Structural Plasticity

and Hippocampal

Function

Benedetta, Leuner, and Elizabeth Gould





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.

Keywords: adult neurogenesis, anxiety, learning, memory, synapse

Regressive events also sculpt hippocampal circuitry during development—pruning of dendritic branches occurs on the granule cells during this time. [159] Similar events occur throughout the hippocampus—postnatal development of dendritic arbors and the formation of dendritic spines followed by dendritic pruning and synapse elimination are also features of the pyramidal neuron population. [120]





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. (AB) 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).

(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 …

Negative Versus Positive Stress

Stressors are typically defined in terms of their ability to activate the hypothalamic-pituitary-adrenal (HPA) axis and ultimately increase glucocorticoid levels.[207] Most experiences known to cause HPA axis activation are aversive. Exposure to aversive stressors adversely influences numerous aspects of hippocampal structure.
With few exceptions, [11, 190, 204] new cell production in the dentate gyrus is inhibited by a variety of acute and chronic aversive experiences, including both physical and psychosocial stressors.[135] Stress-induced suppression of cell proliferation has been demonstrated in various species (mouse, rat, tree shrew, monkey) and occurs throughout life, with similar results reported for the early postnatal period, young adulthood, and aging. [32, 71, 73, 188, 200, 201, 215] When stressor exposure occurs during development, the effects are enduring and can persist into adulthood. [111, 121, 136] However, it is unclear whether stress experienced in adulthood has a long-lasting influence on hippocampal neurogenesis. Prolonged effects of stress on new neuron production [84, 126,156] and survival [103, 204, 222] have been observed. Yet, others have shown that the influence of stress on adult neurogenesis is temporary, decreasing cell proliferation and immature neuron production without altering the number of new neurons that survive to maturity. [136, 190, 201] The reason for these discrepancies is unknown but may be related to the duration or intensity of the stressor or timing of BrdU labeling or sacrifice relative to the stressful experience.
In addition to suppressing neurogenesis, aversive stressful experiences alter dendritic architecture in the hippocampus. For example, repeated stress in adulthood induces retraction of CA3 pyramidal neuron dendrites as well as a loss of synapses in adult male rats and tree shrews. [124, 133, 194] Within hours of stressor onset, dendritic spine density in the CA3 region is also reduced29. The effects of stress on dendritic architecture in other hippocampal regions have been less well-studied. Chronic stress causes dendritic regression and spine synapse loss in the dentate gyrus and CA179, 193. Acute stress also alters dendritic spine density on CA1 pyramidal cells of adult rats, but the direction of the effect is dependent on the sex of the animal, increasing the number of dendritic spines in males but decreasing the number of dendritic spines in females. [184]
Some evidence demonstrates that glucocorticoids regulate structural plasticity in the hippocampus and are the primary mediator underlying the detrimental effects of aversive stress on hippocampal structure. First, an inhibition of neurogenesis occurs in response to natural changes in glucocorticoids across the lifespan. Neurogenesis in the dentate gyrus is maximal during the early postnatal period, when levels of circulating glucocorticoids are low [76] but diminished during life stages when glucocorticoids are elevated, including aging and the postpartum period. [24, 106, 116, 118] Second, glucocorticoid administration during the early postnatal period and in adulthood suppresses neurogenesis. [23, 76] Conversely, removal of circulating glucocorticoids by bilateral adrenalectomy increases neurogenesis in adult and aged rats [23, 24] and prevents the stress-induced reduction in neurogenesis. [136, 201] Third, blocking glucocorticoid receptors can reverse the reduction in neurogenesis after glucocorticoid treatment131 or stressor exposure151. Like neurogenesis, the stress-induced atrophy of CA3 pyramidal neurons is prevented by pharmacological blockade of the glucocorticoid stress response and can be mimicked by exogenous glucocorticoid administration. [123, 226]

Physical Activity

It is becoming increasingly clear, however, that glucocorticoids are not the sole factor mediating the suppressive action of stress on hippocampal structure [71, 103, 208] and that the effects of glucocorticoids on structural plasticity are complex. Notably, conditions associated with elevated glucocorticoids do not necessarily have detrimental effects on structural plasticity and in some cases, those conditions can be beneficial. Physical activity is an example of this paradox—despite substantial elevations in circulating glucocorticoids, running enhances adult neurogenesis [195, 211, 231] and dendritic architecture [46, 196] in the hippocampus.

Learning

This effect persists until the new neurons are at least two months old. [117] Other hippocampus-dependent tasks, such as long-delay eye blink conditioning, as well as spatial learning in the Morris water maze and conditioned food preference, also increase the number of newborn cells. [6, 41, 43, 70, 78, 111, 119, 148]
In addition to differences in BrdU injection protocols and training paradigms employed, the maturity of the labeled adult-born cells at the time of learning may determine whether and how learning alters them. Both spatial learning and trace eyeblink conditioning encourage the survival of new cells born about one week prior to training, when these cells are immature but already differentiated into neurons. [6, 43, 52, 70, 78] In contrast, some studies suggest that spatial learning induces the death of cells that are less mature (i.e., ≤4 days of age)[43, 138], whereas others show that the death of older and perhaps more mature cells occurs (i.e., ≥10 days of age).[7] Therefore, learning may have a differential capacity to influence neurogenesis depending on the age of the cell. This is consistent with observations showing that experience-induced modulation of adult neurogenesis occurs at a critical period during an immature stage. [202]
The purpose of a learning-induced enhancement of neurogenesis remains to be fully determined. One possibility is that these newborn neurons can contribute to learning and memory by creating a neural representation of previous experience. [2] Work showing that neurons made to survive by exposure to an enriched environment are preferentially activated at a later time to the same, but not a different, experience lends some support to the possibility that such a process takes place. [202]
Experimental Approaches to Study the Role of Structural Plasticity in Hippocampal Function
Several strategies have been used to link structural change to hippocampal function. One is correlative and involves evaluating whether there is a positive relationship between structural plasticity and hippocampal function. Another is more direct and involves blocking structural changes and examining whether hippocampal functions are altered. With respect to adult neurogenesis, the depletion of newborn cells has been achieved pharmacologically by systemic administration of the antimitotic agent methylazoxymethanol (MAM) [19, 186] or the DNA-alkylating agent temozolomide (TMZ)[62] as well as by central infusion of the mitotic blocker cytosine arabinoside (AraC). [125] However, none of these agents diminish the number of newborn neurons exclusively within the dentate gyrus. Irradiation is another approach to block hippocampal neurogenesis and when applied focally, spares neurogenesis in the rest of the brain, [31, 170, 172, 223] One downside common to all of these methods is their nonspecific side effects that may complicate the interpretation of results. [44, 139] Genetic ablation of dividing progenitors may be less susceptible to this criticism, but again assessing behavioral consequences is difficult because inhibition of the dividing precursors is not restricted to the dentate gyrus. [61, 172] For this reason, virus-based strategies have been developed to prevent neurogenesis exclusively in the dentate gyrus at a specific time in adulthood. [31, 91] However, the possibility that postmitotic neurons are affected by the virus and may contribute to behavioral alterations cannot be ruled out. Most recently, inducible genetic approaches to ablate specific populations of adult-generated neurons in a temporally and spatially precise manner have been used [88, 162, 230], although these too are not without practical drawbacks.

A Possible Role in Learning and Memory

The role of the hippocampus in learning and memory has long been recognized. However, the hippocampus has been associated with a range of learning tasks (e.g., trace conditioning, contextual fear conditioning, social transmission of food preference, spatial navigation, and object recognition, to name a few) that do not readily fall into a single category, making a unifying theory of hippocampal function difficult to pin down. One reason for this may be related to findings from recent studies incorporating a subregional analysis of the hippocampus that suggests a heterogeneous distribution of function within its different subfields [165] as well as along the septotemporal axis. [12, 142] Despite this complexity, it has been proposed that learning and memory might require structural changes in the hippocampus. [108, 145] In support of this, numerous positive correlations between learning and structural plasticity have been demonstrated.
In rodents, a variety of conditions that decrease adult neurogenesis in the dentate gyrus are associated with learning impairments. These include stress, increased levels of circulating glucocorticoids, and aging. [42, 140] Similarly, adverse prenatal or early-life experiences produce persistent reductions in neurogenesis and reduced learning abilities in adulthood. [111] Conversely, conditions that increase neurogenesis, such as environmental enrichment and physical exercise, also tend to enhance performance on hippocampal-dependent learning tasks. [99, 211, 214] There are also a number of studies that have found no correlation or even a negative correlation between neurogenesis and learning. [115] However, it is important to keep in mind that a positive correlation between the number of new neurons and learning performance implies a relationship between neurogenesis and learning, although not necessarily a causal one. Another issue to consider is that the time course for alterations in cell production may not correspond to changes in learning abilities. For example, it seems unlikely that the production of new cells would have an immediate effect on processes involved in learning because the cells probably require a certain level of differentiation to have an impact on behavior. Perhaps an even more important consideration, and one that is impossible to discount, is the fact that many of the factors known to affect neurogenesis alter other aspects of brain structure, such as dendritic architecture and synapse number. Since these types of changes are also likely to be involved in hippocampal-dependent learning, it is difficult to interpret correlations between new neurons and learning.
Because of the caveats associated with correlative studies, other work has attempted to demonstrate a casual relationship between learning and neurogenesis, but these too have yielded mixed findings. [115] Reducing or blocking hippocampal neurogenesis disrupts various hippocampal-dependent forms of learning and memory. [31, 45, 62, 85, 91, 88, 122, 158, 164, 172, 186, 187, 191, 223, 230] Recent findings further suggest that the correct differentiation and integration of new neurons may be necessary for acquisition of new information and the recall of memories consolidated in tasks previously performed. [56] However, a large number of studies have failed to demonstrate an involvement of newly generated cells in hippocampal-dependent learning [85, 91, 187, 191, 230], and there is at least one demonstration of enhanced learning following the suppression of neurogenesis. [173] These discrepancies can be attributed to numerous factors, including the animal species and strain tested and the method of ablation, as well as the specifics of the design, analysis, and interpretation of the learning paradigm employed. [62]

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