Producing and interpreting experimental olfactory deficits

doi:10.1016/0031-9384(74)90216-9

Physiology & Behavior

Volume 12, Issue 4, April 1974, Pages 657-670

https://doi.org/10.1016/0031-9384(74)90216-9 Get rights and content

Abstract

Producing and measuring olfactory deficits is a significant problem in experimental studies of olfaction and behavior. On the basis of anatomical considerations a multicomponent olfactory organ system is described, consisting of an interrelated group of chemosensitive receptor systems: the olfactory (I) nerve, the vomeronasal apparatus, portions of the trigeminus, and the nervus terminalis, plus a set of efferent projections to olfactory structures. Within this framework, nine olfactory system manipulations and a variety of experimentally and clinically recognized olfactory abnormalities are reviewed. The various manipulations of the olfactory organ system can differentially affect component organ subsystems, produce different olfactory deficits and, in some instances, introduce secondary, nonsensory effects which can confound interpretation of behavioral and physiological measures. Suggestions are made for conceptual, procedural, and terminological standardization in studies of olfaction and behavior.

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Since disfunction in these brain areas is thought to underlie MDD, this view has been used to justify the use of the OBX rodent as a model of this complex disorder. The evidence supporting this canon is almost exclusively based on comparisons of the OBX procedure to a classic method of shutting off peripheral input by chemically destroying olfactory sensory neurons using ZnSO4 nasal cavity lavage, a process that has repeatedly failed to reproduce key behaviors of the OBX syndrome, including hyperactivity [4,6,7,50]. However, there are at least three major drawbacks with this technique that cast doubt on its status as a means of producing complete anosmia without confounding side effects.
The olfactory bulbectomized rodent has long been one of the preferred animal models of depression and certain other neuropsychiatric diseases. In fact, it is considered unparalleled, by some, in the search for antidepressant medication and the literature generated about the model is prodigious. We have revisited the “syndrome” of behavioral sequela following bulbectomy choosing ecologically valid tests likely to be underpinned with evolutionarily preserved neural circuits. Our test battery included measurements of activity, intermale aggression, pleasure seeking, stress/fear and non-spatial memory. The emphasis was on the timetable of syndrome emergence, since this has been understudied and bears on the widely held belief that non-olfactory effects dominate. Our results largely agree with previous reports describing the behavioral syndrome in that we document bulbectomized mice as hyperactive, non-aggressive and fearless. However, we did not find deficits in memory as have frequently been reported in previous studies. Notably, our results revealed that some syndrome behaviors—including the hallmark of hyperactivity—appear immediately or soon after surgery. This rapid appearance casts doubt on the widely held view that compensatory reorganization of limbic and prefrontal cortical areas following bulbectomy underlies the syndrome. Rather, hyperactivity, non-aggressiveness, reduced fear and diminished sucrose preference in the olfactory bulbectomized mouse find ready explanations in the loss of smell that is the immediate and irreversible outcome of bulbectomy. Finally, after a critical consideration of the literature and our results, we conclude that the olfactory bulbectomy model lacks the validity and simplicity previously credited to it. Indeed, we deem this lesion unsuitable as a model of most neuropsychiatric diseases since its effects are at least as complex and misunderstood as the disorders it is purported to model.
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Animals treated with ZnSO4 remained anosmic throughout the duration of the experiment, suggesting that one instillation of zinc sulfate is sufficient to damage the nasal epithelium, resulting in loss of olfactory function. These results are in accordance with previous reports (Alberts, 1974; Mar et al., 2000) Because animals treated with ZnSO4 remained anosmic throughout the duration of the experiment, histological verification was not necessary. Moreover, van Denderen et al. (2001) provided histological evidence that ZnSO4 infusion leads to damage of the olfactory fiber density and consequently anosmia.
Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated. This diet was tested on the olfactory bulbectomized rat (OBX), an established animal model of depression and cognitive decline. The ingredients of the diet have been individually shown to attenuate glutamate excitoxicity, exert potent anti-oxidant/anti-inflammatory properties, and improve synaptogenesis; processes that all have been implicated in neurodegenerative diseases and in the cognitive deficits following OBX in rodents. Dietary treatment started 2 weeks before OBX surgery, continuing for 6 weeks in total. The diet attenuated OBX-induced cognitive and behavioral deficits, except long-term spatial memory. Ameliorating effects of the diet extended to the control animals. Furthermore, the experimental diet reduced hippocampal atrophy and decreased the peripheral immune activation in the OBX rats. The ameliorating effects of the diet on the OBX-induced changes were comparable to those of the NMDA receptor antagonist, memantine, a drug used for the management of Alzheimer's disease. This proof-of-concept study suggests that a diet, which simultaneously targets multiple disease etiologies, can prevent/impede the development of a neurodegenerative and depressive disorders and the concomitant cognitive deficits.
Both olfactory epithelial and vomeronasal inputs are essential for activation of the medial amygdala and preoptic neurons of male rats
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These findings support our common belief that the OE receives volatile chemicals, while the VNO detects involatile chemicals. Because of the regeneration ability of OE sensory neurons, the effectiveness of anosmia induced by zinc sulfate lesion is limited in period (Alberts, 1974; Alberts and Galef, 1971; Thor and Flannelly, 1977). After the application of zinc sulfate, we first confirmed the anosmic effect within 2 days and tested for olfactory preference within a week.
Chemosensory inputs signaling volatile and nonvolatile molecules play a pivotal role in sexual and social behavior in rodents. We have demonstrated that olfactory preference in male rats, that is, attraction to receptive female odors, is regulated by the medial amygdala (MeA), the cortical amygdala (CoA), and the preoptic area (POA). In this paper, we investigated the involvement of two chemosensory organs, the olfactory epithelium (OE) and the vomeronasal organ (VNO), in olfactory preference and copulatory behavior in male rats. We found that olfactory preferences were impaired by zinc sulfate lesion of the OE but not surgical removal of the VNO. Copulatory behaviors, especially intromission frequency and ejaculation, were also suppressed by zinc sulfate treatment. Neuronal activation in the accessory olfactory bulb (AOB), the MeA, the CoA, and the POA was analyzed after stimulation by airborne odors or soiled bedding of estrous females using cFos immunohistochemistry. Although the OE and VNO belong to different neural systems, the main and accessory olfactory systems, respectively, both OE lesion and VNO removal almost equally suppressed the number of cFos-immunoreactive cells in those areas that regulate olfactory preference. These results suggest that signals received by the OE and VNO interact and converge in the early stage of olfactory processing, in the AOB and its targets, although they have distinct roles in the regulation of social behaviors.
Increased squalene concentrations in the clitoral gland during the estrous cycle in rats: An estrus-indicating scent mark?
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The VNO-ablation was carried out in the males as previously described [28]. Rats were anesthetized under light dose of diethyl ether and 5% ZnSO4 solution was administrated intranasally, to rupture the main olfactory epithelial cells [29]. Odor preferences of intact, VNO-ablated and ZnSO4–irrigated male rats were tested.
Squalene in the rat clitoral gland is reported to be semi-volatile and may serve as a chemo-signal. The objective was to determine squalene concentrations in the clitoral gland throughout the reproductive cycle. Clitoral glands were extracted with dichloromethane; 23 compounds were identified with Gas Chromatography linked Mass Spectrometry (GC-MS). Since squalene concentrations were significantly higher during proestrus and estrus, and remarkably reduced during metestrus and diestrus, we inferred that it could be an ovulation-indicating chemosignal in the female rat, acting as a scent mark for the male. This hypothesis was tested by investigating its efficacy to attract males, including studying the role of the olfactory-vomeronasal system of the male in perceiving squalene. For detection of squalene, males used their conventional olfactory system when at a distance from the female, whereas the vomeronasal organ was used when they were in close proximity to the female. We concluded that squalene was a female-specific chemosignal that attracted males, and furthermore, that the olfactory-vomeronasal system had an important role in the perception of squalene.
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^☆: This paper was prepared during the author's tenure as a National Institute of Mental Health Predoctoral Fellow.

²: I thank C. S. Sherrick for his critical readings and discussions, as well as J. E. Ahlskog, M. M. Clark, B. G. Galef, Jr., D. E. Klotzbach and P. K. Randall for their help.

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Theoretical reviewProducing and interpreting experimental olfactory deficits☆

Abstract

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Brain Res.

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Life Sci.

Brain Res.

Behav. Biol.

Physiol. Behav.

Behav. Biol.

Physiol. Behav.

Expl. Neurol.

Physiol. Behav.

Behav. Biol.

Physiol. Behav.

Life Sci.

Life Sci.

Physiol. Behav.

Physiol. Behav.

Brain Res.

J. Biol. Chem.

Physiol. Behav.

Physiol. Behav.

The postnatal growth of the vomeronasal organ of the albino rat (Mus norvegicus albinus)

J. comp. Neurol.

Olfactory bulb removal but not anosmia increases emotionality and mouse-killing

Nature

Olfaction and movement: stimuli mediating intra-specific aggression in wild rats

J. comp. physiol. Psychol.

Olfactory and trigeminal conditioned reflexes in dogs

Am. J. Physiol.

Effect of ablating the pyriform-amygdaloid areas and hippocampi on positive and negative olfactory conditioned reflexes and on conditioned olfactory differentiation

Am. J. Physiol.

The morphology of the olfactory system in vertebrates

Biol. Rev.

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Experimental studies on the fiber connections of the rhinencephalon. I. Albino rat

Med. J. Osaka Univ.

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J. comp. physiol. Psychol.

A reversible nasal block for the rat

Physiol. Behav.

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Pavlov. J. Higher Nerv. Activ.

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Unlike reactions to different individuals to fragrance in Verbena flowers

Science

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Pseudemys scripta Elegan. J. Expl. Biol.

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Physiol. Behav.

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J. comp. physiol. Psychol.

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Physiol. Behav.

Treatment of uncomplicated anosmia by vitamin A

Arch. Otolar.

Olfactory bulb removal produces a selective deficit in behavioral thermoregulation

Physiol. Behav.

Theoretical review
Producing and interpreting experimental olfactory deficits☆