Jason S. Snyder

Adult hippocampal neurogenesis buffers stress responses and depressive behaviour

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

A role for adult neurogenesis in spatial long-term memory.

Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.

Adult-Born Hippocampal Neurons Are More Numerous, Faster Maturing, and More Involved in Behavior in Rats than in Mice

Neurons are born throughout adulthood in the hippocampus and show enhanced plasticity compared with mature neurons. However, there are conflicting reports on whether or not young neurons contribute to performance in behavioral tasks, and there is no clear relationship between the timing of maturation of young neurons and the duration of neurogenesis reduction in studies showing behavioral deficits. We asked whether these discrepancies could reflect differences in the properties of young neurons in mice and rats. We report that young neurons in adult rats show a mature neuronal marker profile and activity-induced immediate early gene expression 1–2 weeks earlier than those in mice. They are also twice as likely to escape cell death, and are 10 times more likely to be recruited into learning circuits. This comparison holds true in two different strains of mice, both of which show high rates of neurogenesis relative to other background strains. Differences in adult neurogenesis are not limited to the hippocampus, as the density of new neocortical neurons was 5 times greater in rats than in mice. Finally, in a test of function, we find that the contribution of young neurons to fear memory is much greater in rats than in mice. These results reveal substantial differences in new neuron plasticity and function between these two commonly studied rodent species.

Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training.

Hippocampal function varies in a subregion‐specific fashion: spatial processing is thought to rely on the dorsal hippocampus, whereas anxiety‐related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus (DG) proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion‐specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in DG subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c‐fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral DG. In contrast, c‐fos expression in adult‐born granule cells, identified by PSA‐NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral DG. Interestingly, c‐fos expression in the entire granule cell population was equivalent in water maze‐trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally‐relevant experience activates young and mature neurons in different DG subregions and with different experiential specificity, and suggest that adult‐born neurons may play a specific role in anxiety‐related behavior or other nonspatial aspects of hippocampal function.

The effects of exercise and stress on the survival and maturation of adult-generated granule cells†

Stress strongly inhibits proliferation of granule cell precursors in the adult dentate gyrus, whereas voluntary running has the opposite effect. Few studies, however, have examined the possible effects of these environmental manipulations on the maturation and survival of young granule cells. We examined the number of surviving granule cells and the proportion of young neurons that were functionally mature, as defined by seizure‐induced immediate‐early gene (IEG) expression, in 14‐ and 21‐day‐old granule cells in mice that were given access to a running wheel, restrained daily for 2 h, or given no treatment during this period. Treatments began 2 days after BrdU injection, to isolate effects on survival from those on cell proliferation. We found a large increase in granule cell survival in running mice when compared with controls at both time points. In addition, running increased the proportion of granule cells expressing the IEG Arc in response to seizures, suggesting that it speeds incorporation into circuits, i.e., functional maturation. Stressed mice showed no change in Arc expression, compared with control animals, but, surprisingly, showed a transient increase in survival of 14‐day‐old granule cells, which was gone 7 days later. Examination of cell proliferation, using the endogenous mitotic marker PCNA showed an increase in cell proliferation after 12 days of running but not after 19 days of running. The number of proliferating cells was unchanged 24 h after the 12th or 19th episode of daily restraint stress. These findings demonstrate that running has strong effects on survival and maturation of young granule cells as well as their birth and that stress can have positive but short‐lived effects on granule cell survival. Published 2009 Wiley‐Liss, Inc.

Could adult hippocampal neurogenesis be relevant for human behavior

Although the function of adult neurogenesis is still unclear, tools for directly studying the behavioral role of new hippocampal neurons now exist in rodents. Since similar studies are impossible to do in humans, it is important to assess whether the role of new neurons in rodents is likely to be similar to that in humans. One feature of adult neurogenesis that varies tremendously across species is the number of neurons that are generated, so a key question is whether there are enough neurons generated in humans to impact function. In this review we examine neuroanatomy and circuit function in the hippocampus to ask how many granule neurons are needed to impact hippocampal function and then discuss what is known about numbers of new neurons produced in adult rats and humans. We conclude that relatively small numbers of neurons could affect hippocampal circuits and that the magnitude of adult neurogenesis in adult rats and humans is probably larger than generally believed.

Late Maturation of Adult-Born Neurons in the Temporal Dentate Gyrus

Hippocampal function varies along its septotemporal axis, with the septal (dorsal) pole more frequently involved in spatial learning and memory and the temporal (ventral) pole playing a greater role in emotional behaviors. One feature that varies across these subregions is adult neurogenesis. New neurons are more numerous in the septal hippocampus but are more active in the temporal hippocampus during water maze training. However, many other aspects of adult neurogenesis remain unexplored in the context of septal versus temporal subregions. In addition, the dentate gyrus contains another functionally important anatomical division along the transverse axis, with the suprapyramidal blade showing greater experience-related activity than the infrapyramidal blade. Here we ask whether new neurons differ in their rates of survival and maturation along the septotemporal and transverse axes. We found that neurogenesis is initially higher in the infrapyramidal than suprapyramidal blade, but these cells are less likely to survive, resulting in similar densities of neurons in the two blades by four weeks. Across the septotemporal axis, neurogenesis was higher in septal than temporal pole, while the survival rate of new neurons did not differ. Maturation was assessed by immunostaining for the neuronal marker, NeuN, which increases in expression level with maturation, and for the immediate-early gene, Arc, which suggests a neuron is capable of undergoing activity-dependent synaptic plasticity. Maturation occurred approximately 1–2 weeks earlier in the septal pole than in the temporal pole. This suggests that septal neurons may contribute to function sooner; however, the prolonged maturation of new temporal neurons may endow them with a longer window of plasticity during which their functions could be distinct from those of the mature granule cell population. These data point to subregional differences in new neuron maturation and suggest that changes in neurogenesis could alter different hippocampus-dependent behaviors with different time courses.

Septo-temporal gradients of neurogenesis and activity in 13-month-old rats

Recent studies suggest that hippocampal function is partially dissociable along its septo-temporal axis: the septal hippocampus is more critical for spatial processing, while the temporal hippocampus may be more important for non-spatial-related behavior. In young adults, water maze training specifically activates new neurons in the temporal hippocampus, but it is unknown whether subregional differences are maintained in older animals, which have reduced neurogenesis levels. We therefore examined gradients of activity-related Fos expression and neurogenesis in 13-month-old rats and found that neurogenesis occurs relatively evenly throughout the dentate gyrus. Water maze experience significantly increased Fos expression in the suprapyramidal blade and Fos was highest in the septal pole of the dentate gyrus whether the animal learned a platform location, swam in the absence of a platform or remained in their cage. No Fos+ young neurons were found using typical markers of immature neurons. However, Fos expression in the subgranular zone, where adult-born neurons predominate, was disproportionally high in the temporal dentate gyrus. These findings indicate that adult-born neurons in the temporal hippocampus are preferentially activated compared with older neurons.

Complementary activation of hippocampal–cortical subregions and immature neurons following chronic training in single and multiple context versions of the water maze

Neurobiological studies of memory typically involve single learning sessions that last minutes or days. In natural settings, however, animals are constantly learning. Here we investigated how several weeks of spatial water maze training influences subsequent activation of neocortical and hippocampal subregions, including adult-born neurons. Mice were either trained in a single context or in a variant of the task in which the spatial cues and platform location changed every 3 days, requiring constant new learning. On the final day, half of the mice in each training group were tested in a novel context and the other half were tested in their previous, familiar context. Two hours later mice were perfused to measure subregion-specific expression of the immediate-early gene zif268, a marker of neuronal activation. None of the training paradigms affected the magnitude of adult neurogenesis. However, different neuronal populations were activated depending on prior training history, final context novelty, or a combination of these 2 factors. The anterior cingulate cortex was more activated by novel context exposure, regardless of the type of prior training. The suprapyramidal blade of the dentate gyrus and region CA3 showed greater activation in mice trained in multiple contexts, primarily after exposure to a familiar context. In immature granule neurons, multiple context training enhanced activation regardless of final context novelty. CA1 showed no significant changes in zif268 expression across any training condition. In naïve control mice, training on the final day increased zif268 expression in CA3, CA1 and the anterior cingulate cortex, but not the dentate gyrus, relative to mice that remained in their cages (transport controls). Unexpectedly, immature granule cells showed a decrease in zif268 expression in naïve learners relative to transport controls. These findings suggest novel and complementary roles for hippocampal, neocortical, and immature neuronal populations in learning and memory.

A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis

Abstract The growth of research on adult neurogenesis and the development of new models and tools have greatly advanced our understanding of the function of newborn neurons in recent years. However, there are still significant limitations in the ability to identify the functions of adult neurogenesis in available models. Here we report a transgenic rat (TK rat) that expresses herpes simplex virus thymidine kinase in GFAP+ cells. Upon treating TK rats with the antiviral drug valganciclovir, granule cell neurogenesis can be completely inhibited in adulthood, in both the hippocampus and olfactory bulb. Interestingly, neurogenesis in the glomerular and external plexiform layers of the olfactory bulb was only partially inhibited, suggesting that some adult-born neurons in these regions derive from a distinct precursor population that does not express GFAP. Within the hippocampus, blockade of neurogenesis was rapid and nearly complete within 1 week of starting treatment. Preliminary behavioral analyses indicate that general anxiety levels and patterns of exploration are generally unaffected in neurogenesis-deficient rats. However, neurogenesis-deficient TK rats showed reduced sucrose preference, suggesting deficits in reward-related behaviors. We expect that TK rats will facilitate structural, physiological, and behavioral studies that complement those possible in existing models, broadly enhancing understanding of the function of adult neurogenesis.