This Week in The Journal
- Teresa Esch, Ph.D.
Choice Improves Memory Because It Is Rewarding
Vishnu P. Murty, Sarah DuBrow, and Lila Davachi
(see pages 6255–6264)
Much research has shown that students learn better when they are actively engaged in the learning process. An obvious benefit of some active learning techniques, such as pausing lectures for discussion, is that they allow students to identify and revisit material they have not fully grasped. Giving students a chance to refocus attention is another important benefit. In fact, simply allowing people to determine when the next study item is displayed improves memory retention, possibly because it allows subjects to prepare and refocus (Markant et al., 2014, Mem Cogn 42:1211).
Murty et al. suggest that the intrinsically rewarding properties of self-agency also contribute to the benefit of active learning. They instructed participants to memorize objects that were initially hidden behind screens. A cue first informed subjects whether they would be told to remove a specific screen or allowed to choose which screen to remove. The subjects then removed the screen and studied the revealed object. Remarkably, although similar actions and timing were involved in both trial types, memory was better for objects studied on choice trials than those studied on instructed trials. Thus, memory benefits seemed to result simply from making a choice.
Supporting the hypothesis that reward contributed to enhanced memory, activation of the striatum—an area central to reward processing—was greater when the initial cue indicated an upcoming choice trial than when it indicated an instructed trial. Moreover, the level of striatal activity during choice trials was significantly correlated with memory performance. In addition, many brain regions, including the hippocampus, were more active while subjects studied objects in the choice condition than in the instructed condition. Importantly, greater activation of striatum during the cue period was associated with greater hippocampal activity during the study period on choice trials, and this correlation was strongest for objects that were later remembered.
These results are consistent with previous studies that indicate activation of the striatum promotes memory formation through interactions with the hippocampus. They further suggest that giving people even a slight amount choice is rewarding enough to enhance declarative memory. Such choices should be easy to introduce into classrooms to enhance learning.
A Homeobox Gene Controls M2-Like Microglial Phenotype
Zhongwang Yu, Dingya Sun, Jifeng Feng, Weixing Tan, Xue Fang, et al.
(see pages 6350–6365)
Macrophages exhibit a spectrum of phenotypes defined by the genes expressed and the cytokines secreted. These phenotypes, which are induced by different extracellular signals, range from the pro-inflammatory “M1” to the anti-inflammatory “M2.” In multiple sclerosis (MS), M1 macrophages enter the CNS and promote inflammation and demyelination. Conversely, M2 macrophages reduce inflammation and promote remission in a rodent model of MS [experimental autoimmune encephalomyelitis (EAE)]. Microglia, the resident macrophages of the CNS, also exhibit phenotypes ranging from M1-like to M2-like, and a shifting balance of these phenotypes might contribute to relapse and remission in MS and some psychiatric diseases.
Microglia overexpressing MSX3 (left) increased axon survival (indicated by neurofilament staining, green) and myelination (indicated by myelin basic protein staining, red) in mouse spinal cord. MSX3-deficient microglia had the opposite effect (right). See the article by Yu et al. for details.
Given the potential benefits of M2 microglia, it is important to define the molecular pathways that produce this phenotype. Therefore, Yu et al. asked how interleukin-4 (a cytokine that induces the M2 phenotype) and interferon-γ (which induces the M1 phenotype) affected microglial gene expression. Interestingly, they found that the homeobox transcription factor msh-like homeobox-3 (MSX3)—which was previously found to be expressed only during early embryonic development—was upregulated by interleukin-4 and downregulated by interferon-γ. Furthermore, overexpressing MSX3 in cultured microglia increased expression of M2 markers and decreased expression of M1 markers, whereas interfering with MSX3 expression had the opposite effects. Finally, chromatin immunoprecipitation assays indicated that MSX3 directly interacted with the promoter areas of three genes involved in M2 polarization. Expression of these genes was elevated in MSX3-overexpressing microglia and suppressed in MSX3-deficient microglia.
Notably, MSX3 was also upregulated in mouse spinal cord after induction of EAE. Moreover, transplanting MSX3-overexpressing microglia after EAE induction promoted recovery and increased survival of axons in the lumbar spinal cord, whereas transplanting MSX3-deficient microglia worsened clinical scores of EAE and increased axonal loss. Even when transplanted after the peak phase of EAE, MSX3-overexpressing microglia promoted recovery and remyelination.
Together, these results suggest that MSX3 has a central role in pushing microglia toward the protective M2 phenotype, and they provide further evidence that this phenotype promotes remission in EAE. If it is true that MSX3 does not have other roles in the adult CNS, selectively upregulating its expression in microglia might become a valuable treatment for MS and other neuroinflammatory diseases.
