Elsevier

Neuroscience Letters

Volume 692, 23 January 2019, Pages 143-149
Neuroscience Letters

Research article
Combined effects of olfactory dysfunction and chronic stress on anxiety- and depressive- like behaviors in mice

https://doi.org/10.1016/j.neulet.2018.11.010Get rights and content

Highlights

  • Reversible olfactory dysfunction by intranasal zinc sulfate infusion induced depressive-like behaviors in mice.

  • Reversible olfactory dysfunction by intranasal zinc sulfate infusion impaired spatial learning in mice.

  • Behaviors of olfactory deficit mice could be modulated by chronic stresses with a stressor intensity dependent way.

Abstract

There is a close relationship between olfactory dysfunction and depression, but the underlying mechanism remains unknown. Studies have shown that olfactory deprived animal experience a higher level of stress compared with controls. In the present study, we aimed to investigate whether olfactory deprived mice would be more vulnerable to develop cognitive and emotional impairments under chronic stresses. Mice were treated with intranasal zinc sulfate infusion which resulted in a complete but reversible loss of olfactory function, and then they were treated with either chronic restraint stress (CRS) or chronic unpredictable mild stress (CUMS) for three consecutive weeks. After that, anxiety- and depressive-like behavior, as well as spatial learning and memory were measured. We found that olfactory deficit induced depressive-like behavior and impaired spatial learning and memory in mice, and the olfactory scores were significantly correlated with depressive-like behavior or the spatial learning. After CRS, olfactory deprived mice showed less anxiety- and depressive- like behaviors and better olfactory recovery than non-stressed anosmia mice. In contrast, CUMS led to increased anxiety- and depressive-like behavior and deterred the olfactory recovery. These results indicated that transient olfactory deprivation induces emotional and cognitive impairment in mice, which could be modulated by chronic stresses with a stressor intensity dependent way.

Introduction

Olfaction is critical for a wide range of behaviors, such as food localization, emotional modulation, sexual and social behaviors and aggressive behavior [2]. Olfactory bulb (OB) projects to brain areas playing crucial roles in cognition and emotion, such as amygdala, hippocampus and orbitofrontal cortex [22]. Olfactory dysfunction is related with a variety of neuropsychiatric disorders, such as depression [20]. Functional and structural impairment in olfactory system especially the OB and olfactory epithelium were commonly seen in depressed patients [17,28] and depressed rats [12]. Olfactory bulbectomy (OBX) was widely used to establish animal model of depression in rats [11,21]. Congenitally anosmic transgenic Cnga2 mice showed increased anxiety- and depressive-like behaviors [5]. However, the underlying mechanism how olfactory dysfunction elicits depressive-like behavior in rodents remains unknown.

OBX rats showed increased behavioral stress reactivity than sham rats [24]. Increased plasma corticosterone level was shown in OBX rats. They showed extreme elevation of plasma corticosterone level after foot-shock stresses [4]. Stressful life events is robustly and causally associated with major depressive episodes [10,23], which is accompanied by dendritic atrophy and spine loss in hippocampus and prefrontal cortex [6,18]. Thus, the cognitive and emotional impairments after olfaction deficit might be due to either dysfunction of OB, or stress induced by olfaction loss, or synergistic action of both.

In the present study, we aimed to investigate whether olfactory deficit mice are more sensitive to negative effects of stress to develop cognitive deficiency and depressive like behavior. Intranasal application of zinc sulfate (ZnSO4) which resulted in transient lesion of olfactory epithelium is a widely used method to produce brief but essentially total disruption of olfaction in mice [14]. Three days after intranasal ZnSO4 or Saline application, mice were treated with either chronic restraint stress (CRS) or chronic unpredictable mild stress (CUMS) for three weeks. After that, anxiety- and depressive-like behavior, as well as spatial learning and memory were tested. The results might shed some light on the association between olfactory deficit and depression in mice.

Section snippets

Animals

Totally 80 male ICR mice (20-25 g, 4 weeks) from Experimental Animal Institute Sichuan Academy of Medical Science were used. In experiment with CRS, 40 mice were randomly divided into two groups, 20 mice received Sal-E treatment and the other received ZnS-E treatment. Then, the Sal-E or ZnS-E group was subdivided into stressed or non-stressed groups, after which four randomly designed groups were made (Sal-E, Sal-E/CRS, ZnS-E, ZnS-E /CRS). In experiment with CUMS, the same procedure was used.

Effects of olfactory deficits and/or chronic stress on anxiety-like behavior in mice

Olfactory deprivation and CRS did not alter anxiety-like behaviors in the open field (Fig. 2A), but CUMS significantly increased anxiety levels in mice (main effects of CUMS: F(1,29) = 17.443, p < 0.001), mice treated with CUMS spent less time in the center area in both control and olfactory deficit mice (Tukey HSD: Sal-E vs. Sal-E/CUMS: p = 0.009; Sal-E vs. ZnS-E/CUMS: p = 0.002, Fig.2B). In elevated plus maze, no effect of olfactory deficit on anxiety was found (Fig. 2C–D). But there was

Discussion

In the present study, though olfaction partially recovered four weeks after the ZnSO4 treatment, spatial learning and memory were severely impaired, accompanied by increased immobility in the forced swim test, and the olfactory scores were significantly correlated with performances in water maze and forced swim test. CRS and CUMS exerted dichotomous action. CUMS exaggerated the impairment induced by olfactory deprivation while CRS alleviated it. Our results indicated that transient and

Acknowledgments

This study was supported by the National Natural Science Foundation of China under grant numbers 81560234, 81760251, 81760258 and 81560221, and the Yunnan Applied Basic Research Projects under grant numbers 2015HA0036 and 2017FB125.

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