Age-related Changes in the Sleep-dependent Reorganization of Declarative Memories Bengi Baran, Janna Mantua, and Rebecca M. C. Spencer Abstract ■ Consolidation of declarative memories has been associated negatively associated with retrieval-related hippocampal activa- with slow wave sleep in young adults. Previous work suggests tion in young adults. In contrast, in older adults there was no that, in spite of changes in sleep, sleep-dependent consolida- relationship between sleep and memory performance or with tion of declarative memories may be preserved with aging, al- retrieval-related hippocampal activation. Furthermore, com- though reduced relative to young adults. Previous work on pared with young adults, postnap memory retrieval in older young adults shows that, with consolidation, retrieval of declar- adults required strong functional connectivity of the hippocam- ative memories gradually becomes independent of the hippo- pus with the PFC, whereas there were no differences between campus. To investigate whether memories are similarly young and older adults in the functional connectivity of the hip- reorganized over sleep at the neural level, we compared func- pocampus following wakefulness. These results suggest that, al- tional brain activation associated with word pair recall following though neural reorganization takes place over sleep in older a nap and equivalent wake in young and older adults. SWS dur- adults, the shift is unique from that seen in young adults, per- ing the nap predicted better subsequent memory recall and was haps reflecting memories at an earlier stage of stabilization. ■ INTRODUCTION role in retrieval such that with time there is a gradual re- Sleep enhances memory consolidation in young adults organization of storage of recent memories (Alvarez & (Stickgold, 2005). Newly acquired declarative memory Squire, 1994). Evidence for this account comes from pa- traces are transformed into more stable neural represen- tient and animal studies: Insult to the medial-temporal tations during subsequent slow wave sleep (Inostroza & lobes results in temporally graded amnesia whereby re- Born, 2013; Lau, Tucker, & Fishbein, 2010; Tucker et al., cently acquired memories are impaired but remote 2006; Gais & Born, 2004). Aging, even in the absence of memories may be spared (Winocur, Sekeres, Binns, & diminished health, is associated with changes in sleep du- Moscovitch, 2013; Anagnostaras, Maren, & Fanselow, ration and quality (Ohayon, Carskadon, Guilleminault, & 1999; Squire & Spanis, 1984; Squire, Slater, & Chace, Vitiello, 2004; Buysse et al., 1992). SWS duration and 1975; Scoville & Milner, 1957). Furthermore, neuroimaging delta activity (0.5–4 Hz) are particularly reduced in older studies have revealed that retrieval of declarative memories adults (Van Cauter, Leproult, & Plat, 2000; Lombardo is associated with a decline in hippocampal activation et al., 1998). As such, it has been proposed that age-related coupled with an increase in prefrontal activation when memory impairments are associated with changes in sleep measured over 90 days (Takashima et al., 2006, 2009). (Buckley & Schatzberg, 2005; Hornung, Danker-Hopfe, & SWS is thought to support this reorganization of mem- Heuser, 2005). However, recent studies that examine the ories through neural reactivation. Reactivation of newly effects of aging on declarative memory consolidation have encoded memories initiates a hippocampo-neocortical provided conflicting evidence. Although some studies dialogue, via slow oscillations, that eventually results in report superior performance in older adults following a reorganization (Inostroza & Born, 2013). Supporting this, 12-hr interval with sleep compared with an equivalent inter- in rodents, hippocampal place cells that were active dur- val awake (Sonni & Spencer, 2015; Wilson, Baran, Pace- ing spatial learning are reactivated during subsequent Schott, Ivry, & Spencer, 2012; Aly & Moscovitch, 2010), non-rapid eye movement (NREM) sleep, and this replay others show impaired sleep-dependent declarative mem- maintains the same firing pattern as initial experience ory consolidation with aging (Mander et al., 2013; Scullin, (Lee & Wilson, 2002; Wilson & McNaughton, 1994). Fur- 2013). thermore, re-presenting auditory cues associated with a Models of systems level consolidation posit that the learned task during NREM sleep triggers selective neural medial-temporal lobes have a critical, albeit temporary, reactivation of memory associated with the cue (Bendor & Wilson, 2012). Such experimentally triggered reactiva- University of Massachusetts tion through sensory cueing has also been demonstrated © 2016 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 28:6, pp. 792–802 doi:10.1162/jocn_a_00938 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00938 by guest on 01 October 2021 in humans. For instance, postsleep memory performance chiatric, or cardiovascular disease or sleep disorders, use is better if an odor cue that was presented during learn- of medication known to affect cognition or sleep (based ing is presented again during SWS (Rasch, Büchel, Gais, on Cooke & Ancoli-Israel, 2011), habitual nocturnal sleep & Born, 2007). Odor-on periods during SWS activate the < 5 hr/day, habitual napping regimen of more than twice hippocampus. Importantly, sensory cueing benefits mem- per week, BMI > 30, and excessive alcohol (>10 drinks/ ory only if presented during SWS and not during REM sleep week) or caffeine (>10 of 12-oz caffeinated drinks/week) or wakefulness. Overall, it is clear that neural mechanisms consumption. in SWS activate a cascade that is critical for declarative We administered the Pittsburg Sleep Quality Index memory reorganization. (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) to survey Although the mechanism of sleep-dependent memory habitual sleep quality and the Morningness–Eveningness reorganization is relatively well defined in healthy young Questionnaire (Horne & Ostberg, 1976) to assess chrono- adults, little is known about how declarative memories type. Participants also completed a sleep and wake diary, evolve offline in older adults at the neural level. Given which was used to monitor nocturnal sleep, naps, and that aging is associated with marked changes in neural en- adherence to experimental protocols (i.e., no strenuous gagement at encoding (Gutchess et al., 2005) and changes exercise, no caffeine or alcohol consumption during test- in sleep physiology (Ohayon et al., 2004; Van Cauter et al., ing days). Testing procedures were approved by the 2000; Lombardo et al., 1998), the difference in retrieval- University of Massachusetts Amherst Institutional Review related activation postsleep compared with postwake Board, and written informed consent was obtained before may be distinct for older compared with younger adults. the experiment. The goal of this study was to examine age-related changes in the neural and physiological correlates of sleep-dependent Word Pair Recall Task declarative memory consolidation using fMRI and polysom- nography (PSG). We tested retention of declarative learn- The task was a word pair learning task reported in previ- ing and recall-related brain activation following a midday ous studies (Wilson et al., 2012; Donohue & Spencer, nap and following continuous wakefulness in young and 2011) and programmed using E-Prime (Psychology Soft- older adults. We postulated that the mechanism and the ware Tools, Inc., Sharpsburg, PA). Stimuli consisted of timescale of consolidation would differ for young and older single-syllable, high-frequency, concrete nouns that were adults, yet changes in retrieval-related activation following paired to create two lists of 40 semantically unrelated sleep compared with wake would be present in both cue–target word pairs (e.g., bath–grass, rail–bag). groups. Moreover, based on prior studies that suggest that The task had three phases: Encoding, Immediate Re- sleep modulates hippocampal-neocortical dialogue in call, and Delayed Recall. In the Encoding phase, each young adults (Wierzynski, Lubenov, Gu, & Siapas, 2009; word pair was presented for 4 sec, in a random order, Siapas & Wilson, 1998) and that retrieval success is pre- with an ISI of 250 msec. Participants were instructed to dicted by changes in the functional connectivity of the hip- study each pair carefully for subsequent recall and try pocampus (King, de Chastelaine, Elward, Wang, & Rugg, to remember them by forming associations between 2015), we investigated age-related changes in the functional the words (see Wilson et al., 2012). After a 5-min break, connectivity of the hippocampus during postnap and post- participants continued the Encoding phase by practicing wake memory retrieval. We hypothesized that, if the neural recall of the encoded words with feedback provided. Par- mechanisms underlying sleep-dependent consolidation ticipants were presented a cue word and asked to ver- are similar in young and older adults, connectivity of the bally report the target word, which the experimenter hippocampus during postsleep recall would be similar typed into the computer. If their response was incorrect, across age groups. Alternatively, if aging alters memory re- the correct target word was displayed for 750 msec. If the organization, then we may see hippocampo-prefrontal de- response was correct, the word “correct” appeared on coupling exclusively in young adults. Importantly, by the screen and the participant moved on to the next pair.