Pattern and predictability in memory formation: From molecular mechanisms to clinical relevance

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Highlights

  • The spacing effect is a highly conserved feature of memory formation from humans to invertebrates.

  • Recent molecular studies provide new insights into how learning occurs across a broad range of spaced training intervals.

  • An increased understanding of inter-trial signaling mechanisms will help identify and optimize novel learning strategies.

  • Neurological disorders can alter training pattern sensitivity, while leaving intact the actual ability to learn.

  • Novel training patterns, informed by mechanistic studies of inter-trial signaling, may mitigate deficits in memory disorders.

Abstract

Most long-term memories are formed as a consequence of multiple experiences. The temporal spacing of these experiences is of considerable importance: experiences distributed over time (spaced training) are more easily encoded and remembered than either closely spaced experiences, or a single prolonged experience (massed training). In this article, we first review findings from studies in animal model systems that examine the cellular and molecular properties of the neurons and circuits in the brain that underlie training pattern sensitivity during long-term memory (LTM) formation. We next focus on recent findings which have begun to elucidate the mechanisms that support inter-trial interactions during the induction of LTM. Finally, we consider the implications of these findings for developing therapeutic strategies to address questions of direct clinical relevance.

Introduction

All animals must use their experience to create a statistical model of their world. This model is driven by both pattern and predictability. The regularity (or pattern) of an experience is predictive of the likelihood of an encounter with the same or related experiences in the future, and therefore facilitates the acquisition and maintenance of adaptive behavior. The maintenance of such a predictive model depends on the formation of long-term memory (LTM). Yet not all repeated experiences are retained in LTM. The timing of experiences is critical. In psychological terms, the benefit to LTM induction of temporally distributed experiences (trials), compared to more closely spaced trials, is often termed the spacing effect and can be traced to the earliest formal studies of human learning and memory by Hermann Ebbinghaus (1885/1913). Since these seminal observations more than a century ago, it has become increasingly evident that the spacing effect is a ubiquitous phenomenon that governs LTM formation in a wide range of species and across a wide variety of tasks. Yet even after decades of study, we still understand relatively little about the properties of neural circuits in the brain that determine the benefit of spaced training. In this review we will briefly discuss major findings that elucidate some of the cellular and molecular mechanisms that can, at least in principle, contribute to the spacing effect. We will then focus on recent studies that provide novel and fundamental insights into how effective spacing intervals are determined and may benefit LTM formation. Finally, we conclude with a discussion of the implications of experimental studies for the development of effective learning strategies in humans, as well as the potential for these studies to inform questions of direct clinical relevance.

Section snippets

General principles of the spacing effect

The benefit of spaced training to LTM formation is widely observed in both vertebrate and invertebrate model systems, and provides striking parallels to the general principles observed in humans. The spacing effect in LTM is observed across a variety of tasks, including spatial reference memory (Bolding & Rudy, 2006), working memory (Klapdor & Van Der Staay, 1998), appetitive associative conditioning (Colomb, Kaiser, Chabaud, & Preat, 2009), aversive associative conditioning (Amano and

Cellular and molecular correlates of the spacing effect

Both vertebrates and invertebrates express memory across multiple temporal domains. Each domain has unique cellular and molecular mechanisms that support its induction. Short-term memory (STM) typically develops following a single experience (training trial), lasts on the order of minutes, and relies on the transient modification of pre-existing proteins to establish short-lasting plasticity within underlying neural circuits (Alkon and Naito, 1986, Barondes, 1970, Castellucci et al., 1989,

Why is massed training ineffective in recruiting the mechanisms of LTM consolidation?

Although spaced training clearly supports the recruitment of many signaling mechanisms that support LTM induction, an inverse question can be raised: Why is massed training ineffective? One answer is that it is simply unable to recruit the same signaling that supports LTM induction across spaced training. However, in many cases massed training actually recruits signaling which actively opposes LTM induction (Abel et al., 1998, Yin and Tully, 1996). In a recent study in Drosophila, the

Molecular windows in LTM formation

The studies reviewed thus far have principally focused on understanding how mechanisms known to be important for the induction of LTM are selectively recruited over repeated spaced experiences. However, an important question remains: How do temporally spaced experiences interact and build upon one another to support LTM formation? We will now focus our discussion on two recent studies [i.e., Philips et al., 2013, Parsons and Davis, 2012] that have begun to address this question.

The study of the

Effective versus optimal learning strategies

In reviewing the mechanistic insights gained from studies of the spacing effect in model systems, a final fascinating study by Zhang et al. (2012) warrants mention: These authors combined computer simulations with cellular and behavioral studies to ask whether a standard, regularly spaced training pattern of five sensitizing trials in Aplysia was the optimal training pattern for LTM induction. The investigators began with the assumption that the maximal recruitment of CREB during learning would

Implications of spaced training in health and disease

In humans, the benefits of spaced training for memory formation in young healthy adults are well documented (for a recent meta-analysis see Cepeda et al., 2006), and also appear to benefit learning throughout the lifespan. Children, including infants as young as 3 months old, and both young and old cognitively intact adults, retain more information when it is presented in a spaced training pattern than when it is presented in a massed pattern (Galluccio and Rovee-Collier, 2006, Grassi, 1971,

Could time be the best medicine?

As mentioned in the molecular component of this review, studies of animal models have begun to utilize knowledge of the molecular mechanisms of inter-trial interactions to predict the optimal training paradigms for LTM (Zhang et al., 2012). Given the newly emerging molecular framework of roles for the widely conserved PKA/MAPK/CREB signaling pathways in defining effective training windows over temporally distributed experiences, an important next step will be to incorporate these findings into

Acknowledgments

We would like to thank Dr. Xiaojing Ye for helpful comments on an earlier version of this manuscript. The work included in this review was supported by the NIMH (R01MH041083 and R01MH094792 to TJC, and R01MH081151 to TJC and KC Martin).

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