Behavioral Neuroscience
2013, Vol. 127, No. 1, 126 –129

© 2013 American Psychological Association
0735-7044/13/$12.00 DOI: 10.1037/a0031512

COMMENTARY

Neurogenic Evangelism: Comment on Urbach et al. (2013)
Paul W. Frankland
The Hospital for Sick Children, Toronto, Canada, and University of Toronto, Canada
The continued production of new dentate granule cells throughout life has led to the idea thatneurogenesis critically modulates hippocampal memory function. Consistent with this view, manystudies have shown that experimental reduction of adult neurogenesis impairs hippocampal memory
formation. However, impairments are not universally observed following suppression of adultneurogenesis. A new article by Urbach et al. falls into this latter category. A global deletion of thecyclin D2—a cell cycle regulation gene—induces a profound reduction in adult neurogenesis. Yet,despite this reduction, this knockout mouse was able to acquire a hippocampus-dependent spatial
memory normally. These results suggest that ongoing adult neurogenesis is not necessary for many
forms of hippocampus-dependent learning, and in this commentary, I discuss the implications ofthese types of results for the field.
Keywords: Barnes maze, adult neurogenesis, memory, hippocampus, cyclin D2

acquired this form of spatial learning as quickly as controls, usedequivalently “spatial” search strategies in finding the target holeand showed equivalent spatial bias in a probe test conducted at theend of training (Urbach et al., 2013). So, despite having no adultneurogenesis, cyclin D2 knockout mice were quite able to form aspatial memory.
How general are these effects? It might be easy to dismiss thefindings of this article had the analyses been limited to single,
albeit unquestionably hippocampus-dependent, paradigm. However, this is not the case. This work builds on previous articles
from the same group where they tested the same mice in acollection of other hippocampus-dependent tasks (Jaholkowski etal., 2009; Jedynak et al., 2012). Similar to the results in the Barnes
maze they observed normal learning in the water maze and contextual fear conditioning and even enhanced learning in a trace fear
conditioning paradigm. The mice were additionally tested in assays of sensorimotor function and emotion and, again, passed withflying colors. These findings are not unprecedented either. There’s
a sizable (and growing) collection of articles that come to exactly
the same conclusion as Urbach and colleagues: That suppressing ongoing adult neurogenesis does not always lead to
impaired hippocampus-dependent memory formation (e.g.,
Arruda-Carvalho, Sakaguchi, Akers, Josselyn, & Frankland,
2011; Denny, Burghardt, Schachter, Hen, & Drew, 2012; Drew,
Denny, & Hen, 2010; Martinez-Canabal, Akers, Josselyn, &Frankland, 2012; Meshi et al., 2006; Snyder, Hong, McDonald, &Wojtowicz, 2005).
These types of results challenge the conventional wisdom—that
ongoing adult neurogenesis is required for normal hippocampusdependent memory formation. So, where does this leave us? Are
articles such as Urbach et al. the exception or the rule? How might
we account for the absence of effects of suppressing adult neurogenesis on memory in this study?

The discovery that new neurons are generated in the adulthippocampus has led to the popular idea that they are critical for
memory function. Even within the field of adult neurogenesis there
tends to be a mood of unwavering optimism: New neurons are
good! Increasing their production must boost memory function.
Decreasing their production must, conversely, impair memory.
The danger of this neurogenic evangelism (a term a colleague ofmine coined) is that it becomes tempting to ignore studies that do
not fit snugly into this simple framework. A new article by Urbachand colleagues (2013) represents one such study, and in thiscommentary I will discuss what I think their findings mean for thefield of neurogenesis and memory.
In exploring the relationship between adult hippocampal neurogenesis and memory, the vast majority of studies have conducted
the following kind of experiment: first, in adult rodents, neurogenesis is up- or down-regulated, and then some time later (usually a
few weeks) hippocampus-dependent memory formation is evaluated. Urbach and colleagues (2013) follow this now well-trodden
path. In their case, they used mice lacking the gene for cyclin
D2—a key cell cycle regulator. They found that this genetic
manipulation powerfully suppressed neurogenesis in adult mice
(Jaholkowski et al., 2009). They went on to test spatial memory inthese mice and found, maybe surprisingly, it essentially unaltered.
The spatial memory task they used was a Barnes maze, in whichmice learn to locate an escape route in a circular arena. Detailed
analysis of the behavior indicated that cyclin D2 knockout mice

Correspondence concerning this article should be addressed to Paul W.
Frankland, Program in Neurosciences and Mental Health, The Hospital for
Sick Children, Departments of Psychology and Physiology, Universityof Toronto, Toronto, Ontario, Canada M5G 1X8. E-mail: paul.frankland@sickkids.ca
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COMMENTARY

Right Approach, Wrong Behavior?
This article uses two key methodologies: first, a genetic approach to experimentally reduce adult neurogenesis, and, second,
behavioral analyses to evaluate the impact on memory function.
We’ll start with the approach taken to reduce neurogenesis. A wide
range of approaches have been used to experimentally manipulate
adult neurogenesis ranging from chemical (e.g., antimitotic agents
such methylazoxymethanol acetate [MAM]) to irradiation to genetic. In the current study, they used mice where the cell cycle
regulator gene, cyclin D2, is deleted in all tissues and throughout
development. They concede that there are possible “off-target”
effects of this manipulation. Furthermore, more targeted genetic
ablation strategies are widely used that allow the specific elimination of neural precursor cells and their progeny (Imayoshi,
Sakamoto, & Kageyama, 2011). However, because the micelearned normally in a number of different situations, it is hard to
imagine how a potential lack of manipulation specificity could
confound the interpretation of the results. Is the cyclin D2 associated reduction in adult neurogenesis sufficient in magnitude? If
neurogenesis was only modestly reduced, then it might be trivial tofind hippocampus-dependent memory function unaffected. However, this doesn’t appear to be the case—previous analyses of thesemice revealed an approximate 95% reduction in neurogenesis(measured by numbers of cells expressing the immature neuronalmarker, DCX; Jaholkowski et al., 2009). This is a sizable reduction, matching or exceeding what is observed using other manipulations.
So, if the approach to reducing adult neurogenesis is adequate,
then what about the behavior? The initial observations of adultneurogenesis in the hippocampus were made in the 1960s (Altman,
1962, 1963; Altman & Das, 1965). However, it was not until 30
years later, and the advent of more efficient techniques for labelingand phenotyping adult-generated neurons (Cameron, Woolley,
McEwen, & Gould, 1993), that interest in adult neurogenesis was
rekindled. Soon after, attention quickly turned to the question of
how new neurons in the hippocampus might impact behavior, andin particular, memory function. These studies, not unreasonably,
asked whether reducing adult neurogenesis would produce similar
deficits to those observed after hippocampal lesions. The firststudy of this kind used MAM to reduce adult neurogenesis in rats
and showed that the acquisition of trace eyeblink conditioning was
blocked (Shors et al., 2001). Subsequent studies used other popular
hippocampus-dependent paradigms, including various forms ofspatial learning, fear learning, and recognition tasks (Deng, Aimone, & Gage, 2010).
While these were the tasks of choice initially, more recently
there’s been a shift toward tasks that emphasize spatial discrimination. This is mainly motivated by recognition that dentate gyrus
may be important for pattern separation (Treves & Rolls, 1994)—
the process of transforming overlapping input representations intoless overlapping or distinct output representations—and, by extension, that dentate neurogenesis may modulate the efficiency ofsuch a process (Sahay, Wilson, & Hen, 2011). Indeed, genetic or
chemical suppression of adult neurogenesis impairs population
coding of similar (but not dissimilar) contexts in the CA3 region of
the hippocampus, consistent with the idea that perturbing hippocampal neurogenesis perturbs a pattern separation-like process
in the hippocampus (Niibori et al., 2012). To study behavioral

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correlates of pattern separation a variety of tasks have been used.
These include contextual fear discrimination (where animals learn
to discriminate between similar vs. dissimilar contexts), radial-arm
maze (where animals learn to discriminate adjacent vs. nonadjacent arms), and touchscreen-based operant tasks (where animals
learn to discriminate close vs. distant locations on a touchscreen).
In these tasks, suppression of adult neurogenesis usually impedes
discrimination (Clelland et al., 2009; Kheirbek, Tannenholz, &Hen, 2012; Sahay et al., 2011; Tronel et al., 2012), whereas
promoting adult neurogenesis may facilitate discrimination (Nakashiba et al., 2012; Sahay, Scobie, et al., 2011). Therefore, it isplausible that testing cyclin D2 knockout mice in these tasks would
reveal deficits relevant to reduced adult neurogenesis. Whether or
not any potential deficits in these paradigms would reflect deficient pattern separation is less clear, however. For example, it isquestionable as to whether discriminating between two similar
contexts or between two adjacent arms in the radial arm mazeengages a pattern separation process any more than discriminating
between an array of potential escape holes in the Barnes maze.
Clearly, these tasks differ in several dimensions (e.g., difficulty),
and therefore it is possible that dimensions other than dependency
on pattern separation makes these paradigms sensitive to fluctuations in levels of adult neurogenesis.

Wrong Approach, Right Behavior?
Let’s instead consider the alternate possibility that there isnothing wrong with the behavior. The behavioral analyses of thesemice—spanning both the current article as well as a previous
article—are certainly comprehensive, encompassing many of theparadigms that have been used (successfully) in these types ofstudies. Moreover, they have been conducted thoughtfully, withcareful attention to detail. Maybe it’s something about the approach used to suppress neurogenesis?
I’ve already covered issues of specificity and magnitude of thedecrease in neurogenesis in the cyclin D2 knockout mice, andneither of these can account for the absence of memory phenotype.
What other features of the approach might account for normal
memory? The strategy that Urbach et al. (2013) adopted is thestrategy that has been used in most (if not all) previous studies:
That is, they have examined the impact of reducing neurogenesis
on subsequent learning. The limitation of this type of pretraining
manipulation is that it leaves open the possibility of compensation:
Adult-generated neurons represent only a small fraction of alldentate granule cells, and when they’re removed before learning,
there’s huge potential for compensation by the large numbers ofremaining developmentally generated, granule cells. This potential
for compensation is further compounded by the fact that adultgenerated and developmentally generated neurons converge on
similar cellular phenotypes: While adult-generated cells are transiently more excitable and more plastic, they eventually assume
similar physiological and morphological properties to those generated earlier on during development (Ge, Yang, Hsu, Ming, &Song, 2007; Gu et al., 2012; Laplagne et al., 2006; Marin-Burgin,
Mongiat, Pardi, & Schinder, 2012; Mongiat, Esposito, Lombardi,& Schinder, 2009; Stone et al., 2011). Therefore, developmentally
generated cells can be thought of as perfect substitutes for (at least
mature) adult-generated cells.

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One way to circumvent this potential for compensation is totarget adult-generated granule cells only after they have had theopportunity to be integrated into a memory trace (i.e., to become
memory-committed). Two recent studies have done exactly this.
First, Arruda-Carvalho et al. (2011) developed a genetic approachto conditionally ablate populations of adult-generated neurons, andcontrasted the effects of removing these cells before or after
memory formation. Only removal of cells after training led tomemory deficits, suggesting that if new neurons are present at thetime of learning (and sufficiently mature), they become integrated
into memory traces and come to represent a critical component ofthat trace. However, if they are absent at the time of learning, thenexisting granule cells (for the most part generated during development) can do the job. A very similar dissociation between preand posttraining manipulations of adult-generated granule cells
was found using an optogenetic approach (Gu et al., 2012). Using
retroviral vectors to express light-activatable channels only inadult-generated neurons, they found that silencing at the time of
retrieval impaired memory expression. Silencing during training
failed to impair acquisition, again, presumably, because residual
granule cells were able to compensate once adult-generated granule cells had been taken “offline.”

Right Conclusion?
Urbach and colleagues conclude their article by saying that adultneurogenesis is not necessary for learning in the Barnes maze.
Based on their previous work (Jaholkowski et al., 2009; Jedynak etal., 2012), I am sure they would extend this conclusion to manyother forms of hippocampus-dependent paradigms. While thismight offend the die-hard evangelist, this is almost certainly theright conclusion when coupled with the two caveats highlighted inthis commentary. First, it may be possible to detect memory
deficits in cyclin D2 knockout mice using other, more sensitive
behavioral paradigms. Nonetheless, it is noteworthy that thesemice with greatly reduced adult neurogenesis are not profoundly
impacted in hippocampus-dependent memory paradigms. Second,
the absence of any profound memory phenotype in these micecertainly does not exclude the likelihood that new neurons normally play a role in hippocampal memory formation. However,
because of the potential for compensation, manipulating these cells
once they are committed to memory storage is perhaps a more
powerful approach to reveal their role in hippocampal memory
function.

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Received December 10, 2012
Accepted December 12, 2012 䡲