Review

The olfactory bulbectomy model in mice and rat: One story or twotails?

Hendrikus Hendriksen n, S. Mechiel Korte, Berend Olivier, Ronald S. OostingDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

a r t i c l e i n f o

Article history:Accepted 9 October 2014

Keywords:AntidepressantCognitive declineNeurodegenerationSpecies-specificAnimal modelRodent

a b s t r a c t

Olfactory bulbectomy (OBX), the surgical removal of the olfactory bulbs, lead, both in mice and rats, to aspecific set of behavioral changes in social behavior, cognitive function and activity. The latter is oftenused as a readout measure to predict antidepressant effects of new compounds. More recently, themodel is used to study neurodegeneration and the associated cognitive decline. Although most of theOBX-induced behavioral and neurochemical changes seen in mice and rats are very similar, there are alsosome remarkable differences. For instance, OBX has different effects on BDNF and the 5-HT2c receptor ofthese two species. These species differ also in how they respond to certain treatments after OBX. In thisreview we describe these species-specific differences and discuss what they may mean in terms oftranslational value.

& 2014 Published by Elsevier B.V.

1. Introduction

Surgical removal of the olfactory bulbs (OBX) in rats or mice leadsto a number of behavioral, cognitive and neurochemical changes. TheOBX-paradigm is often used as a pharmacological model for predictingantidepressant efficacy. A wide range of known or presumed anti-depressant drugs has been tested for their ability to normalize thetypical hyperactivity that results from removal of the olfactory bulbs.Whether the underlying neurobiological mechanisms of this modelresemble the neurobiological state of depressed patients is still amatter of debate. But the overwhelming number of antidepressantdrugs tested in this model, not only acting on the serotonin transporter(Cryan et al., 1998; Breuer et al., 2007; Roche et al., 2007) or the 5HT1Areceptor (Borsini et al., 1997; Mar et al., 2000), but also on very diversereceptors like the dopamine D3 receptor (Breuer et al., 2009a), thenoradrenalin transporter (Harkin et al., 1999), the vassopressin V1B

receptor (Breuer et al., 2009b; Iijima et al., 2014), the corticotropin-releasing factor receptor 1 (Chaki et al., 2004; Frisch et al., 2010) andthe neuropeptide Y receptor 1 (Goyal et al., 2009) makes it a valuabletool for assessing the effects of novel antidepressant drugs.

Moreover, this model is also studied for the robust cognitiveimpairments it shows. These cognitive impairments are thought tobe the result of the neurodegeneration secondary to removal of theolfactory bulbs. Both the abilities to acquire and to retrieve memoryare impaired after OBX surgery. Although most OBX studies are done

in rats, there are also an extensive number of studies done in mice.Most effects of OBX are comparable in both species. Most impor-tantly, both species become hyperactive and have serious memorydeficiencies after removal of the olfactory bulbs.

However, there is a difference between rats and mice in theway they respond to some types of antidepressant treatment butalso in the recovery of learning and memory deficiencies.

The differences in the effects of OBX between rats and mousemay have implications for the translation of the results to thehuman patient.

It might be less valid to extrapolate results from a species thatshows a high potential to recover from severe neurodegeneration,because this seems less related to the human condition. On the otherhand, studying such species-specific differences in the ability torecover from neurodegenerative processes, might eventually lead toa better understanding of how we may promote regeneration in thehuman brain.

2. Brief history of the olfactory bulbectomy model

In 1971, Marks et al. investigated rats with bilateral lesions ofthe olfactory bulbs to evaluate the effect of anosmia on learningperformance. A little bit later, a clear impairment in passive avoidancelearning after olfactory bulbectomy (OBX) was reported (Thomas,1973). Further studies showed other OBX induced behavioral changesin sexual behavior (Sato et al., 1974; Larsson, 1975; Pollak and Sachs,1975), in food intake and the preference for food (Leung et al., 1972;Larue, 1975), in the effects of handling (Loyber et al., 1977), and inmaternal care (Schwartz and Rowe, 1976). In 1976, Van Riezen et al.

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n Correspondence to: Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.Tel.: þ31 681429599.

E-mail address: h.hendriksen@uu.nl (H. Hendriksen).

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speculated that the behavioral changes of olfactory bulbectomizedrats could be used to detect novel anti-depressants (van Riezen et al.,1976) and a year later the olfactory bulbectomized rat was presentedas a model for depression and the detection of anti-depressantefficacy (van Riezen et al., 1977; Wren et al., 1977).

After its proposal as a pharmacological predictive model forantidepressants, the research expanded further in this direction.The brain chemistry of the animals (Tonnaer et al., 1980) was furtherexamined and the list of tested antidepressants grew. Currently theOBX-model is used both as a pharmacological predictive test forantidepressant efficacy of drugs as well as a model to study cognitivedecline and neurodegeneration.

3. Technical procedure

The procedure for surgical removal of the olfactory bulbs ofrodents has been described by different groups. The methods usedshow little variation. Animals are anesthetized with either isofluor-ane gas (Breuer et al., 2007) or injection anesthetic (Cairncross et al.,1977; van der Stelt et al., 2005) and subsequently placed in astereotaxic instrument. An incision is made in the scalp above theolfactory bulbs, lidocaine (5%) is administered as local anesthetic tothe periosteum (van der Stelt et al., 2005; Breuer et al., 2007). Twoholes (2 mm in diameter) are drilled in the skull, 8 mm anterior tobregma and 2 mm from the midline of the frontal bone overlyingthe olfactory bulbs. Next, the olfactory bulbs are removed using ablunt hypodermic needle attached to a vacuum pump (van der Steltet al., 2005; Breuer et al., 2007) or are excised using a sharp needle(Wang and Hull, 1980). Blood loss is prevented as much as possibleby hemostatic sponges. Next the incision is sutured using resorb-able material. Sham operated rats undergo the same procedurewithout removing the olfactory bulbs. Subcutaneous carprofen(5 mg/kg) is administered post operatively for relief of pain. Animalsare allowed to recover for two weeks before further testing (Wangand Hull, 1980; Breuer et al., 2007). This two-week recovery periodalso allows for the completion of the OBX induced alterations in therest of the brain. The procedure in mice is very similar (Nesterovaet al., 1997; Hozumi et al., 2003).

4. Key features of the OBX model

4.1. Physiology

Some physiological parameters change after olfactory bulbect-omy: circadian rhythmicity alters, nocturnal body temperatureincreases and heart rate decreases. These changes appear withindays of the surgery (van Riezen and Leonard, 1990; Vinkers et al.,2009). OBX also induces a decrease in REM sleep (Sakurada et al.,1976). Interestingly, this effect could be normalized with acuteadministration of fluoxetine (Wang et al., 2012). In mice a shift incircadian rhythm was measured after OBX that could partly benormalized with chronic fluoxetine treatment. (Possidente et al.,1996). A study of (Wollnik, 1992) showed that fluoxetine had noeffect on the circadian wheel-running rhythms of rats. This latterstudy, however, was performed with rats that had intact olfactorybulbs and it might well be that the effects of fluoxetine are morepronounced in animals that underwent OBX surgery than in intactanimals.

4.2. Immunology

A number of changes in the immune system are observed afterOBX-surgery. In rats, lower numbers of lymphocytes and reducedneutrophil phagocytosis (Cai and Leonard, 1994; Song et al., 1994)

and increased macrophage and monocyte activity were found(Song et al., 1994; Song et al., 1996). Another remarkable changeseen in the immune response of OBX rats is the attenuatedproduction of interleukin (IL)-1beta and tumor necrosis factor(TNF) when challenged with lipopolysaccharide (LPS) (Connoret al., 2000). Whether similar changes happen in OBX mice isunknown. For a review on the changes in the immune system afterOBX see (Leonard and Song, 2002). In mice, an OBX-inducedreduction in Lyt2-positive suppressor T cells and an increase inL3T4-positive T helper cells ratio was seen, indicating a persistentactivation of the immune system (Komori et al., 2002).

Whether a similar shift in T-lymphocytes occurs in rats follow-ing OBX is unknown.

4.3. Endocrinology

Changed activity of the hypothalamus after OBX surgery leadsto increases in circular ACTH and corticosterone levels (Marcilhacet al., 1997; Marcilhac et al., 1999a; Breivik et al., 2006), suggestedto underlie the enhanced sensitivity for mild stressors of OBXanimals. Handling, for example, has a different effect on corticos-terone levels in OBX animals compared to controls (Loyber et al.,1977). The higher hypothalamic activity is probably not the resultof enhanced levels of hypothalamic CRF, but is more likely causedby higher levels of vasopressin secreted from the increasednumber of vasopressin positive cells in the external layer of themedian eminence (Marcilhac et al., 1999b). In contrast a studywith mice did not show increased serum corticosterone levelsafter bulbectomy (Machado et al., 2012). To complicate matters,also in OBX rats, increased corticosterone levels are not alwaysfound (Broekkamp et al., 1986).

4.4. Neurochemistry

The serotonin (5-HT) system seems to play a crucial role in thebehavioral changes induced by OBX. 5-HT as well as its metabolite 5-hydroxyindole acetic acid (5-HIAA) are consistently decreased post-operatively. Changes in the serotonergic system are most prominentin the frontal cortex, nucleus accumbens, amygdala and dorsalhippocampus (Jancsar and Leonard, 1984; Redmond et al., 1997;Connor et al., 1999; van der Stelt et al., 2005). Not just the decreasedlevels, but in particular the imbalance in 5-HT synthesis betweendifferent brain areas is thought to be responsible for the typicalbehavioral features of the OBX model (Watanabe et al., 2003). Also inmice the serotonin system is affected. Less tryptophan hydroxylaseand a decreased rate of 5-HT synthesis was found in bulbectomizedmice (Neckers et al., 1975; Hellweg et al., 2007), while higher levels of5-HT2 receptors are reported (Gurevich et al., 1993).

The concentration of noradrenaline in the telencephalon alsodecreases after bulbectomy and at the same time the density ofbeta-adrenoceptors increases in the cortical areas (Jancsar andLeonard, 1984; van Riezen and Leonard, 1990).

The relation between the amount of damage to the olfactorybulb and the changes in noradrenalin (and dopamine) levels in thebrain are well studied in rats by (Edwards et al., 1977). Only totalbulbectomy with damage to the olfactory penduncle leads to asubstantial decrease of noradrenalin in the telencephalon,whereas, partial bulbectomy (only two third of the olfactory bulbsdamaged) leads to an increase of noradrenalin in the telencepha-lon. No significant effects on dopamine content were seen in thisstudy. Unfortunately these authors did not investigate the effectsof the partial bulbectomy on behavior.

In OBX mice higher noradrenaline levels in the hypothalamus(Yoshimura and Ueki, 1981) and reduced noradrenalin turnover inthe prefrontal cortex (Kamei et al., 2007) have been measured. Inrats post OBX levels of glutamate were reported to be lower only

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in the olfactory tract, while the levels of aspartate were decreasedin the lateral olfactory tract, periamygdaloid cortex, olfactorytubercle and the piriform cortex (Collins, 1984).

A decrease in NMDA receptor binding was found in a number ofbrain areas three weeks after OBX. In some areas (e.g.thalamusand amygdala) however, these change were already observed inthe first week after surgery (Robichaud et al., 2001). Administra-tion of Memantine, a non-competitive NMDA receptor antagonist,for 28 days starting two days before the OBX surgery preventedOBX-induced hyperactivity and partly the loss of fear memory inrats (Borre et al., 2012a). Importantly, when memantine wasadministered 14 days after surgery (the paradigm used for asses-sing antidepressant activities in this model), this Alzheimer drugwas without an effect. These findings may indicate that 1)Mementine acts as a neuroprotective agent in this model byreducing the NMDA receptor-mediated excitotoxicity and 2) thatthis mechanism only plays a role in the onset of the OBXsyndrome. Also in mice, drugs that affect the NMDA receptorfunction ameliorate the cognitive deficiencies due to OBX (Tadanoet al., 2004; Moriguchi et al., 2009).

Also the GABA system is affected by OBX in rats. A higher GABAturnover in the amygdala (Jancsar and Leonard, 1984) and higherlevels of GABA-A and lower levels of GABA-B receptors in theprefrontal cortex were found (Dennis et al., 1993). Also a reduction,reversible with mianserin, of muscarinic receptors in the brain wasobserved (Earley et al., 1995). We did not find studies in miceinvestigating the role of the GABA system after OBX surgery.

Taken together ablation of the olfactory bulbs changes a widerange of neurotransmitter systems in various parts of the brain.

4.5. Social behavior (aggression, nursing, sexual behavior)

Removal of the olfactory bulbs in male rats leads to a reductionin sexual activity (Larsson, 1975; Chambliss et al., 2004). OBX onfemale animals at young age delayed their sexual maturation (Satoet al., 1974). Also the time spent nursing their pups was decreasedin lactating OBX mothers. Often pups are cannibalized shortly postpartum by mothers that underwent OBX surgery (Schwartz andRowe, 1976)In mice, increased pup killing by the mothers thatunderwent OBX surgery was comparable with the rat, whileaggression towards adult conspecifics seems to be decreased afterOBX (Neckers et al., 1975; Mucignat-Caretta et al., 2006).

4.6. Cognitive functions

Olfactory bulbectomy leads to cognitive decline. Several cognitivechanges are described in rats such as a decreased ability for bothpassive and active avoidance learning (Marks et al., 1971; van Riezenand Leonard, 1990; Borre et al., 2012a; Hendriksen et al., 2012) andimpaired extinction of conditioned taste aversion (Jancsar andLeonard, 1984). Remarkably the cognitive decline appears already3 days after surgery while at that time the hyperactivity in the openfield is not yet seen (Borre et al., 2012b).

Not only fear learning is affected by OBX, but also other cognitivefunctions are affected by OBX. Spatial navigation, as studied in theMorris water maze, is reduced in OBX rats compared to shamoperated rats (Redmond et al., 1997). Also in mice deficiencies inpassive avoidance learning after OBX are described (Fig. 3) (Jarosiket al., 2007) as well as impaired special memory performance in thewater maze (Mucignat-Caretta et al., 2006; Ostrovskaya et al., 2007).Short-term memory tested in the t-maze is worse in OBX animals,both in rats (Hendriksen et al., 2012) and mice (Zueger et al., 2005).Both acquisition and retention in the holeboard task were impairedin rats after OBX (Borre et al., 2012a). Together with the finding thatobject place but not object recognition is diminished in OBX rats(Hendriksen et al., 2012) these cognitive tests suggest that at least

hippocampus dependent memory is affected by OBX. However, alsodamage to other brain structures, like the amygdala and prefrontalareas, are probably causally involved in these cognitive deficits. Bothin rats and mice, OBX leads to degeneration in the piriform cortexand to changes in the amygdaloid nuclei, which may play a role inthe cognitive decline (Capurso et al., 1997; Wrynn et al., 2000;Koliatsos et al., 2004; Jarosik et al., 2007). While it is not clearwhether anosmia or secondary OBX induced neuronal changes areresponsible for the alterations in social behavior, Borre et al. haveshown that the cognitive changes that follow to OBX were not theresult of ZnSO4-induced anosmia (Borre et al., 2014).

4.7. Hyperactivity

In rats hyperactivity in the home cage is already measured3 days after OBX (Vinkers et al., 2009), while the activity in theopen field test at this time point is not changed. In mice and ratshyperactivity in the open field test was measured first one weekafter surgery. The hyperactivity of OBX animals in an open field testis a robust effect that has been shown in our lab alone already formore than 20 separate experiments. Also in mice this phenomena isrobust and described often (Possidente et al., 1996; Zueger et al.,2005; Han et al., 2009). A large number of studies in rat and mousehave shown that OBX induced hyperactivity is normalized afterchronic treatment with antidepressants (Otmakhova et al., 1992;Cryan et al., 1998; Breuer et al., 2007; Jarosik et al., 2007; Rocheet al., 2007). As in humans, the antidepressant treatment is notacutely effective but needs a period of daily administration. Forinstance after 3 days of treatment with citalopram (Lucas et al.,2007) or one day of imipramine (Breuer et al., 2007), OBX rats werestill more active than control animals. The reduction of hyperactiv-ity in the open field remained for up to six weeks after cessation ofchronic treatment with imipramine (Breuer et al., 2007).

5. Validity of the OBX model

The wide range of antidepressant compounds tested combinedwith the robust and stable effects of these drugs on hyperactivityhave established the OBX model as a screening model for novelantidepressants. In contrast to the OBX model, the forced swimtest or the tail suspension tests are antidepressant screening teststhat do not depend on the long-term treatment with antidepres-sants that is needed in depressed patients. Due to this similar timepath for the onset of the treatment effect the predictive validity ofOBX model might be of a high translational value for the screeningof putative antidepressant compounds. However, care should betaken with negative results obtained with this model. Becausecurrently we do not understand the mechanism underlying thereduction of the hyperactivity, new compounds that have anti-depressant effects that do not act via the same pathways thatreduce hyperactivity in the OBX animal might be erroneouslydismissed.

6. Species differences

OBX in rats leads to similar behavioral changes as seen in mice.Also on the neurochemical and pharmacological level a number ofOBX related changes are comparable between both species. So theablation of the olfactory bulbs affects rats and mice in more or lessthe same way. However, there are also some remarkable OBXrelated differences between both species.

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6.1. Species differences in the reversal of hyperactivity

We measured hyperactivity in the open field test 10 weeks afterolfactory bulbectomy in male C57/b16 mice and in Sprague Dawleyrats (Fig. 1). After five weeks of enriched housing (as described in(Hendriksen et al., 2012)) hyperactivity in rats was normalized. InOBX mice, however, the five 5 weeks of enriched housing did notreduce the hyperactivity in the open field.

6.2. Species differences in the retention of memory withcholinesterase inhibitor physostigmine

In a study in mice by Hozumi et al. in 2003 the memory declineafter OBX was tested in a passive avoidance apparatus (Hozumi et al.,2003). Acquisition was done before OBX surgery. Memory in thepassive avoidance test was impaired 14 days after surgery but could berescued with systemic administration of the choline esterase inhibitorphysostigmine (0.1 mg/kg). The authors also described lower levels ofcholine acetyltransferase in cortex, hippocampus and amygdala andconcluded that the cholinergic system must play an important role inthe memory decline after OBX and that memory improvementis gained via the muscarinic receptors. In our rat study (see Fig. 2)however, we came to a different finding. The OBX induced impairedpassive avoidance memory did not improve after physostigmine.We studied the effect of 3 different doses (0.003, 0.01, 0.1 mg/kg)of physostigmine 48 h and 28 days after OBX but none of these dosesimproved the memory of the OBX rats (Fig. 2A). The higher dose didhowever decrease the activity in the open field (Fig. 2B) and resultedin clear observable muscle tone changes hampering the locomotion ofthe animals.

6.3. Environmental enrichment rescues the impairment in fearmemory induced by OBX in mice but not in rats

OBX results in significant reduction of the latency time inthe passive avoidance test mice (Fig. 3). Passive avoidance trainingwas performed 8 weeks after surgery. The latency times weretested 7 days after passive avoidance acquisition. Enriched housingimproved contextual fear memory in these mice. Mean latencytimes to enter the dark compartment were significantly lower inOBX mice kept under standard housing conditions than in theenriched housed mice. Although the set-up of the passive avoid-ance test was different (latency times were tested ten weeks afteracquisition) it is remarkable that in rats environmental enrich-ment did not rescue the impairment in passive avoidance memoryinduced by OBX (Hendriksen et al., 2012).

6.4. Amitriptyline prevents the impairment in memory acquisitioninduced by OBX in rats but not in mice

Passive avoidance training performed 21 days after surgery wasimpaired in OBX rats. Chronic treatment for 7 days with thetricyclic antidepressant amitriptyline starting 14 days after surgeryprevented this impairment of acquisition (van Riezen et al., 1977).In C57/BL6 mice chronic amitriptyline treatment for 14 days didnot restore performance in the passive avoidance acquisition(Jarosik et al., 2007). On the contrary, in another study, usingtwo different mouse strains (C57B1/6J and DBA/2J), amitriptylinesignificantly improved passive avoidance acquisition (Otmakhovaet al., 1992).

Fig. 1. Species differences in the reversal of hyperactivity olfactory bulbectomy-induced hyperactivity in the open field (5 min.) as measured in male C57/b16 mice,1A (42�42�40 cm3 arena, N¼6) (ANOVA, (F(3,20)¼14.36, Po0.05 and inSprague–Dawley rats, 1B (90�90�40 cm3 arena, n¼12) (ANOVA F(3,42)¼10.6,Po0.001). Both open field tests were performed 10 weeks after surgery. After fiveweeks of enriched housing (as described in (Hendriksen et al., 2012)) hyperactivityin rats was reduced (OBX-ST vs OBXEE Po0.05). In OBX mice however, there wasno significant effect of the housing (5 weeks of EE) condition.

Fig. 2. A. Effect of physostigmine on passive avoidance behavior in rats The OBXinduced impaired passive avoidance memory did not improve by the administra-tion of physostigmine. We studied the effect of 3 different doses (0.003, 0.01,0.1 mg/kg) of physostigmine 48 h and 28 days after OBX but non of them improvedthe memory of the OBX rats. Latency times after OBX surgery were significantlyshorter in OBX rats regardless of the dose of physostigmine Kruskal–Wallis H(8)¼38.1, Po0.0001, post-Hoc test, Dunn's multiple comparison test. *Po0.05,***Po0.001, ****Po0.0001. B.The highest dose of physostigmine decreased theactivity in the open field (Statistical analysis revealed a significant effect of surgery:*** two factorial ANOVA F(1,40)¼16.1, Po0.001 and an effect of physostigmine(0.1 mg/kg): ### F(1,40)¼31.9, Po0.001 on locomotion in the open field.

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6.5. Serotonin receptors

In addition to the above mentioned differences in behavior, alsodifferences in the neurochemistry between different mice strains,and between mice and and rats have been reported. For instancebulbectomy had no effect on the number of 5-HT2C receptors inDBA/2J mice (Gurevich et al., 1993), while an increase was seen inthe C57B1/6J strain. In rats however, not only an up-regulation ofthe 5-HT2C receptor was seen after OBX (Earley et al., 1994), butalso the 5-HT2C agonist way-163909 was effective in decreasingthe hyperactivity in the OBX rat (Rosenzweig-Lipson et al., 2007).

6.6. Brain derived neurotrophic factor

In mice brain derived neurotrophic factor (BDNF) levels in thehippocampus are up-regulated after OBX (Hellweg et al., 2007) whilethe levels in rats are decreased after OBX (Hendriksen et al., 2012).The hippocampal weight of rats was reduced after OBX surgery.Environmental enrichment resulted in normalization of hippocampalweight but had no significant effect on BDNF levels in that study(Hendriksen et al., 2012). In the rat, other neurotrophic factors, suchas VEGF, may play a role in the recovery of hippocampal weight.

7. Discussion

7.1. Of mice and rats

According to the Rat Genome Sequencing Consortium 2004about 90% of the rat genome has its counterpart in the mousegenome (Gibbs et al., 2004). In comparison, the difference betweenthe genomes of man and chimpanzee is about 1.23% (Mikkelsenet al., 2005). In other words, rats and mice have quite an evolu-tionary distance. In general, the behavioral spectrum of rats seemsto be more complex than that of mice (Whishaw et al., 2001). AsCryan and Mombereay put it sweet and short: “Mice are not smallrats” (Cryan and Mombereau, 2004). In this respect it is should notbe so much of a surprise that contradicting results are obtained inOBX studies in the two species (table 1). Even so these speciesdifferences raise a couple of concerns. In the scientific literature onolfactory bulbectomy, the results of OBX in rats and mice are usedintermingled which might cloud the understanding of the under-lying mechanism of OBX. The species differences might be evenmore problematic for the translational value for the model, since itis difficult to determine whether results in rats or in mice are morevaluable for the human condition. Still the differences between ratand mice in the reaction to olfactory bulbectomy might not be thatbad. Studying these differences in regenerative potential might leadto more insight in this process.

7.2. Underlying mechanisms for the species-specific reaction to OBX

In the OBX studies described here mice reacted sometimesdifferently than rats to OBX surgery or showed different effects oftreatment following OBX surgery. The mechanism responsible forthese differences are difficult to determine and we are not awareof studies that were focused on this issue until now. Here wepropose three possibilities leading to the OBX related speciesdifferences.

7.3. Species-specific differences in the OBX induced changes

The differences in the reaction to treatment after OBX might be aconsequence of differences in the changes induced by the OBXsurgery. For instance the levels of BDNF after OBX (Hellweg et al.,2007; Hendriksen et al., 2012) might play a role in the reaction toenvironmental enrichment or antidepressant treatment with ami-triptyline. If we assume that elevated BDNF levels are one of thenecessary components for the recovery from the OBX-inducedmemory deficits it might be much harder to establish effectivelevels in rats, where BDNF is down-regulated, than in mice where

Fig. 3. Effect of environmental enrichment on passive avoidance behavior in mice.OBX results in significant reduction of the latency time in the passive avoidanceKruskal–Wallis H(4)¼12.6, Po0.01. Post-Hoc analysis (Dunn's multiple compar-ison test) revealed that OBX animals housed under standard conditions hadsignificant lower latencies than Sham, standard housed mice Po0.01. The latencytimes were tested 7 days after passive avoidance acquisition. The passive avoidancetraining was performed 8 weeks after surgery. In OBX mice that were housed underenriched conditions however, contextual fear memory was not different from shamoperated animals P40.05.

Table 1Species-specific OBX induced changes.

Effect ofbulbectomy

Effect of Treatment in mice Strain Authors Effect of treatment in rat Strain Authors

Hyperactivity inopen field

Environmental enrichment had noeffect on hyperactivity

C57B1/6 Fig. 1 Normalized by enriched housing SpragueDawley

(Hendriksen et al., 2012)

Passive avoidancedeficits

Physostigmine normalized deficits ddY (Hozumiet al., 2003)

No effect of physostigmine on passiveavoidance deficits

SpragueDawley

Fig. 2

Passive avoidancedeficits

Environmental enrichment normalizeddeficits

C57B1/6 Fig. 3 No effect of environmental enrichmenton passive avoidance deficits

SpragueDawley

(Hendriksen et al., 2012)

Passive avoidancedeficits

Amitriptyline ineffective at normalizingpassive avoidance deficits

C57Bl/6J (Jarosiket al., 2007)

Amitriptyline normalized passiveavoidance deficits

SpragueDawley

(van Riezen et al., 1977)

5-HT2 receptoralterations

OBX had no effect on these receptors(but an increase in C57B1/6J strain)

DBA/2J (Gurevichet al., 1993)

Increased number of receptors, effect of5-HT2 agonist way-163909

SpragueDawley

(Earley et al., 1994;Rosenzweig-Lipson et al.,2007)

BDNF inhippocampus

OBX increased BDNF in hippocampus C57Bl/6N (Hellweget al., 2007)

OBX decreased BDNF in hippocampus SpragueDawley

(Hendriksen et al., 2012)

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levels are increased after OBX. Also the changed number of 5-HT2receptors after OBX (Gurevich et al., 1993; Earley et al., 1994;Rosenzweig-Lipson et al., 2007) may play a role in the reaction topharmacological treatments and might determine whether a treat-ment successfully changes the OBX induced behavior or not. Forexample, in rats amitriptyline down-regulates the number of post-synaptic 5-HT2 receptors (Clements-Jewery and Robson, 1982).5-HT2 receptor numbers are increased after OBX in rats andC57B1/6J mice but stays unaltered in the non-responding DBA/2Jmouse (Gurevich et al., 1993; Earley et al., 1994). It might be that thedown-regulation of the 5-HT2 receptor is only beneficial when it wasup-regulated before. Thus, the OBX induced state in mice may createa different starting point for the successive treatment than the OBXinduced state in rats.

7.4. Treatment following OBX is acting in a species-specific way

It might be that the treatment itself is acting on mouse braindifferently than on rat brain. For instance the reaction of mousebrain to physostigmine results in recovery of the cognitive decline(Hozumi et al., 2003), but in the rat this treatment was not able torestore cognitive capabilities (Fig. 2). A difference in sensitivity forcholinergic drugs is a possible explanation for this. A comparisonof the effect of cholinergic drugs on the avoidance responseshowed that mice were more sensitive to physostigmine than rats(Kuribara and Tadokoro, 1983). Also the discrepancy between theeffect of amitriptyline on passive avoidance learning in rats andmice could be a matter of differences in target availability (vanRiezen et al., 1977; Jarosik et al., 2007). In synaptosome prepara-tions, for instance, amitriptyline showed a higher affinity in guineapigs when compared to rats, indicating that this drug does not actidentical in different species (Hornsby et al., 1992).

This could mean that not the biological consequences of theOBX surgery itself are different between the two species, but theavailable therapeutic targets in the two species may differ. Alsodifferences in the subjective experience of a treatment could be anexplanation for the differences in the effect of certain treatmentsbetween rats and mice. Because mouse behavior is less compli-cated and more reliant on elementary actions than rat behavior(Whishaw et al., 2001), both species might experience an enrichedenvironment in a different way. For example, environmentalenrichment promotes the level of agonistic behaviors in mice(Haemisch and Gartner, 1997; McQuaid et al., 2012), while on thecontrary agonistic behavior for rats living in enriched cages isreduced (Abou-Ismail et al., 2010). In this scenario enrichmentprovides a variable environment in which the levels of stress andsocial engagement depend on the species involved.

7.5. Regenerative potential of the brain

A third option is that the potential of the brain to regenerate ingeneral varies between mice and rat. This might be so for sponta-neous regeneration or regeneration aided by some kind of treat-ment. When, for example, wound healing after spinal cord injury iscompared between rats and mice the latter show a more pro-nounced wound-healing response, increased levels of vascularendothelial growth factor (VEGF) contributing to an environmentbetter suited for axon sprouting/regeneration and protectingagainst secondary axon damage (Surey et al., 2014). Another factorthat might contribute to the possibility of regeneration is thepotential for adult neurogenesis. Neural stem cells differ in theabsolute number, rate of proliferation, distribution and develop-ment between different vertebrates and even between differentmammals (Grandel and Brand, 2013). Even between differentstrains of mice responses in relation to stress can be importantlydifferent. After 7 days exposure to high corticosterone levels

hippocampal cell proliferation in MRL/MpJ mice stayed unalteredwhile cell proliferation and BDNF levels in C57BL/6J mice weresignificantly reduced (Hodes et al., 2012). Taken together thisexplanation of species-specific or even strain specific potential forregeneration forms a broad and general interpretation. Conse-quently it is less useful for explaining the typical OBX related rat/mouse differences. However, it should make us cautious in relyingtoo much on the findings in one species.

7.6. Importance of the distinction between the species-specificunderlying mechanisms

The neurochemical changes in BDNF and 5-HT2 receptors afterOBX suggests that there is truth in the first idea. The increasedlevel of BDNF, but probably also other molecules, might result in aspecies-specific post OBX state with a difference in treatmentsensitivity. This does not exclude the possibility however, that thevariability in the response after treatment is also partly due to thespecies-specific differential expression of specific therapeutictargets or the more general difference in the potential forregeneration. The species-specific OBX related differences forman interesting phenomenon that should be further explored tomake a better assessment of the translational value of OBX studies,but also get more insight in the process of neuroregeneration. Inorder to do so, we have to appreciate the distinction between theabove-mentioned underlying reasons for the species-specificdifferences.

7.7. Translational value of the OBX model

What does it mean for the translational value of the OBX modelthat treatment leading to recovery in mice does not always has itsanalog in rats and vice versa? For instance in the study of (Bobkovaet al., 2014) memory loss in bulbectomized mice was decreased byimmunization with prion protein fragment 95–123. The authorsused immunization as a method to prevent memory loss due toneurodegeneration. Moreover, they suggest that this model maybe a useful tool for preclinical therapeutic research. An interestingquestion is now whether the same phenomena can be observed inrats. The same question underlies other studies in mice in whichOBX induced memory decline is rescued. Nobilutin rescuedcholinergic neurodegeneration and restores memory functionafter OBX (Nakajima et al., 2007) Another example, also in mice,is vanadium (VI) which rescued the septo-hipocampal cholinergicneurons from OBX induce degeneration (Han et al., 2008).

Although these studies point out important processes thatcould contribute to our understanding of neurodegenerativeprocesses, we should be careful with regard to the interpretationand take into account that mouse and rat have different potentialto recover from the ablation of the olfactory bulbs. Which specieshas the better predictive value remains the question, but it isnoteworthy that most studies involving the rescue of cognitivedecline or neurodegeneration are done in mice.

8. Conclusion

Although OBX leads to a large number of comparable results inmice and rat there are also some remarkable species-specific dis-crepancies. The interpretation of the beneficial effects of antidepres-sant treatments but also recovery from cognitive decline should beseen in the light of the species studied. In terms of translational valuewe must be careful not to choose for a species that shows a highpotential to recover from severe neurodegeneration in comparison tohumans. On the other hand, studying species-specific differences inthe ability to recover or to be protected from neurodegenerative

H. Hendriksen et al. / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎6

Please cite this article as: Hendriksen, H., et al., The olfactory bulbectomy model in mice and rat: One story or two tails? Eur J Pharmacol(2014), http://dx.doi.org/10.1016/j.ejphar.2014.10.033i

processes, might lead to better understanding of how we eventuallycan promote protection and regeneration of the human brain. At leastthese species-specific differences point out that we should be carefulin our interpretation of results found in one species or the other.

Acknowledgment

We acknowledge Y. Borre for the mice data shown in Figs. 1 and 3.The authors have no conflict of interest and did not receive any

payment in preparation of this manuscript.

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