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Published in final edited form as: Neurobiol Learn Mem. 2020 Jan 19;169:107168. doi: 10.1016/j.nlm.2020.107168

Rolipram treatment during consolidation ameliorates long-term object location memory in aged male mice

Mathieu E Wimmer 1, Jennifer Blackwell 2, Ted Abel 3
PMCID: PMC7106430  NIHMSID: NIHMS1551654  PMID: 31962134

Abstract

Normal aging is accompanied by cognitive and memory impairments that negatively impact quality of life for the growing elderly population. Hippocampal function is most vulnerable to the deleterious effects of aging, and deficits in hippocampus-dependent memories are common amongst aged individuals. Moreover, signaling networks such as the cAMP/PKA/CREB pathway, which are critical for memory consolidation, are dampened in healthy aged subjects. Phosphodiesterase (PDE) enzymes that break down cAMP are also affected by aging, and increased break down of cAMP by PDEs may contribute to reduced activity of the cAMP/PKA/CREB signaling network in the brain of aged individuals. Here, we report that the PDE4 inhibitor rolipram administered during consolidation of hippocampus-dependent object location memory improves aged-related spatial memory deficits in aged mice.

Keywords: hippocampus, cAMP, spatial memory, aging, CREB, PDE4

Introduction

Human and animal studies indicate that aging is accompanied by memory deficits and cognitive decline (Bettio, Rajendran, and Gil-Mohapel, 2017; Chen, Volle, Jalil, Wu, and Small, 2019; Tromp, Dufour, Lithfous, Pebayle, and Despres, 2015). The hippocampus is particularly vulnerable to the deleterious effects of aging (Bach, Barad, Son, Zhuo, Lu, Shih, Mansuy, Hawkins, and Kandel, 1999; Belblidia, Leger, Abdelmalek, Quiedeville, Calocer, Boulouard, Jozet-Alves, Freret, and Schumann-Bard, 2018; Gallagher, Bakker, Yassa, and Stark, 2010; Li, Abdourahman, Tamm, Pehrson, Sanchez, and Gulinello, 2015; Oliveira, Hemstedt, and Bading, 2012; Wiescholleck, Emma Andre, and Manahan-Vaughan, 2014; Wimmer, Hernandez, Blackwell, and Abel, 2012), leading to impairments in episodic memory (Miller and O’Callaghan, 2005; Park and Reuter-Lorenz, 2009) and spatial navigation (Barnes, 1979; Gage, Dunnett, and Bjorklund, 1984; Markowska, Stone, Ingram, Reynolds, Gold, Conti, Pontecorvo, Wenk, and Olton, 1989). Another consistent observation has been that neural signaling pathways and molecular correlates of memory are disrupted by aging.

The CREB family of transcription factors and related signaling cascades are key mediators of activity-dependent nuclear responses underlying memory and synaptic plasticity (Josselyn and Nguyen, 2005; Josselyn, Shi, Carlezon, Neve, Nestler, and Davis, 2001; Kandel, 2012; Mizuno and Giese, 2005). Studies in Aplysia (sea slug), Drosophila (fruit fly) and rodents indicate that CREB is required for long-term memory consolidation (Bourtchuladze, Frenguelli, Blendy, Cioffi, Schutz, and Silva, 1994; Josselyn and Nguyen, 2005; Josselyn et al., 2001), the process by which labile short-term memories are stabilized into long-term traces. One activity-dependent mechanisms regulating CREB-mediated transcription begins with a rise in cAMP levels, activation of protein kinase A and phosphorylation of CREB at serine-133 (pCREB), which promotes recruitment of co-activators such as CREB binding protein (CBP) and the transcriptional machinery to active transcription sites (Mayr and Montminy, 2001). The activity of phosphodiesterases (PDEs) enzymes that degrade cAMP and oppose the actions of the cAMP/PKA/CREB pathway (Francis, Blount, and Corbin, 2011) is higher in the hippocampus of aged rodents (Kelly, 2018). Therefore, inhibiting PDEs may be a viable avenue for enhancing memory, particularly in the context of cognitive decline and/or neurological disease (Fusco and Giampa, 2015; Garcia-Barroso, Ugarte, Martinez, Rico, Lanciego, Franco, Oyarzabal, Cuadrado-Tejedor, and Garcia-Osta, 2014; Gulisano, Tropea, Arancio, Palmeri, and Puzzo, 2018; Teich, Nicholls, Puzzo, Fiorito, Purgatorio, Fa, and Arancio, 2015). We hypothesized that rolipram-mediated inhibition of PDE4, one of the phosphodiesterases that impinges upon the cAMP/PKA/CREB pathway, would improve hippocampus-dependent object location memory in aged mice.

Methods

Animals

Young (2–4 months-old) and aged (22–24 months-old) male C57BL/6NIA mice were procured from the National Institute of Aging and used in all experiments. Food and water were provided ad libitum. Lights were maintained on a 12–12 light/dark cycle, and all experiments were performed in the light phase starting at lights one and ending 2–3 hours later (from ZT 0–3). Mice were singly housed a week before training. Animals were handled in the experimental room for 1 minute per day for 3 days prior to the first exposure to the training arena. All experiments were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania and conducted according to National Institutes of Health guidelines.

Drugs

Rolipram (Sigma-Aldrich) was dissolved in a 2% DMSO and 0.9% sterile saline solution. Vehicle or 1mg/kg rolipram was injected intraperitoneally (i.p.).

Object location memory task

Object location memory experiments were performed as described previously (Oliveira, Hawk, Abel, and Havekes, 2010; Wimmer et al., 2012). On the day of training, mice were placed in the training arena for a total of four 10-minute sessions with an inter-session interval of 3 minutes during which mice were returned to their home cages. The first session consisted of a context habituation period without objects in the arena. During the next three sessions, mice were placed in the training arena with two distinct objects. The objects used were a glass bottle, and a metal tower (5“H x 2”W x 2”L). The objects and the arenas were wiped with 70% ethanol before and after each session. 24 hours after training, mice were placed in the original training context for 10 minutes with one object displaced to a new location (displaced object, DO), while the other object was not moved (non-displaced object, NDO). Exploration was recorded during training and testing on a digital camera for subsequent scoring of time spent exploring objects. Exploration of the objects was defined as the amount of time mice were oriented toward an object with its nose within 1 cm of it and was scored by an experimenter blind to age and drug treatment.

Data analysis

Percent preference in the object location experiment was calculated as time spent exploring the DO relative to the total time spent exploring both objects (i.e., preference = DO/(NDO+DO)). Repeated measures 3 way ANOVAs (GLM model) were used to compare age (young vs. aged) and drug treatment (rolipram vs. vehicle) groups with respect to total exploration of objects and to preference during training vs. retrieval test sessions. The within subject factors were either session for total exploration time or training day (train vs. 24-hour test) for preference. Age and drug treatment were between-subject factors in all ANOVAs using GraphPad Prism version 8.1. Bonferroni post-hoc tests were used in the event of a significant session x drug treatment x age interaction or day x drug treatment x age. The post-hoc tests compared preference during training vs. preference during the 24 hour test for each of the four groups: young vehicle, aged vehicle, young rolipram, aged rolipram. p<0.05 was considered significant.

Results

We first tested whether two injections of rolipram administered during the consolidation window of object location memory could ameliorate aged-related deficits in long-term object location memory. Young adult (2–4 months old) and aged (22–24 months old) male C57Bl/6NIA mice were exposed to two identical objects for 3 distinct 10-minute training sessions with a 2-minute inter-trial interval. Vehicle or rolipram (1mg/kg) was injected i.p. immediately after the third training session and again 2.5 hours later (Figure 1A). This dose of rolipram injected systemically has been shown to increase cAMP and pCREB levels in the hippocampus for up to 3 hours post injection (Xiao, O’Callaghan, and O’Donnell, 2011), so this experimental design aimed to boost cAMP/pCREB signaling during the first 5 to 6 hours of the consolidation period. We chose this dose of 1mg/kg because it was amongst the lowest reported to have an impact on cAMP and pCREB in the brain. Our goal was to administer a regimen that would not enhance baseline performance or consolidation of object location memory. 24 hours after training, all animals were returned to the training arena where one of the two objects was moved to a novel location, while the other object remained in its original location. Repeated measures ANOVA revealed that the time spent exploring both objects during training decreased over the course of the three sessions, regardless of age or treatment group (Figure 1B; effect of session: [F(2,52)=55.06, p<.0001]; effect of drug treatment [F(1,26)=0.2024, p=.6566], effect of age: [F(1,26)=0.6999, p=.4104]). During the 24-hour retrieval test, all groups except for the aged vehicle-treated animals showed a preference for the displaced object (Figure 1C; overall effect of treatment: [F(1,26)=0.8647, p=.3610], overall effect of time (train vs. test): [F(1,26)=39.39, p<.0001]; overall effect of age: [F(1,26)=0.00087, p=.9768]; interaction of treatment x age x time [F(1,26)=8.666, p=.0067], post-hoc test compared training preference to 24-hour test preference for each of the 4 groups, Young Vehicle, Young Rolipram, Aged Vehicle and Aged Rolipram using Bonferroni correction). These findings indicate that aging impairs long-term object location and that these deficits are mitigated by 2 injections of rolipram administered during the consolidation period after training on the object location task.

Figure 1. Two injections of rolipram rescued aging-related long-term object location memory deficits.

Figure 1.

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A. Animal were trained on the object location task and treated with either rolipram (1mg/kg) i.p. or vehicle immediately after the last training session and again 2.5 hours later. 24 hours after the end of the last training session, animals were returned to the training arena and object location memory was tested. B. The total time spent exploring both objects during each of the three ten minute training session for object location memory. The exploration time decreased over the course of the three session and neither treatment nor age impacted this effect. C. Preference for the displaced object during training and during the 24-hour memory test is shown for each group. Aged animals treated with vehicle do not show a preference for the displaced object 24 hours after training but all other groups show an increased preference for the displaced object comparing training to the 24-hour memory retrieval test. Mean +/− s.e.m. is shown for all graphs. * indicates p< 0.05 using the Bonferroni post-hoc correction test. n.s. = non-significant.

In a separate cohort of mice, we replicated the same experimental design with one modification: all animals received a single injection of either vehicle or rolipram (1mg/kg) immediately after training (Figure 2A). This time point was chosen to cover the first 2–3 hour window of memory consolidation. Repeated measures ANOVA revealed that total exploration time decreased over the three training sessions regardless of drug treatment or age (Figure 2B; overall effect of session: [F(2,85)=22.02, p<.0001]; overall effect of treatment [F(1,43)=0.4085, p=.5261]; overall effect of age [F(1,43)=1.4210, p=.2398; interaction of age x treatment x session: [F(2,86)=2.542,p=.0846]). During the 24-hour retrieval test for object location memory, all groups except vehicle-treated aged mice showed a preference for the displaced object compared to training (Figure 2C; overall effect of treatment: [F(1,42)=3.8010, p=.0579], overall effect of time (train vs. test): [F(1,42)=23.32, p<.0001]; overall effect of age: [F(1,42)=6.060, p=.0124]; interaction of treatment x age x time [F(1,42)=5.176, p=.0281], post-hoc test compared training preference to 24-hour test preference for each of the 4 groups, Young Vehicle, Young Rolipram, Aged Vehicle and Aged Rolipram using Bonferroni correction). These findings indicate that a single injection of rolipram administered immediately after training on the object location task is sufficient to ameliorate long-term memory in aged animals.

Figure 2. A single injection of rolipram is sufficient to ameliorate age-related long-term object location memory deficits in aged animals.

Figure 2.

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A. Immediately following the last training session on the object location task, young and aged animals received an i.p. injection of either vehicle or rolipram (1mg/kg). 24 hours later all mice were returned to the training arena where one of the objects was moved to a novel location. B. The total time exploring objects during each of the three 10 minute training sessions for object location memory was not impacted by age or drug treatment. The exploration time decreased over the course of training. C. Preference for the displaced object increased comparing training to the 24 hour retrieval test in all groups except the vehicle-treated aged mice. Each graph represents mean +/− s.e.m. * indicates p<0.05 using the Bonferroni correction post-hoc tests. n.s.= non-significant.

Discussion

Previous studies from our lab and others suggest that aging is accompanied by hippocampus-dependent memory deficits on object location memory in rodents (Belblidia et al., 2018; Li et al., 2015; Oliveira et al., 2012; Wiescholleck et al., 2014; Wimmer et al., 2012). Here, we replicated these results in two separate cohorts of aged male mice treated with vehicle. We also expanded these findings by showing that rolipram treatment administered immediately after training on the object location task ameliorated memory performance 24 hours after training. Chronic injections of rolipram have been shown to enhance performance on memory object location at 24 hours delays after training (Rutten, Prickaerts, Schaenzle, Rosenbrock, and Blokland, 2008).

Moreover, rolipram (0.1 mg/kg) administered 3 hours, but not immediately after training improved performance during a memory test 24 hours after a weak training protocol in rats (Rutten, Van Donkelaar, Ferrington, Blokland, Bollen, Steinbusch, Kelly, and Prickaerts, 2009). It is worth noting that we chose the lowest possible dose of rolipram in an effort to ameliorate performance in aged animals without enhancing consolidation in young mice. Our data do not indicate that this regimen enhanced consolidation in young mice; however this potential caveat cannot be completely excluded given the current experimental design. Additional experiments using a shorter training protocol would be needed to directly test this possibility.

Sleep deprivation covering the first 5 hours after training impairs long-term object memory; a phenotype that can be rescued by increasing cAMP signaling during the sleep deprivation window (Havekes, Bruinenberg, Tudor, Ferri, Baumann, Meerlo, and Abel, 2014). Conversely, treatment with phosphodiesterases inhibitors immediately or 3 hours following training on the object location task led to enhanced performance during a 24 hour memory test (Bollen, Akkerman, Puzzo, Gulisano, Palmeri, D’Hooge, Balschun, Steinbusch, Blokland, and Prickaerts, 2015). Taken together, these results suggest that the hours following training on the object location task represent a sensitive window, during which the consolidation of object location memory can be manipulated. The idea that consolidation of object location memory closely mirrors the well-established critical time window during which consolidation of associative memories can be altered (Bourtchouladze, Abel, Berman, Gordon, Lapidus, and Kandel, 1998) is further supported by the fact that the time course and nature of the changes in gene expression after fear conditioning and object location training share some similarities (Poplawski, Schoch, Wimmer, Hawk, Walsh, Giese, and Abel, 2014). Moreover, a 3-hour window of sleep deprivation beginning 1 hour after training impairs object location memory but if the window is shifted to immediately after training, object location memory is spared (Prince, Wimmer, Choi, Havekes, Aton, and Abel, 2014). The goal of the current studies was to determine whether inhibiting PDE4 during portions of memory consolidation of object location memory could improve performance in aged animals. We chose two treatment regimens: either two injections (1mg/kg) interspersed by 2.5 hours immediately after training, which would impact the entire consolidation window or a single rolipram injection (1mg/kg) delivered immediately after training, a time of the consolidation period that appears largely insensitive to manipulations (Prince et al., 2014; Rutten et al., 2009). Both treatment regimens with rolipram ameliorated long-term object location memory in aged male mice, suggesting that PDE4 inhibition during the early phase of the memory consolidation period is sufficient to improve long-term object location memory in aged mice.

We chose to focus on spatial object-based memory tasks to circumvent some of the potentially confounding changes in motor behavior, anxiety-like behavior and stress response that accompany aging (Save, Buhot, Foreman, and Thinus-Blanc, 1992; Save, Poucet, Foreman, and Buhot, 1992; Sharma, Rakoczy, and Brown-Borg, 2010). Probing object location memory allowed the use of a single set of training events, which was preferable to test the efficacy of rolipram in ameliorating hippocampus-dependent location memory acutely (Baker and Kim, 2002; de Lima, Luft, Roesler, and Schroder, 2006; Oliveira et al., 2010). Many studies have demonstrated that object location memory critically engages and requires the hippocampus (Ennaceur and Aggleton, 1997; Ennaceur, Neave, and Aggleton, 1997; Oliveira et al., 2010; Roozendaal, Hernandez, Cabrera, Hagewoud, Malvaez, Stefanko, Haettig, and Wood, 2010). We posit that the impact of systemic rolipram treatment on long-term object location memory in aged animals is mediated by its actions within the hippocampus. Micro-injections directly into the hippocampus would be needed to confirm this possibility and other brain regions may also contribute to the effects reported in our study.

Aging is accompanied by substantial signaling changes in the cAMP/PKA/CREB pathway (Kelly, 2018). Despite some discrepancies in the direction of the changes for cAMP and PDEs, the consensus of this literature points toward an overall decrease in CREB-mediated gene expression in aged neural networks compared to young, which may be partly responsible for some of the age-related cognitive decline reported in human and animal studies. Basal cAMP levels are not changed with age in the rodent hippocampus but are decreased in cortex, thalamus and hypothalamus (Hara, Onodera, Kato, and Kogure, 1992; Puri and Volicer, 1981; Schmidt and Thornberry, 1978; Titus, Furones, Kang, and Atkins, 2013). PKA activity as well as phosphorylated CREB levels, which often result from PKA activation, are lower in the hippocampus of aged animals (Brightwell, Gallagher, and Colombo, 2004; Countryman and Gold, 2007; Karege, Lambercy, Schwald, Steimer, and Cisse, 2001; Karege, Schwald, Lambercy, Murama, Cisse, and Malafosse, 2001; Kudo, Wati, Qiao, Arita, and Kanba, 2005; Porte, Buhot, and Mons, 2008; Tomobe, Okuma, and Nomura, 2007). Moreover, CREB deficient mice are more sensitive to age-related cognitive impairments (Hebda-Bauer, Luo, Watson, and Akil, 2007), whereas boosting CaMKIV expression and p-CREB levels in the hippocampus of aged animals can rescue cognitive deficits (Fukushima, Maeda, Suzuki, Suzuki, Nomoto, Toyoda, Wu, Xu, Zhao, Ueda, Kitamoto, Mamiya, Yoshida, Homma, Masushige, Zhuo, and Kida, 2008). Taken together, this rich body of literature suggests that aging is accompanied by an overall decrease in the cAMP/PKA/CREB signaling pathway, which may partly contribute to the cognitive decline associated with healthy aging.

Consistent with the idea that reduced cAMP/PKA/CREB activity and increased PDE activity functionally influence age-related cognitive decline, many compounds and manipulations that target the cAMP/PKA/CREB pathway have been shown to ameliorate age-associated deficits in memory or cognitive function. CREB overexpression in the hippocampus was sufficient to rescue age-related memory deficits (Yu, Curlik, Oh, Yin, and Disterhoft, 2017). Additionally, a number of PDE inhibitors have been shown to have therapeutic effects in animal models and human studies. Caffeine, which partly inhibits PDEs has been shown to slow the rate of cognitive decline in aged individuals (Vercambre, Berr, Ritchie, and Kang, 2013). Inhibition of PDE4 either pharmacologically or by genetic deletion also provided protection against the deleterious effects of aging on memory (Bach et al., 1999; Drott, Desire, Drouin, Pando, and Haun, 2010). In addition to these chronic manipulations, acute treatment with the PDE4 inhibitor rolipram rescued spatial memory deficits in a mouse model of Alzheimer’s disease (Kumar and Singh, 2017) and enhanced long-term fear conditioning in 18 months old rats (Barad, Bourtchouladze, Winder, Golan, and Kandel, 1998). Interestingly, this study also demonstrated that rolipram did not impact short-term fear conditioning in young animals, suggesting that the impact of these acute treatments are primarily mediated by enhancements of memory consolidation. We did not directly test short-term memory after rolipram treatment in the current study but our results are consistent with previous research demonstrating the impact of rolipram on consolidation of hippocampus-dependent memory consolidation. Another PDE4 inhibitor, HT-0712 also rescued hippocampus-dependent fear conditioning in aged mice by increasing the expression of CREB target genes (Peters, Bletsch, Stanley, Wheeler, Scott, and Tully, 2014). Our results add to a growing list of studies suggesting that inhibition of PDE4 may be a viable therapeutic avenue for improving hippocampal function and hippocampus-dependent memory deficits associated with healthy aging.

Highlights.

  • Aged mice show long-term object location memory deficits

  • The PDE4 inhibitor rolipram enhanced memory consolidation in aged animals

  • Rolipram rescued age-realted memory impairments

Acknowledgements:

This work was supported by NIA P01 AG017628 (A.I. Pack, PI), NHLBI T32 HL007953 (A.I. Pack, PI), R01 AG 062398 (Abel, T, PI). Ted Abel was supported by the Brush Family Professor of Biology at the University of Pennsylvania and by the Roy J. Carver Chair in Neuroscience at the University of Iowa.

Footnotes

The authors have no conflict of interest to report.

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