Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging

Abstract

The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6-42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats.

Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

“…Our group and others have recently highlighted the importance of group 1 mGluRrelated synaptic plasticity in successful cognitive aging (Menard and Quirion 2012b;Menard et al 2013bMenard et al , 2014bYang et al 2013a). Eight mGluR have been identified and divided into three groups: group 1 includes postsynaptic mGluR1 and mGluR5, while group 2 (mGluR2, mGluR3) and group 3 (mGluR4, mGluR6, mGluR7, mGluR8) are mainly presynaptic (for a review, see Nicoletti et al 2011).…”

“…Interestingly, the ability to recognize a familiar versus novel stimulus (Rowe et al 1998) or objects (Menard et al 2013b(Menard et al , 2014b declines with normal aging in rodents. Recognition memory tests compared time spent exploring familiar versus novel objects, smells, or tastes in distinct spatial locations (Fedulov et al 2007;Dere et al 2007;Tse et al 2007;Menard et al 2013b).…”

“…While the hippocampus is still involved in the formation of fear learning and memory (Radulovic and Tronson 2010), the amygdala is central to these processes (Maren and Quirk 2004;McGaugh 2004;Hermans et al 2014 (Bouwknecht and Paylor 2002;Ducottet and Belzung 2005;Crawley 2008;Menard et al 2013b). Old rodents are generally characterized by exacerbated anxious behaviors and stress responses (Menard et al 2013b(Menard et al , 2014b which affects brain synaptic plasticity and memory formation.…”

“…This type of memory involves efficient pattern separation and inhibitory learning processes which can be affected by aging Menard and Quirion 2012b;Menard et al 2013b). Stimulation of group 1 mGluRs could act as a molecular switch to facilitate synaptic plasticity (Bortolotto et al 2005;Manahan-Vaughan and Braunewell 2005;Bikbaev et al 2008;Neyman and Manahan-Vaughan 2008) particularly in the aging brain (Menard and Quirion 2012a, b;Menard et al 2013bMenard et al , 2014bYang et al 2013a). …”

“…However, in aging rats of similar ages, important inter-individual differences in cognitive abilities have been reported (Gallagher et al 1993Aubert et al 1995;Quirion et al 1995;Rowe et al 1998;Wilson et al 2003;Menard and Quirion 2012b). Sex and strain differences have also been observed (Markowska 1999;Menard et al 2014b) but will not be specifically addressed in this chapter. Variations of cognitive status in aged rats are not related to neuronal loss, as cell death in the hippocampus and neocortex does not characterize normal aging in rodents (Rapp and Gallagher 1996;Rasmussen et al 1996;Merrill et al 2001;Gallagher et al 2003).…”