The Journal of Neuroscience, March 31, 2010 • 30(13):4523– 4525 • 4523

Journal Club
Editor’s Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral
fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more
information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

Functional Contribution of Adult-Generated Olfactory Bulb
Interneurons: Odor Discrimination versus Odor Memory
Katherine G. Akers,1 Masanori Sakaguchi,1 and Maithe Arruda-Carvalho1,2
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, and 2Institute of Medical Science, University ofToronto, Toronto, Ontario M5S 1A8, Canada

1

Review of Breton-Provencher et al.

Processing olfactory information is critical for an animal’s ability to locate food,detect danger, recognize conspecifics, findmates, and rear offspring. The olfactory
bulb (OB) is the initial site of olfactory
information processing in the brain.
Within the OB, mitral cells receive input
from sensory neurons in the olfactory epithelium and send output to higher-order
structures such as the piriform cortex. Mitral cell activity is tightly regulated by dendrodendritic synapses with two types of
local inhibitory interneurons: granule andperiglomerular cells. Interestingly, OB
granule and periglomerular cells differ
from most neurons in that their production continues well beyond embryogenesis and into adulthood, prompting thequestion of whether adult-generated OB
interneurons make a unique contribution
to OB function.
In a recent article in The Journal of
Neuroscience, Breton-Provencher et al.
(2009) examined the impact of reducing
adult neurogenesis on OB function. They
decreased neurogenesis by infusing cytosine arabinoside (AraC) via osmotic
Received Jan. 26, 2010; revised Feb. 18, 2010; accepted Feb. 22, 2010.
K.G.A. is supported by a postdoctoral fellowship from the Ontario Ministry of Research and Innovation. M.S. is supported by Japanese Society for
the Promotion of Science Postdoctoral Fellow for Research Abroad. M.A.-C.
is supported by a Restracomp Award from The Hospital for Sick Children.
Correspondence should be addressed to Katherine G. Akers, Neurosciences and Mental Health, The Hospital for Sick Children, 555 University
Avenue, 6020 McMaster Building, Toronto, ON M5G 1X8, Canada. E-mail:katherine.akers@sickkids.ca.
DOI:10.1523/JNEUROSCI.0443-10.2010
Copyright © 2010 the authors 0270-6474/10/304523-03$15.00/0

minipump into the lateral ventricle ofmice for 28 d. AraC is an antimitotic drugthat incorporates into the DNA of dividing cells and induces apoptotic cell death,
thereby disrupting the proliferation ofneural progenitor cells in the subventricular zone and their subsequent migration
to the OB. After infusion, mice treatedwith AraC exhibited a 75% reduction in
the number of OB cells expressing doublecortin, a marker for immature neurons,compared with control mice treated withsaline.
Breton-Provencher et al. (2009)
found that although the reduction of
adult neurogenesis left the basic structure of the OB intact, it had significant
consequences for OB network function.
Single-cell recordings revealed that mitralcells from AraC-treated mice exhibited
less frequent spontaneous IPSCs andsmaller evoked dendrodendritic inhibitory
currents compared with control mice, indicating that reduction of neurogenesis decreased mitral cell inhibition. Thisdecreased inhibition was not due to intrinsic
changes in the electrophysiologicalproperties of mitral cells, which displayed normal postsynaptic GABAA receptor function as well as normal passive
membrane properties and spontaneous
firing activity. Rather, the decreased inhibition appeared to result from fewer inhibitory synapses made onto the mitralcells, as the lateral dendrites of mitral cells
from AraC-treated mice had fewer sites
immunopositive for gephryn, a postsyn-

aptic GABAA receptor scaffolding protein.
Because the lateral dendrites are where
granule cells form inhibitory contacts, thisfinding suggests that the decrease in mitralcell inhibition resulted from fewer granuleto-mitral cell synapses. As dendrodendritic
interactions between granule and mitralcells are largely responsible for driving
gamma frequency oscillations (Lagier et al.,2004), the authors predicted that AraCtreated mice would have alterations in thistype of oscillatory activity. Indeed, local fieldpotential recordings revealed that AraCtreated mice showed a reduction in the peakfrequency of gamma frequency oscillations
measured from the mitral cell layer after
stimulation of the olfactory nerve (⬃45 Hz
in saline-treated mice vs ⬃39 Hz in AraCtreated mice).
These findings suggest that adult-generated OB interneurons are critical forshaping the overall pattern of OB network
activity and, therefore, may make an important contribution to olfactory-associatedbehavior. In particular, OB interneurons
may play a role in perceptual discrimination between odors. Because each granulecell forms dendrodendritic contacts withmultiple mitral cells, the excitation of a
granule cell by a mitral cell leads to the inhibition of neighboring mitral cells. This process of lateral inhibition may sharpen the
distinction between neural representationsof similar odors and thereby facilitate odor
discrimination. For example, in the rabbit,
individual mitral cells showing excitatory
responses to certain odorants showed inhib-

Akers et al. • Journal Club

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Table 1. Impairment in olfactory-associated behavior after reduction of adult OB neurogenesis
Study

Method of reducing OB neurogenesis⫺/⫺

Gheusi et al., 2000

NCAM

Enwere et al., 2004

Aging, Lifr⫹/⫺, TGF␣wa1/wa1

Bath et al., 2008

BDNF⫹/⫺, TrkB⫹/⫺, BDNFMet/Met

Imayoshi et al., 2008
Lazarini et al., 2009

Nestin-CRE-ERT2 ⫻ NSE-DTA
Focal SVZ irradiation

Breton-Provencher
et al., 2009

LV AraC infusion

Impact on immature
adult-generated neurons

Impact on mature adult-generated
neurons

Odor
discrimination

Migration in RMS: impaired

GCL width: 35% reduction

Impaired

BrdU⫹/Calretinin⫹ cells (4 wk
postinjection): 59% reductionin GL in aged mice
Proliferation: no change

BrdU⫹/GABA⫹ cells (4 wk postinjection):
41% reduction in GL, 55% reductionin GCL in aged mice
BrdU⫹ cells in GCL (4 wk postinjection):
30% reduction
NeuN⫹ cells in GCL: 10% reduction

Impaired

DCX⫹ cells in RMS: reduced
DCX⫹ cells in GL and GCL:
70% reduction
DCX⫹ cells in GCL:
75% reduction

NeuN⫹ cells in GCL: no change

Odor memory
Impaired short-term(80 –100 min)

ImpairedNo deficit
No deficit
No deficit

No deficit
Impaired long-term(30 d)
Impaired short-term(60 –120 min)

BrdU, Bromodeoxyuridine; CRE, cAMP response element; GCL, granule cell layer; GL, glomerular layer; LV, lateral ventricle; RMS, rostral migratory stream; SVZ, subventricular zone.

itory responses to odorants with similar molecular structures, and this odor-specificresponse pattern was eliminated by blockade of inhibitory neurotransmission (Yokoi
et al., 1995). Synchronous oscillatory activity in the OB may also be important for odor
discrimination. In the honeybee, pharmacological desynchronization of odor-evoked
oscillations impaired perceptual discrimination between structurally similar odorants (Stopfer et al., 1997).
Given that reduced neurogenesis leads todecreased mitral cell inhibition and altered
OB oscillatory activity, mice with reduced
adult OB neurogenesis might be expected
to exhibit poor discrimination between
odors. Surprisingly, Breton-Provencher etal. (2009) found that AraC-treated mice displayed normal odor discrimination but
showed poor odor memory. Like control
mice, AraC-treated mice showed a decrease
in investigative behavior on repeated presentations of one odor (i.e., habituation)
and an increase in investigative behavior on
presentation of a second odor (i.e., dishabituation), indicating that they perceived
the two odors as being different. When the
delay between repeated presentations of thesame odor was lengthened from 30 to 60
min, however, AraC-treated mice failed tohabituate, suggesting that they could not remember an odor for ⬎30 min. These findings, therefore, implicate adult-generated
OB interneurons in memory for odors but
not perceptual discrimination between
odors.
A perplexing finding is that although
AraC-treated mice showed no evidence ofmemory for a previously encounteredodor after 60 min, they were able to remember an association between an odor and afood reward for at least 7 d. If mice cannot
recognize an odor after a short span of time,
it is difficult to understand how they could
form long-term odor associations. One possible reason for this discrepancy is thatshort- and long-term odor memories wereassessed by two different behavioral tasks,
the former involving odor habituationand the latter involving odor–food associations, which may have differential
requirements for adult-generated OB interneurons. For instance, odor–food associative memory might be unaffected by
reductions in adult OB neurogenesis because associations between odors andnonolfactory stimuli rely on piriform andorbitofrontal cortices (Wilson et al., 2006)
more than the OB.
This study is the latest in a growing collection of studies investigating the impactof reducing adult OB neurogenesis on
olfactory-associated behavior in mice
(Table 1). These studies, however, appear toprovide conflicting results. Whereas some
report that reduced neurogenesis impairs
odor discrimination (Gheusi et al., 2000;
Enwere et al., 2004; Bath et al., 2008), others
report that reduced neurogenesis leaves
odor discrimination intact but impairs odor
memory (Breton-Provencher et al., 2009;
Lazarini et al., 2009), and yet another reports that reduced neurogenesis impairs
neither odor discrimination nor odor memory (Imayoshi et al., 2008).
One factor that may influence whether
reduced OB neurogenesis impairs odor
discrimination may be the difficulty ofthe discrimination. As noted by BretonProvencher et al. (2009), adult-generated
OB interneurons may be exclusively involved in discrimination between highly
similar odors (e.g., odors with similar molecular structures or similarly comprised
mixtures of odors). For instance, aged or
mutant mice with reduced OB neurogenesis discriminated between two distinct
odors (100% almond vs 100% coconut)
but not two similarly comprised mixturesof the odors (58% almond/42% coconut
vs 42% almond/58% coconut) (Enwere etal., 2004). Perhaps some studies (Imayoshi

et al., 2008; Breton-Provencher et al.,2009) did not find deficits in odor discrimination because the odors were too
distinct, leaving open the possibility thatusing more similar odors could reveal impairments. A recent study (Lazarini et al.,2009), however, demonstrated that irradiated mice with reduced OB neurogenesis
showed normal odor discrimination despite being extensively tested in tasks withhighly similar odors, providing evidence
that adult OB neurogenesis is not necessary for even the most difficult odor
discriminations.
A second factor that might influence
whether reduced OB neurogenesis impairs
odor discrimination is the developmental
timing of the experimental manipulation.
As proposed by Lazarini et al. (2009), impairments in odor discrimination may beobserved when OB neurogenesis is disrupted during embryogenesis but notduring adulthood. That is, the ability todiscriminate between odors may dependon the initial formation of OB neural circuitry brought about by the early wave ofneurogenesis during the prenatal andearly postnatal periods, but may not depend on the continued addition of newneurons to that circuitry during adulthood. Consistent with this idea, odor
discrimination was impaired by genetic
mutations that likely affected OB neurogenesis throughout development (Gheusi
et al., 2000; Enwere et al., 2004; Bath et al.,2008) but was not impaired by manipulations that targeted neurogenesis specifically during adulthood (Imayoshi et al.,2008; Breton-Provencher et al., 2009;
Lazarini et al., 2009). Furthermore, Enwere etal. (2004) found that a declining rate ofneurogenesis in aged mice was associatedwith poor odor discrimination, suggesting that impairments in odor discrimination may emerge when OB circuitry
breaks down during senescence.

Akers et al. • Journal ClubA third factor that may influence thetype of behavioral impairment observed
after reduction of OB neurogenesis is theage of the affected neurons. After theirgeneration in the subventricular zone,
newborn neurons destined for the OB undergo several migrational and maturational stages before fully integrating into
OB circuitry. In the study by BretonProvencher et al. (2009), AraC-treatedmice possessed the same number of mature OB granule cells as control mice yet
exhibited alterations in OB network function and odor memory, suggesting thatimmature granule cells play a special rolein OB function. In support of this possibility, immature adult-generated granulecells display greater immediate early gene
expression in response to novel odors
compared with mature cells (Magavi etal., 2005), and only immature adult-generated granule cells exhibit long-term potentiation of synaptic strength (Nissant etal., 2009). To determine how different
ages of adult-generated OB interneurons
might differentially contribute to olfactoryassociated behavior, it will be critical to target the cells at specific maturational stages.
The study by Breton-Provencher et al.
(2009) is valuable in that it uses a multilevel approach from cell to behavior todemonstrate the importance of adult neurogenesis in olfactory information processing. Their finding of impaired odor
memory after reduction of adult neurogenesis invites future studies to focus on
precisely how adult-generated OB interneurons are involved in the retention of

J. Neurosci., March 31, 2010 • 30(13):4523– 4525 • 4525

odor memories. Furthermore, as a complement to studies showing that reductionof OB neurogenesis impairs olfactory
function, future studies could examine
whether enhancement of OB neurogenesis improves olfactory function. Suchstudies would increase our understandingof how new neurons can be successfully
integrated into existing neural circuits,
which could propel efforts to improvefunctional recovery from brain injury or
disease. A comprehensive knowledge of
how brain pathology and/or the recoveryof brain function might involve adult neurogenesis in the OB, hippocampus, andneocortex will be fundamental for thetranslation of basic research findings toclinically relevant situations.

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