Structural plasticity and hippocampal function

Abstract

The hippocampus is a region of the mammalian brain that shows an impressive capacity for structural reorganization. Preexisting neural circuits undergo modifications in dendritic complexity and synapse number, and entirely novel neural connections are formed through the process of neurogenesis. These types of structural change were once thought to be restricted to development. However, it is now generally accepted that the hippocampus remains structurally plastic throughout life. This article reviews structural plasticity in the hippocampus over the lifespan, including how it is investigated experimentally. The modulation of structural plasticity by various experiential factors as well as the possible role it may have in hippocampal functions such as learning and memory, anxiety, and stress regulation are also considered. Although significant progress has been made in many of these areas, we highlight some of the outstanding issues that remain.

Figure 1

Schematic diagram of the hippocampus showing a mature granule neuron of the dentate gyrus and mature pyramidal neurons of areas CA3 and CA1 as well as their main axonal connections. For each of these cell types, the size and complexity of the dendritic trees as well as the size, shape, and number of dendritic spines can change. In the dentate gyrus, substantial numbers of new neurons (red) are also produced in adulthood.

Figure 2

Cell birth and cell death in the dentate gyrus across the lifespan. On postnatal day 1, granule neurons that were generated embryonically have begun to form the tip of the suprapyramidal blade of the granule cell layer (GCL). During the first postnatal week, the GCL continues to be formed from progenitor cells located within the hilus along four general gradients—caudal to rostral, suprapyramidal to infrapyramidal, suprapyramidal tip through crest to infrapyramidal tip, and superficial to deep. Thereafter, the production of new granule neurons tapers off but remains substantial in adulthood until animals reach middle age and become aged. Alongside neurogenesis, there is substantial death of granule neurons. Cell death peaks at the end of the first postnatal week as indicated by the presence of pyknotic (i.e., dying) cells. In adulthood, substantial cell death continues, especially of newborn neurons located primarily within the subgranular zone (SGZ) or deep within the GCL.

Figure 3

(A, B) Photomicrographs of newly born neurons (arrows) in the dentate gyrus of an adult rat labeled with BrdU (red) coexpressing (A) NeuN (green), a marker of mature neurons or (B) TuJ1 (green), a marker of immature and mature neurons. Scale bars, 10 μm. Eventually, adult-generated neurons become morphologically indistinguishable from granule neurons generated during development, like those shown in (C) which were labeled with the lipophilic tracer DiI. Scale bar, 25 μm. Parts of this panel have been previously published (Leuner et al. 2004, Stranahan et al. 2007).

Figure 4

Methods for studies of adult neurogenesis are not equally sensitive. (A) BrdU antibodies do not label the same number of newborn cells in the dentate gyrus. Vector and Novocastra antibodies stain fewer BrdU-labeled cells as compared to BD, Roche, Dako, and Accurate antibodies (two-hour post-BrdU survival time). (B) Additional variability in BrdU labeling occurs with different DNA denaturation pretreatment methods. HCl alone and HCl + formamide pretreatments stain more newborn cells in the dentate gyrus than does steam heating. (C) Pretreatments also differentially affect immunoflurorescent staining for the mature neuronal marker, NeuN; greater staining is observed with HCl-alone pretreatment. *p < 0.05. Adapted from Leuner et al. (2009).