Experience-dependent structural plasticity in the cortex

Synapses are the fundamental units of neuronal circuits. Synaptic plasticity can occur through changes in synaptic strength, as well as through the addition/removal of synapses. Two-photon microscopy in combination with fluorescence labeling offers a powerful tool to peek into the living brain and follow structural reorganization at individual synapses. Time-lapse imaging depicts a dynamic picture in which experience-dependent plasticity of synaptic structures varies between different cortical regions and layers, as well as between neuronal subtypes. Recent studies have demonstrated that the formation and elimination of synaptic structures happens rapidly in a subpopulation of cortical neurons during various sensorimotor learning experiences, and that stabilized synaptic structures are associated with long lasting memories for the task. Therefore, circuit plasticity, mediated by structural remodeling, provides an underlying mechanism for learning and memory.

Introduction

Neuronal plasticity refers to structural and functional changes in neuronal circuits in response to experience. This concept was first proposed by William James in the 19th century to correlate structural changes of the brain with the habitual behavior of animals [1]. In the 1960 s and 1970 s, Hubel and Wiesel examined the plasticity of cat and monkey visual systems and identified a ‘critical period’ during which deprivation of normal visual experience irreversibly altered neuronal connections and functions in the visual cortex 2, 3, 4, 5. Since then, similar findings have been made in other systems, and the ‘critical period’ is defined as a period of time during which neuronal connections are susceptible to experience-dependent modifications [6]. For a long time it was believed that neuronal circuits lost plasticity after the end of the critical period and remained fixed in adult life. However, this idea has been greatly challenged in recent decades. Cumulative data have shown that experience-dependent plasticity occurs in adulthood, and it is now well accepted that neuronal circuits of the mammalian brain are capable of changing in response to new experience throughout life 7, 8, 9, 10, 11.

The mammalian neocortex participates in a variety of brain functions such as sensory perception, movement control and cognition. Various cortical functions build upon different neuronal circuits, which are made up of different types of neurons communicating at individual synapses. It is generally believed that a functional mature neuronal circuit is formed from an initial pool of less precise synaptic connections. Experience modifies these connections by selectively stabilizing some synapses and removing others 8, 12, 13. In the adult brain, synaptic plasticity continues through modifications of synaptic strength, as well as through formation and elimination of synapses 8, 10. Up to a decade ago, much of our knowledge about neuronal structural changes had been inferred from single time-point observations of fixed tissues. Given the complexity of neuronal circuits and the variability among animals, it is crucial to obtain longitudinal data from the same synapses over time to understand their dynamics 14, 15. Recent developments in both imaging and molecular tools enable the visualization of synapses in living animals (Figure 1). In particular, two-photon laser scanning microscopy offers low phototoxicity and deep penetration through thick scattering preparations, which makes it suitable for imaging in the intact brain [16]. Both turnover (formation and elimination) and morphological changes of synaptic structures have been examined in various cortical regions over periods ranging from minutes to years. In this review, we will summarize recent in vivo studies on the structural plasticity of the cortex. We will also discuss how these structural changes relate to changes in synaptic connectivity and outline open questions that remain to be addressed in the field.