Memory Consolidation

Our primary collection of literature was gathered by searching online electronic databases for articles relevant to our topic of interest through December 2008. The four databases used were PsycINFO, Medline, Web of Science, and EBSCO MegaFile. In each of these databases, we conducted a search using a combination of the following terms: sleep deprivation or sleep restriction and cognition, attention, memory, performance, vigilance, and executive function (12 combinations in all). This search yielded 4,276 hits in total. We next scanned the abstracts of these articles to determine their suitability for inclusion in the analysis. In total, 176 of the articles were empirical studies that employed SD as a primary independent variable and used at least one cognitive measure as a dependent outcome. We subsequently obtained the full text of these articles to determine whether they met full inclusion criteria. These criteria were as follows:
Because of the restrictions imposed by Criterion 3, a number of subareas within the realm of SD research necessarily had to be omitted from this analysis. A survey of the literature on SD and decision making revealed that outcome variables on these tests did not form a cluster that was homogeneous enough to warrant a quantitative synthesis. This was because many of these experiments employed complex, real-world scenarios, opting for ecologically valid designs over more controlled neuropsychological tests (for a review, see Harrison & Horne, 2000 (link)). Moreover, it is unclear how outcome variables from standardized decision-making tests (e.g., the Iowa Gambling Test) should be compared with the accuracy measures obtained from other cognitive domains. Finally, experiments on implicit and procedural memory were also excluded, as these form a separate body of literature pertaining to sleep and memory consolidation (Stickgold & Walker, 2005 (link)), the analysis of which is beyond the scope of this article.
In addition to this online literature search, we obtained data from several other sources. We conducted hand searches of the journal Sleep and the Journal of Sleep Research from 1988 to 2008. We also reviewed the reference lists of the major review articles on SD and cognitive performance that have been published over the last several years. Finally, to mitigate the “file drawer” problem (Strube & Hartmann, 1983 ), we contacted eight major sleep laboratories conducting research in this field to request unpublished data from experiments, as well as master’s and doctoral theses. We received additional data from one of these laboratories, as well as replies from all but one of the remaining investigators informing us that they did not have suitable data for inclusion. In total, 70 articles and 147 data sets met inclusion criteria and were included in the meta-analysis (see Table 1). Among these, numerous data sets contained more than one cognitive outcome; these were coded separately, according to the recommendations of Hunter and Schmidt (2004) . Altogether, 209 aggregated effect sizes and 5,104 individual effect sizes were calculated from these data sets.

Cyclodextrin-encapsulated 17β-estradiol (E₂; Sigma, St. Louis, MO) at a dose of 0.2 mg/kg was dissolved in physiological saline in a volume of 4 ml/kg, and injected intraperitoneally (i.p.). This dose in mice facilitates object memory consolidation in the task used here (Gresack and Frick, 2004 (link), 2006 (link)). The vehicle, hydroxypropyl-β-cyclodextrin (HBC), was dissolved in an equal volume of saline and contained the same amount of cyclodextrin as E₂. The MEK inhibitor SL327 (α-[Amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl) benzeneacetonitrile; Sigma), at a dose of 30 mg/kg, was dissolved in 100% dimethyl sulfoxide (DMSO) and injected i.p. in a volume of 2.0 ml/kg. Vehicle controls received HBC or both HBC and DMSO. For intrahippocampal (IH) infusions, physiological saline or cyclodextrin-encapsulated E₂ dissolved in physiological saline (5.0 μg/0.5μl) was infused at 0.5 μl/min for 1 minute.
To demonstrate that E₂-induced increases in object recognition were dependent on dorsal hippocampal ERK activation, other mice received IH infusions of vehicle or the MEK inhibitor U0126 (1,4-Diamino-2,3-dicyano-1,4-bis (o-aminophenylmercapto) butadiene; 2.0 μg/μl; Sigma) concurrently with i.p. E₂ injection or intracerebroventricular (ICV) infusion of bovine serum albumin-conjugated 17β-estradiol (see below) into the dorsal third ventricle. U0126 was dissolved in 100% DMSO to 4 μg/μl as a stock solution and then serially diluted in physiological saline for infusion of various doses. U0126 or vehicle (50% DMSO) were infused at a rate of 0.50 μl/min and a volume of 0.50 μl/side. Other mice received ICV infusions of vehicle or bovine serum albumin-conjugated 17β-estradiol (β-Estradiol 6-(O-carboxy-methyl)oxime; BSA-E₂; Sigma). The covalent conjugation of E₂ to the large BSA molecule prevents E₂ from passing through the cell membrane and binding to intracellular ERs (Taguchi et al., 2004 (link)). Thus, effects of BSA-E₂ should be mediated by membrane-bound ERs. BSA-E₂ was dissolved in Tris-HCl to a concentration of 5.0 μM. Either 5.0 μM BSA-E₂ or vehicle (Tris-HCl) was infused at a rate of 0.5 μl/min at a volume of 1.0 μl.
To demonstrate that the effects of BSA-E₂ on memory and ERK activation were independent of nuclear estrogen receptors, other mice received ICV infusions of BSA-E₂ conducted as described above concurrently with IH infusions of the nuclear estrogen receptor antagonist ICI 182,780 ((7a,17b)-7-[9[(4,4,5,5,5pentafluoropentyl) Sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol; 10 μg/μl; Sigma). ICI 182,780 is an antagonist of ERα and ERβ that impairs E₂-induced ER dimerization (Weatherman et al., 2002 (link)) and translocation of ERs into the cell nucleus (Dauvois et al., 1993 (link)). If ICI 182,780 does not block the effects of BSA-E₂ on memory and ERK activation, then this would indicate that these effects are mediated by membrane-associated estrogen receptors rather than nuclear receptors. Intrahippocampal infusions of ICI 182,780 were conducted at a rate of 0.5 μl/min and a volume of 0.5 μl/side, resulting in a dose of 5.0 μg/side. In other mice, ICI 182,780 was infused intrahippocampally without concurrent ICV infusion as a control due to a report that this compound in female rats can act as an estrogen receptor agonist to enhance place learning when administered in the absence of E₂ (Zurkovsky et al., 2006 (link)). To compare effects of ICI 182,780 with those of traditional E₂, 0.2 mg/kg E₂ was administered i.p. either alone or with ICI 182,780 infused intrahippocampally. The E₂ + IH ICI 182,780 group also served as a control for the effectiveness of the ICI compound in blocking the effects of traditional, non-BSA conjugated E₂ on object memory consolidation and ERK activation. Vehicle controls for the aforementioned groups received ICV and IH infusions of saline or BSA dissolved in saline.
Finally, to demonstrate that the effects of BSA-E₂ on memory and ERK activation involved the dorsal hippocampus, BSA-E₂ was infused bilaterally into the dorsal hippocampus of another set of mice. Intrahippocampal infusions were conducted at a rate of 0.5 μl/min and at a volume of 0.5 μl/side, resulting in doses of 5.0 μM/side. As a control, these mice also received ICV infusions of vehicle (BSA dissolved in saline). Additional mice received ICV BSA-E₂ + IH vehicle as a control to replicate the effects of ICV BSA-E₂ observed above. As an additional method of demonstrating hippocampal involvement in the BSA-E₂ effect, other mice received ICV infusions of BSA-E₂ conducted as described above concurrently with IH infusions of the GABA_A receptor agonist muscimol (3-Hydroxy-5-aminomethyl-isoxazole; 0.50 μg/μl dissolved in saline; Sigma). Muscimol temporarily inactivates a brain region of interest by increasing GABAergic inhibition without permanently damaging the tissue (Martin, 1991 (link)). Therefore, if muscimol interferes with the beneficial effects of ICV BSA-E₂ on memory, then this would suggest critical involvement of the dorsal hippocampus in this effect. Intrahippocampal infusions of muscimol were conducted at the same rate and volume as above. Vehicle controls for all of the aforementioned groups received ICV and IH infusions of saline or BSA dissolved in saline.
Injection cannulae for IH and ICV infusions remained in place for 1 minute after infusion to prevent drug diffusion up the injection track. For behaviorally tested mice, all solutions were administered immediately after the sample phase of object recognition training.