 57 36 60; fax: +33 5 57 57 36 69. E-mail address: olivier.george@bordeaux.inserm.fr (O. George). ondly, a decrease in the amplitude (the difference between the maximum and the rhythm-adjusted mean of the best fit- ting curve) of the sleep/wake circadian rhythm is one of the most marked change observed with aging [50,64]. Finally, the prevalence of sleep disorders and AAMI are very similar [12,47]. Even though the causal relationship between experi- mentally induced sleep deficits and memory impairments has been extensively demonstrated in young subjects (for review see [65]), direct evidences for a physiological relationship between age-related sleep/wake circadian rhythm deficits and episodic-like memory impairments are still lacking. To address this issue, we investigated at the behav- ioral, anatomical and molecular levels the potential relation- ships between sleep/wake circadian rhythm alterations and episodic-like memory impairments using the model of the aging rodent. This is a relevant model since in rodents and in 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.10.014