Progress in Neuro-Psychopharmacology & Biological Psychiatry 54 (2014) 26–30
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Roles of olfactory system dysfunction in depression Ti-Fei Yuan a,⁎, Burton M. Slotnick b a b
School of Psychology, Nanjing Normal University, China Department of Psychology, American University, United States
a r t i c l e
i n f o
Article history: Received 20 March 2014 Received in revised form 22 May 2014 Accepted 22 May 2014 Available online 29 May 2014 Keywords: Antidepressant Depression Limbic system Neurogenesis Olfactory bulbectomy
a b s t r a c t The olfactory system is involved in sensory functions, emotional regulation and memory formation. Olfactory bulbectomy in rat has been employed as an animal model of depression for antidepressant discovery studies for many years. Olfaction is impaired in animals suffering from chronic stress, and patients with clinical depression were reported to have decreased olfactory function. It is believed that the neurobiological bases of depression might include dysfunction in the olfactory system. Further, brain stimulation, including nasal based drug delivery could provide novel therapies for management of depression. © 2014 Published by Elsevier Inc.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of depression . . . . . . . . . . . . . . . . . . . Olfactory bulbectomy as the animal model for depression . . . . . Loss of olfaction in depression in human patients and animal models 4.1. Human evidences . . . . . . . . . . . . . . . . . . . . 4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . 5. Adult neurogenesis in the olfactory system in depression . . . . . . 6. Olfactory system as the target for depression . . . . . . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Several lines of evidence indicate that the olfactory bulbs and their central connections may play an important role in affective behavior. Olfactory bulb removal has been shown to cause depression-like behaviors in animals, requiring a “period of incubation” (Leonard,
Abbreviations: OB, olfactory bulb; OBX, olfactory bulbectomy; AON, anterior olfactory nucleus; BNST, bed nucleus of stria terminalis; QOL, quality of life; HPA, hypothalamic pituitary adrenal. ⁎ Corresponding author at: School of Psychology, Nanjing Normal University, Nanjing 210097, China. E-mail address: [email protected] (T.-F. Yuan).
http://dx.doi.org/10.1016/j.pnpbp.2014.05.013 0278-5846/© 2014 Published by Elsevier Inc.
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1984; Leonard and Tuite, 1981; Song and Leonard, 2005). This incubation period may represent the time needed for subsequent changes in limbic and hypothalamic bulbar targets that play an important role in emotion regulation and memory. Thus, the depression-like behaviors in bulbectomized animals were found to be associated with changes in neurotransmission, endocrine, and immunological responses (Kelly et al., 1997; Song and Leonard, 2005), changes that have parallels to those in human patients suffering from depression (Dowlati et al., 2010). Interestingly, patients with major depression also exhibit olfactory deficits (Naudin et al., 2012; Pause et al., 2001). One mechanism by which depression may affect olfaction is via stress. An increase in stress hormones leads to a decrease in adult neurogenesis both in the hippocampus and the olfactory system (Mirescu and Gould,
T.-F. Yuan, B.M. Slotnick / Progress in Neuro-Psychopharmacology & Biological Psychiatry 54 (2014) 26–30
2006). Because adult neurogenesis contributes to multiple aspects of olfaction (Lledo et al., 2008) olfactory deficits in depression may stem, in part, from changes in neurogenesis. Interestingly, activating the olfactory system using oil-derived odors has demonstrated its usefulness in repairing memory deficits in depression (Ito et al., 2011). Here we further propose that deep brain stimulation or non-invasive brain stimulation targeting the olfactory system would offer new therapeutic opportunities for depression treatment. 2. Pathogenesis of depression Depression is characterized by low mood status and a decrease in multiple physical activities. It can be caused by long-term or acute stressful events, medical treatments as well as diseases. Psychological stressors routinely activate the hypothalamic–pituitary–adrenal (HPA) axis, leading to secretion of glucocorticoids, such as cortisol in human. Glucocorticoids bind to the glucocorticoid receptors (GR) on neurons (in the hippocampus, for example), causing reduced expression of neurotrophic factors and neuronal atrophy (Altar, 1999). For instance, expression of BDNF and BDNF-related genes was downregulated in both animal models of depression (Smith et al., 1995) and postmortem brain samples from clinical patients with depression (Tripp et al., 2012). A neurotrophic theory of depression is also supported by the fact that slowly increased BDNF levels occur in the chronic but not acute administration of antidepressants, such as fluoxetine (Altar et al., 2003; De Foubert et al., 2004). Depression is also accompanied by suppressed adult neurogenesis. Chronic stress led to decreased cell proliferation and reduced survival of new neurons; while chronic antidepressant (such as fluoxetine) administration resulted in restoration of adult neurogenesis that was temporally correlated with behavioral improvement in animal models of depression (Duman et al., 2001; Eisch and Petrik, 2012; Schoenfeld and Gould, 2012). In addition, new neurons generated in the hippocampus during adult hood are believed to be important for learning and memory functions, the decrease in which contributes to both impaired cognition in animal models of depression and clinical depression patients (Aimone et al., 2010; Zhao et al., 2008). In recent years, it is believed that multiple factors including immune system activation, inflammation and oxidative stress pathway activations could concomitantly contribute to the pathogenesis of clinical depression (Leonard and Maes, 2012). Thus, the increased levels of pro-inflammatory cytokines such as IL-6 and tumor necrosis factoralpha were reported in clinical patients with depression (Dowlati et al., 2010). IL-6 administration to the animals induces depressionlike behaviors (Sukoff Rizzo et al., 2012) which may interfere with the effects of antidepressant treatment. Interestingly, many of these proinflammatory cytokines could also suppress hippocampal neurogenesis (Vallieres et al., 2002), and anti-inflammation drugs were found to restore adult neurogenesis (Monje et al., 2003). Of course, depression probably involves multiple factors and different molecular pathways that could lead to changes in many brain regions in addition to the hippocampus. 3. Olfactory bulbectomy as the animal model for depression Surgical removal of the olfactory bulbs results in anterograde and retrograde transneuronal degeneration and in vascular degeneration in multiple regions of the central olfactory projections (Leonard, 1984). These include the piriform cortex, anterior olfactory nucleus (AON), components of the amygdala, entorhinal cortex, and bed nucleus of stria terminalis (BNST). The bulb also receives cholinergic, GABAergic, serotoninergic and noradrenergic inputs from ventral, midbrain and brain stem regions (Shipley and Ennis, 1996). The bulbectomy therefore can affect a substantial number of brain regions following denervation or terminal axotomy.
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Olfactory bulbectomy (OBX) has been proven as a useful animal model of depression (Kelly et al., 1997; Song and Leonard, 2005). A successful outcome requires complete removal of the bulbs, followed by foam filling of the space to prevent olfactory nerve regrowth. After 2–4 weeks, OBX animals gradually exhibit a variety of behavior changes, including increased exploratory behavior in enclosed open field, reduced taste aversion, passive avoidance deficit, impaired spatial learning in radial maze and Morris maze, as well as impaired food-motivated behaviors (Kelly et al., 1997; Leonard, 1984; Song and Leonard, 2005). In addition, decreased turnover of neurotransmitters and altered regional synthesis of serotonin were described in a series of different studies (Hellweg et al., 2007; Jancsar and Leonard, 1984; Watanabe et al., 2003), the restoration of which was correlated to the behavioral normalization (Sato et al., 2008). These animals had physiological, biochemical, endocrine, immunological and behavioral changes similar to those characteristic of depression. Further, OBX animals exhibit similar changes in neurotransmitter levels as observed in depression patients (Jesberger and Richardson, 1985), including reductions in noradrenaline content and turnover, reduced brain serotonin, decreased glutamate receptors, and increased GABAergic tone (Hirsch, 1980; Jancsar and Leonard, 1984; Tonnaer et al., 1980; van Riezen and Leonard, 1990). Interestingly, secretion of corticosterone, the stress-related hormone, is normal in the light phase, but increased during the dark phase of the cycle (Broekkamp et al., 1986), reflecting the dys-regulated HPA axis. In accordance with the neuroinflammation theory underlying depression, immune system changes are observed in OBX animals. For instance, these animals demonstrate reduced neutrophil phagocytic response, reduced lymphocyte proliferation and increased monocyte proliferation, increased positive acute phase proteins, reduced thymus and spleen weight, and increased α1-acid glycoproteins (which can suppress the immune functions) (Cai and Leonard, 1994; Kelly et al., 1997). Following chronic (more than 2 weeks) treatment with antidepressants, OBX rats showed normal performances in open-field behaviors and passive avoidance tests (Jancsar and Leonard, 1981; Roche et al., 2007; Sato et al., 2008). Interestingly, this is accompanied by the disappearance of the immune abnormalities (Cai and Leonard, 1994). OBX rats demonstrated high consistency in antidepressant efficacy tests, and provide a unique insight into the neuropathological mechanisms underlying depression. 4. Loss of olfaction in depression in human patients and animal models An intriguing phenomenon is the changes in olfactory functions in early phase of several chronic neurodegenerative diseases (including Alzheimer and Parkinson diseases, changes that occur even before other symptoms appear (Doty, 2012; Hou et al., 2014a; Rezek, 1987; Singh and Schwankhaus, 2009)). Indeed, olfactory function tests have been proven useful in diagnosis and prognosis of certain neurodegenerative diseases (Doty, 2012; Haehner et al., 2013; Li et al., 2013). In animal models of neurodegenerative diseases, the olfactory system could act both as a starting point (e.g. route of invasion) and an important effector for neuronal loss (Loseva et al., 2009). Interestingly, due to their distinct vulnerability, different bulbar cell types exhibited early or late degeneration in transgenic mice overexpressing alpha-synuclein, which was taken as a transgenic animal model for Parkinson's disease (Lelan et al., 2011; Ubeda-Banon et al., 2010). Such stage-dependent specific disruption to the bulbar circuit might provide important diagnostic cues to the onset of degenerative diseases in the premotor phase. 4.1. Human evidences Olfactory deficits, commonly found in depressed patients are correlated with the severity of the clinical depression symptoms (Buron et al., 2013; Clepce et al., 2010; Croy et al., 2013b; Croy et al., 2014; Hardy
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et al., 2012; Krusemark et al., 2013; Naudin et al., 2012; Naudin et al., 2014; Negoias et al., 2010; Pause et al., 2001; Seo et al., 2009). For instance, neuroimaging studies found reduced olfactory bulb volume in both depressive patients, and subjects with childhood maltreatment (Croy et al., 2013b; Negoias et al., 2010). The congenital anosmia patients as well exhibited enhanced depression syndromes (Croy et al., 2012; Croy et al., 2013a). In addition, the level of olfactory performance, such as detection acuity was correlated to emotion status of the subject (Hardy et al., 2012; Krusemark et al., 2013). The central olfactory processing was also altered in depression patients, showing “olfactory anhedonia” (Naudin et al., 2012), and perceptive biases (Naudin et al., 2014). Last but not least, antidepressant treatment or psychological therapy that relieved the clinical symptoms of depression could also improve olfactory function (Croy et al., 2014; Gross-Isseroff et al., 1994; Naudin et al., 2012). Whether olfactory deficits in depression and in neurodegenerative diseases are due to the changes in sensitivity or quality perception, or both, remains unclear (Scinska et al., 2008). Unfortunately, the sensitivity of casual or even clinical tests for olfaction may not be optimal and generally cannot specify the nature of olfactory deficit. A potentially more relevant measure of olfaction in depression might be hedonic responses to odors. Interestingly, it has been shown that unipolar depression patients exhibit increased ahedonic responses to olfactory stimuli, when compared to bipolar depression patients (Swiecicki et al., 2009). This is consistent with the fact that limbic processing of aversive stimuli is reduced in depression patients and animals (Der-Avakian and Markou, 2012). As neurodegeneration patients also exhibit emotional disorders, olfactory deficits and the altered olfactory information processing may underlie at least part of the shared clinical symptoms of these disorders with depression patients (Korczyn, 2001; Morley et al., 2011). Interestingly, the loss of olfaction has been associated with depressive symptoms in other disease or treatment processes as well (Grapsa et al., 2010). Last but not least, different types of olfactory disorders, including congenital anosmia may impair the quality of life (QOL), and associated with increased depression scores (Croy et al., 2012; Hummel and Nordin, 2005; Toller, 1999). Interestingly, these patients also exhibited decreased sex-relevant activities (Croy et al., 2013a). It will be important to investigate if restoring olfaction abilities would improve the QOL in at least some of these patients (though not for patients with congenital anosmia, for example).
4.2. Animal studies Olfactory deficits have been reported even in non-OBX animal models of depression. For example, ventricle infusion of anti-P ribosomal autoantibodies which are associated with autoimmune diseases could cause depression-like behavior and impaired olfactory function in mice (Shoenfeld, 2007). Interestingly the depression-like behavior can be partly treated with lemon odor exposure, while olfactory deficits remain after administration of the antidepressant fluoxetine in another model mimicking the social isolation stress (Gusmao et al., 2012). It was found that olfactory enrichment rescued long-term social memory but not the olfactory loss in socially-deprived animals (Mandairon et al., 2006; Schloesser et al., 2010). Whether olfactory deficits are reversible upon long-term antidepressant treatment is yet to be investigated. Currently the potential changes in pheromone and alarm hormone sensing system by the vomeronasal system (Tirindelli et al., 2009) and Grueneberg ganglion (Brechbuhl et al., 2008) are unknown. It has been shown that pheromone induced sexual behavior decreased in the neurokinin-1 receptor deficient mouse, a model of emotional disorders (Berger et al., 2012). Similarly, human odors cause rapid mood changes (Chen and Haviland-Jones, 1999) and in depression patients sexual behaviors are disrupted (Gudziol et al., 2009). However it will be important to differentiate the potential contribution of deficits in peripheral detection and central processing of these stimuli.
5. Adult neurogenesis in the olfactory system in depression In the central nervous system of mammals, adult neurogenesis exists in the hippocampus, subventricular zone (the new born neurons will migrate to the olfactory bulb), hypothalamus and even cortical regions (Ming and Song, 2005; Suh et al., 2009; Yuan and Arias-Carrion, 2011; Zhao et al., 2008). The functions of new neurons include participations in learning and memory formation, mood state regulation for hippocampal neurogenesis (Aimone et al., 2010; Zhao et al., 2008), as well as olfactory discrimination, short-term odor memory, protection from toxic invasion, and certain sex-specific activities for olfactory neurogenesis (Lepousez et al., 2013; Lledo et al., 2008; Loseva et al., 2009; Yuan, 2010). In human the adult neurogenesis in bulb is so far a disputed topic (may not exist) and worth further investigation (Lotsch et al., 2013; Macklis, 2012) while in many diseased conditions or aging processes, neurogenesis can be either upregulated or downregulated. Indeed, depression causes decreased hippocampal neurogenesis in diverse animal models (Eisch and Petrik, 2012), which can be reversed following many types of depression therapies, including electrical shock therapy, antidepressant treatment and environment enrichments (Kempermann, 2002; Sahay and Hen, 2007). Stress hormone (e.g. glucocorticoid) administration could fully mimic the effects of depression on adult hippocampal neurogenesis (Hellsten et al., 2002). Interestingly, glucocorticoid administration could also depress the olfactory system (e.g. the cell proliferation in subventricular zone and even olfactory epithelium), which accompanies the decreased sexual behaviors in male rats (Hou et al., 2014b; Lau et al., 2011). This decrease was rescued by antidepressant (e.g. paroxetine) treatment. Taken together, the defects of both central and peripheral olfactory neurogenesis in depression might play roles in the loss of fine olfactory functions as described above. Yet neurogenesis is more than cell proliferation; future studies are required to identify potential changes of olfactory neurogenesis in new neuron migration, cell survival, differentiation, circuit integration and synaptic transmission under depression. 6. Olfactory system as the target for depression The findings that antidepressant treatment both restores neurogenesis in the hippocampus and the subventricular zone, and serves to normalize behavior in depression animal models, suggest that deficits in olfactory neurogenesis can act as a potential target for depression therapies. As suggested before, odor stimulation can reduce the depression-like behaviors; odor enrichment can also improve the social memory of isolation-raised animals, even before the restoration of olfaction. The presentation of odor that is previously paired with shock during development can restore the adult depression-like behaviors as well (Sevelinges et al., 2011). The mechanisms underlying these observations have not been investigated although speculations abound. For example, it is possible that the activity in the main olfactory system contributes to the generation of different brain oscillations and elevates the activity of connected regions such as the hippocampus/ cortex that are important for new memory formation. However, all such speculations need to take into account that restoration of olfaction may require a long time period to accommodate the time for neurogenesis, migration of new born neurons to the olfactory bulb (Lepousez et al., 2013), and the weeks or even months for new neuron to make connections in the bulbar circuits. Artificial stimulation of the olfactory bulb and piriform cortex can activate multiple brain regions non-invasively (Choi et al., 2011). The bulbar mitral cells exhibit multiple and dense connections to pyramidal neurons in the piriform cortex (Franks and Isaacson, 2006; Ojima et al., 1984), and the direct stimulation of the olfactory bulb/tract can produce olfactory hallucinations, or psychomotor epilepsy (Chen et al., 2003; Kumar et al., 2012), suggesting the powerfulness of the olfactory system in controlling brain activity. In addition, increased bulbar activity may activate serotonergic and noradrenergic afferents to the forebrain
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(Corthell et al., 2013). Such activities may help to normalize the monoamine release inside the brain, and therefore decrease depression behaviors. Clinical stimulation of the olfactory system mainly relies on strong odor presentations for short period, and can have habituation effects (Ebert and Loscher, 2000). Electrical stimulation so far is limited to neurological patients under certain circumstances (e.g. to localize epilepsy sites). In the future, it might be possible to combine deep brain stimulation or non-invasive brain stimulation methods to target the olfactory system. The olfactory bulb in human is relatively small (in percentage to the whole brain), compared to those of macrosmatic mammals (Meisami and Bhatnagar, 1998). Yet the olfactory cortex is targetable with brain stimulation approaches. Deep brain stimulation has been shown to cause “immediate relief” on major depression patients, based on a limited number of neuroanatomical sites (Anderson et al., 2012; Mayberg et al., 2005). It is possible that stimulation of the olfactory system may prove beneficial in depression, epilepsy and other disorders associated with changes in olfaction. 7. Summary In summary, the demonstrated olfaction loss in major depression patients, as well as animal models of depression implicates a role for the olfactory system in pathogenesis of depression. Odor based stimulation therapies have been shown to be effective in restoration of depression-caused memory loss; while deep brain stimulation or other non-invasive stimulations offer further direct and controlled olfactory system-targeted therapies. Conflicts of interest None declared. Acknowledgments TY is supported by “Hundred talents program in NJNU”. References Aimone JB, Deng W, Gage FH. Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 2010;14:325–37. Altar CA. Neurotrophins and depression. Trends Pharmacol Sci 1999;20:59–61. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 2003;54:703–9. Anderson RJ, Frye MA, Abulseoud OA, Lee KH, McGillivray JA, Berk M, et al. Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neurosci Biobehav Rev 2012;36:1920–33. Berger A, Tran AH, Dida J, Minkin S, Gerard NP, Yeomans J, et al. Diminished pheromoneinduced sexual behavior in neurokinin-1 receptor deficient (TACR1(−/−)) mice. Genes Brain Behav 2012;11:568–76. Brechbuhl J, Klaey M, Broillet MC. Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 2008;321:1092–5. Broekkamp CL, O'Connor WT, Tonnaer JA, Rijk HW, Van Delft AM. Corticosterone, choline acetyltransferase and noradrenaline levels in olfactory bulbectomized rats in relation to changes in passive avoidance acquisition and open field activity. Physiol Behav 1986;37:429–34. Buron E, Bulbena A, Barrada JR, Pailhez G. EROL scale: a new behavioural olfactory measure and its relationship with anxiety and depression symptoms. Actas Esp Psiquiatr 2013;41:2–9. Cai S, Leonard BE. The effects of chronic lithium chloride administration on some behavioural and immunological changes in the bilaterally olfactory bulbectomized rat. J Psychopharmacol 1994;8:40–7. Chen D, Haviland-Jones J. Rapid mood change and human odors. Physiol Behav 1999;68: 241–50. Chen C, Shih YH, Yen DJ, Lirng JF, Guo YC, Yu HY, et al. Olfactory auras in patients with temporal lobe epilepsy. Epilepsia 2003;44:257–60. Choi GB, Stettler DD, Kallman BR, Bhaskar ST, Fleischmann A, Axel R. Driving opposing behaviors with ensembles of piriform neurons. Cell 2011;146:1004–15. Clepce M, Gossler A, Reich K, Kornhuber J, Thuerauf N. The relation between depression, anhedonia and olfactory hedonic estimates—a pilot study in major depression. Neurosci Lett 2010;471:139–43. Corthell JT, Stathopoulos AM, Watson CC, Bertram R, Trombley PQ. Olfactory bulb monoamine concentrations vary with time of day. Neuroscience 2013;247:234–41.
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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp
Roles of olfactory system dysfunction in depression Ti-Fei Yuan a,⁎, Burton M. Slotnick b a b
School of Psychology, Nanjing Normal University, China Department of Psychology, American University, United States
a r t i c l e
i n f o
Article history: Received 20 March 2014 Received in revised form 22 May 2014 Accepted 22 May 2014 Available online 29 May 2014 Keywords: Antidepressant Depression Limbic system Neurogenesis Olfactory bulbectomy
a b s t r a c t The olfactory system is involved in sensory functions, emotional regulation and memory formation. Olfactory bulbectomy in rat has been employed as an animal model of depression for antidepressant discovery studies for many years. Olfaction is impaired in animals suffering from chronic stress, and patients with clinical depression were reported to have decreased olfactory function. It is believed that the neurobiological bases of depression might include dysfunction in the olfactory system. Further, brain stimulation, including nasal based drug delivery could provide novel therapies for management of depression. © 2014 Published by Elsevier Inc.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of depression . . . . . . . . . . . . . . . . . . . Olfactory bulbectomy as the animal model for depression . . . . . Loss of olfaction in depression in human patients and animal models 4.1. Human evidences . . . . . . . . . . . . . . . . . . . . 4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . 5. Adult neurogenesis in the olfactory system in depression . . . . . . 6. Olfactory system as the target for depression . . . . . . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Several lines of evidence indicate that the olfactory bulbs and their central connections may play an important role in affective behavior. Olfactory bulb removal has been shown to cause depression-like behaviors in animals, requiring a “period of incubation” (Leonard,
Abbreviations: OB, olfactory bulb; OBX, olfactory bulbectomy; AON, anterior olfactory nucleus; BNST, bed nucleus of stria terminalis; QOL, quality of life; HPA, hypothalamic pituitary adrenal. ⁎ Corresponding author at: School of Psychology, Nanjing Normal University, Nanjing 210097, China. E-mail address: [email protected] (T.-F. Yuan).
http://dx.doi.org/10.1016/j.pnpbp.2014.05.013 0278-5846/© 2014 Published by Elsevier Inc.
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1984; Leonard and Tuite, 1981; Song and Leonard, 2005). This incubation period may represent the time needed for subsequent changes in limbic and hypothalamic bulbar targets that play an important role in emotion regulation and memory. Thus, the depression-like behaviors in bulbectomized animals were found to be associated with changes in neurotransmission, endocrine, and immunological responses (Kelly et al., 1997; Song and Leonard, 2005), changes that have parallels to those in human patients suffering from depression (Dowlati et al., 2010). Interestingly, patients with major depression also exhibit olfactory deficits (Naudin et al., 2012; Pause et al., 2001). One mechanism by which depression may affect olfaction is via stress. An increase in stress hormones leads to a decrease in adult neurogenesis both in the hippocampus and the olfactory system (Mirescu and Gould,
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2006). Because adult neurogenesis contributes to multiple aspects of olfaction (Lledo et al., 2008) olfactory deficits in depression may stem, in part, from changes in neurogenesis. Interestingly, activating the olfactory system using oil-derived odors has demonstrated its usefulness in repairing memory deficits in depression (Ito et al., 2011). Here we further propose that deep brain stimulation or non-invasive brain stimulation targeting the olfactory system would offer new therapeutic opportunities for depression treatment. 2. Pathogenesis of depression Depression is characterized by low mood status and a decrease in multiple physical activities. It can be caused by long-term or acute stressful events, medical treatments as well as diseases. Psychological stressors routinely activate the hypothalamic–pituitary–adrenal (HPA) axis, leading to secretion of glucocorticoids, such as cortisol in human. Glucocorticoids bind to the glucocorticoid receptors (GR) on neurons (in the hippocampus, for example), causing reduced expression of neurotrophic factors and neuronal atrophy (Altar, 1999). For instance, expression of BDNF and BDNF-related genes was downregulated in both animal models of depression (Smith et al., 1995) and postmortem brain samples from clinical patients with depression (Tripp et al., 2012). A neurotrophic theory of depression is also supported by the fact that slowly increased BDNF levels occur in the chronic but not acute administration of antidepressants, such as fluoxetine (Altar et al., 2003; De Foubert et al., 2004). Depression is also accompanied by suppressed adult neurogenesis. Chronic stress led to decreased cell proliferation and reduced survival of new neurons; while chronic antidepressant (such as fluoxetine) administration resulted in restoration of adult neurogenesis that was temporally correlated with behavioral improvement in animal models of depression (Duman et al., 2001; Eisch and Petrik, 2012; Schoenfeld and Gould, 2012). In addition, new neurons generated in the hippocampus during adult hood are believed to be important for learning and memory functions, the decrease in which contributes to both impaired cognition in animal models of depression and clinical depression patients (Aimone et al., 2010; Zhao et al., 2008). In recent years, it is believed that multiple factors including immune system activation, inflammation and oxidative stress pathway activations could concomitantly contribute to the pathogenesis of clinical depression (Leonard and Maes, 2012). Thus, the increased levels of pro-inflammatory cytokines such as IL-6 and tumor necrosis factoralpha were reported in clinical patients with depression (Dowlati et al., 2010). IL-6 administration to the animals induces depressionlike behaviors (Sukoff Rizzo et al., 2012) which may interfere with the effects of antidepressant treatment. Interestingly, many of these proinflammatory cytokines could also suppress hippocampal neurogenesis (Vallieres et al., 2002), and anti-inflammation drugs were found to restore adult neurogenesis (Monje et al., 2003). Of course, depression probably involves multiple factors and different molecular pathways that could lead to changes in many brain regions in addition to the hippocampus. 3. Olfactory bulbectomy as the animal model for depression Surgical removal of the olfactory bulbs results in anterograde and retrograde transneuronal degeneration and in vascular degeneration in multiple regions of the central olfactory projections (Leonard, 1984). These include the piriform cortex, anterior olfactory nucleus (AON), components of the amygdala, entorhinal cortex, and bed nucleus of stria terminalis (BNST). The bulb also receives cholinergic, GABAergic, serotoninergic and noradrenergic inputs from ventral, midbrain and brain stem regions (Shipley and Ennis, 1996). The bulbectomy therefore can affect a substantial number of brain regions following denervation or terminal axotomy.
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Olfactory bulbectomy (OBX) has been proven as a useful animal model of depression (Kelly et al., 1997; Song and Leonard, 2005). A successful outcome requires complete removal of the bulbs, followed by foam filling of the space to prevent olfactory nerve regrowth. After 2–4 weeks, OBX animals gradually exhibit a variety of behavior changes, including increased exploratory behavior in enclosed open field, reduced taste aversion, passive avoidance deficit, impaired spatial learning in radial maze and Morris maze, as well as impaired food-motivated behaviors (Kelly et al., 1997; Leonard, 1984; Song and Leonard, 2005). In addition, decreased turnover of neurotransmitters and altered regional synthesis of serotonin were described in a series of different studies (Hellweg et al., 2007; Jancsar and Leonard, 1984; Watanabe et al., 2003), the restoration of which was correlated to the behavioral normalization (Sato et al., 2008). These animals had physiological, biochemical, endocrine, immunological and behavioral changes similar to those characteristic of depression. Further, OBX animals exhibit similar changes in neurotransmitter levels as observed in depression patients (Jesberger and Richardson, 1985), including reductions in noradrenaline content and turnover, reduced brain serotonin, decreased glutamate receptors, and increased GABAergic tone (Hirsch, 1980; Jancsar and Leonard, 1984; Tonnaer et al., 1980; van Riezen and Leonard, 1990). Interestingly, secretion of corticosterone, the stress-related hormone, is normal in the light phase, but increased during the dark phase of the cycle (Broekkamp et al., 1986), reflecting the dys-regulated HPA axis. In accordance with the neuroinflammation theory underlying depression, immune system changes are observed in OBX animals. For instance, these animals demonstrate reduced neutrophil phagocytic response, reduced lymphocyte proliferation and increased monocyte proliferation, increased positive acute phase proteins, reduced thymus and spleen weight, and increased α1-acid glycoproteins (which can suppress the immune functions) (Cai and Leonard, 1994; Kelly et al., 1997). Following chronic (more than 2 weeks) treatment with antidepressants, OBX rats showed normal performances in open-field behaviors and passive avoidance tests (Jancsar and Leonard, 1981; Roche et al., 2007; Sato et al., 2008). Interestingly, this is accompanied by the disappearance of the immune abnormalities (Cai and Leonard, 1994). OBX rats demonstrated high consistency in antidepressant efficacy tests, and provide a unique insight into the neuropathological mechanisms underlying depression. 4. Loss of olfaction in depression in human patients and animal models An intriguing phenomenon is the changes in olfactory functions in early phase of several chronic neurodegenerative diseases (including Alzheimer and Parkinson diseases, changes that occur even before other symptoms appear (Doty, 2012; Hou et al., 2014a; Rezek, 1987; Singh and Schwankhaus, 2009)). Indeed, olfactory function tests have been proven useful in diagnosis and prognosis of certain neurodegenerative diseases (Doty, 2012; Haehner et al., 2013; Li et al., 2013). In animal models of neurodegenerative diseases, the olfactory system could act both as a starting point (e.g. route of invasion) and an important effector for neuronal loss (Loseva et al., 2009). Interestingly, due to their distinct vulnerability, different bulbar cell types exhibited early or late degeneration in transgenic mice overexpressing alpha-synuclein, which was taken as a transgenic animal model for Parkinson's disease (Lelan et al., 2011; Ubeda-Banon et al., 2010). Such stage-dependent specific disruption to the bulbar circuit might provide important diagnostic cues to the onset of degenerative diseases in the premotor phase. 4.1. Human evidences Olfactory deficits, commonly found in depressed patients are correlated with the severity of the clinical depression symptoms (Buron et al., 2013; Clepce et al., 2010; Croy et al., 2013b; Croy et al., 2014; Hardy
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et al., 2012; Krusemark et al., 2013; Naudin et al., 2012; Naudin et al., 2014; Negoias et al., 2010; Pause et al., 2001; Seo et al., 2009). For instance, neuroimaging studies found reduced olfactory bulb volume in both depressive patients, and subjects with childhood maltreatment (Croy et al., 2013b; Negoias et al., 2010). The congenital anosmia patients as well exhibited enhanced depression syndromes (Croy et al., 2012; Croy et al., 2013a). In addition, the level of olfactory performance, such as detection acuity was correlated to emotion status of the subject (Hardy et al., 2012; Krusemark et al., 2013). The central olfactory processing was also altered in depression patients, showing “olfactory anhedonia” (Naudin et al., 2012), and perceptive biases (Naudin et al., 2014). Last but not least, antidepressant treatment or psychological therapy that relieved the clinical symptoms of depression could also improve olfactory function (Croy et al., 2014; Gross-Isseroff et al., 1994; Naudin et al., 2012). Whether olfactory deficits in depression and in neurodegenerative diseases are due to the changes in sensitivity or quality perception, or both, remains unclear (Scinska et al., 2008). Unfortunately, the sensitivity of casual or even clinical tests for olfaction may not be optimal and generally cannot specify the nature of olfactory deficit. A potentially more relevant measure of olfaction in depression might be hedonic responses to odors. Interestingly, it has been shown that unipolar depression patients exhibit increased ahedonic responses to olfactory stimuli, when compared to bipolar depression patients (Swiecicki et al., 2009). This is consistent with the fact that limbic processing of aversive stimuli is reduced in depression patients and animals (Der-Avakian and Markou, 2012). As neurodegeneration patients also exhibit emotional disorders, olfactory deficits and the altered olfactory information processing may underlie at least part of the shared clinical symptoms of these disorders with depression patients (Korczyn, 2001; Morley et al., 2011). Interestingly, the loss of olfaction has been associated with depressive symptoms in other disease or treatment processes as well (Grapsa et al., 2010). Last but not least, different types of olfactory disorders, including congenital anosmia may impair the quality of life (QOL), and associated with increased depression scores (Croy et al., 2012; Hummel and Nordin, 2005; Toller, 1999). Interestingly, these patients also exhibited decreased sex-relevant activities (Croy et al., 2013a). It will be important to investigate if restoring olfaction abilities would improve the QOL in at least some of these patients (though not for patients with congenital anosmia, for example).
4.2. Animal studies Olfactory deficits have been reported even in non-OBX animal models of depression. For example, ventricle infusion of anti-P ribosomal autoantibodies which are associated with autoimmune diseases could cause depression-like behavior and impaired olfactory function in mice (Shoenfeld, 2007). Interestingly the depression-like behavior can be partly treated with lemon odor exposure, while olfactory deficits remain after administration of the antidepressant fluoxetine in another model mimicking the social isolation stress (Gusmao et al., 2012). It was found that olfactory enrichment rescued long-term social memory but not the olfactory loss in socially-deprived animals (Mandairon et al., 2006; Schloesser et al., 2010). Whether olfactory deficits are reversible upon long-term antidepressant treatment is yet to be investigated. Currently the potential changes in pheromone and alarm hormone sensing system by the vomeronasal system (Tirindelli et al., 2009) and Grueneberg ganglion (Brechbuhl et al., 2008) are unknown. It has been shown that pheromone induced sexual behavior decreased in the neurokinin-1 receptor deficient mouse, a model of emotional disorders (Berger et al., 2012). Similarly, human odors cause rapid mood changes (Chen and Haviland-Jones, 1999) and in depression patients sexual behaviors are disrupted (Gudziol et al., 2009). However it will be important to differentiate the potential contribution of deficits in peripheral detection and central processing of these stimuli.
5. Adult neurogenesis in the olfactory system in depression In the central nervous system of mammals, adult neurogenesis exists in the hippocampus, subventricular zone (the new born neurons will migrate to the olfactory bulb), hypothalamus and even cortical regions (Ming and Song, 2005; Suh et al., 2009; Yuan and Arias-Carrion, 2011; Zhao et al., 2008). The functions of new neurons include participations in learning and memory formation, mood state regulation for hippocampal neurogenesis (Aimone et al., 2010; Zhao et al., 2008), as well as olfactory discrimination, short-term odor memory, protection from toxic invasion, and certain sex-specific activities for olfactory neurogenesis (Lepousez et al., 2013; Lledo et al., 2008; Loseva et al., 2009; Yuan, 2010). In human the adult neurogenesis in bulb is so far a disputed topic (may not exist) and worth further investigation (Lotsch et al., 2013; Macklis, 2012) while in many diseased conditions or aging processes, neurogenesis can be either upregulated or downregulated. Indeed, depression causes decreased hippocampal neurogenesis in diverse animal models (Eisch and Petrik, 2012), which can be reversed following many types of depression therapies, including electrical shock therapy, antidepressant treatment and environment enrichments (Kempermann, 2002; Sahay and Hen, 2007). Stress hormone (e.g. glucocorticoid) administration could fully mimic the effects of depression on adult hippocampal neurogenesis (Hellsten et al., 2002). Interestingly, glucocorticoid administration could also depress the olfactory system (e.g. the cell proliferation in subventricular zone and even olfactory epithelium), which accompanies the decreased sexual behaviors in male rats (Hou et al., 2014b; Lau et al., 2011). This decrease was rescued by antidepressant (e.g. paroxetine) treatment. Taken together, the defects of both central and peripheral olfactory neurogenesis in depression might play roles in the loss of fine olfactory functions as described above. Yet neurogenesis is more than cell proliferation; future studies are required to identify potential changes of olfactory neurogenesis in new neuron migration, cell survival, differentiation, circuit integration and synaptic transmission under depression. 6. Olfactory system as the target for depression The findings that antidepressant treatment both restores neurogenesis in the hippocampus and the subventricular zone, and serves to normalize behavior in depression animal models, suggest that deficits in olfactory neurogenesis can act as a potential target for depression therapies. As suggested before, odor stimulation can reduce the depression-like behaviors; odor enrichment can also improve the social memory of isolation-raised animals, even before the restoration of olfaction. The presentation of odor that is previously paired with shock during development can restore the adult depression-like behaviors as well (Sevelinges et al., 2011). The mechanisms underlying these observations have not been investigated although speculations abound. For example, it is possible that the activity in the main olfactory system contributes to the generation of different brain oscillations and elevates the activity of connected regions such as the hippocampus/ cortex that are important for new memory formation. However, all such speculations need to take into account that restoration of olfaction may require a long time period to accommodate the time for neurogenesis, migration of new born neurons to the olfactory bulb (Lepousez et al., 2013), and the weeks or even months for new neuron to make connections in the bulbar circuits. Artificial stimulation of the olfactory bulb and piriform cortex can activate multiple brain regions non-invasively (Choi et al., 2011). The bulbar mitral cells exhibit multiple and dense connections to pyramidal neurons in the piriform cortex (Franks and Isaacson, 2006; Ojima et al., 1984), and the direct stimulation of the olfactory bulb/tract can produce olfactory hallucinations, or psychomotor epilepsy (Chen et al., 2003; Kumar et al., 2012), suggesting the powerfulness of the olfactory system in controlling brain activity. In addition, increased bulbar activity may activate serotonergic and noradrenergic afferents to the forebrain
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(Corthell et al., 2013). Such activities may help to normalize the monoamine release inside the brain, and therefore decrease depression behaviors. Clinical stimulation of the olfactory system mainly relies on strong odor presentations for short period, and can have habituation effects (Ebert and Loscher, 2000). Electrical stimulation so far is limited to neurological patients under certain circumstances (e.g. to localize epilepsy sites). In the future, it might be possible to combine deep brain stimulation or non-invasive brain stimulation methods to target the olfactory system. The olfactory bulb in human is relatively small (in percentage to the whole brain), compared to those of macrosmatic mammals (Meisami and Bhatnagar, 1998). Yet the olfactory cortex is targetable with brain stimulation approaches. Deep brain stimulation has been shown to cause “immediate relief” on major depression patients, based on a limited number of neuroanatomical sites (Anderson et al., 2012; Mayberg et al., 2005). It is possible that stimulation of the olfactory system may prove beneficial in depression, epilepsy and other disorders associated with changes in olfaction. 7. Summary In summary, the demonstrated olfaction loss in major depression patients, as well as animal models of depression implicates a role for the olfactory system in pathogenesis of depression. Odor based stimulation therapies have been shown to be effective in restoration of depression-caused memory loss; while deep brain stimulation or other non-invasive stimulations offer further direct and controlled olfactory system-targeted therapies. Conflicts of interest None declared. Acknowledgments TY is supported by “Hundred talents program in NJNU”. References Aimone JB, Deng W, Gage FH. Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 2010;14:325–37. Altar CA. Neurotrophins and depression. Trends Pharmacol Sci 1999;20:59–61. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 2003;54:703–9. Anderson RJ, Frye MA, Abulseoud OA, Lee KH, McGillivray JA, Berk M, et al. Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neurosci Biobehav Rev 2012;36:1920–33. Berger A, Tran AH, Dida J, Minkin S, Gerard NP, Yeomans J, et al. Diminished pheromoneinduced sexual behavior in neurokinin-1 receptor deficient (TACR1(−/−)) mice. Genes Brain Behav 2012;11:568–76. Brechbuhl J, Klaey M, Broillet MC. Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 2008;321:1092–5. Broekkamp CL, O'Connor WT, Tonnaer JA, Rijk HW, Van Delft AM. Corticosterone, choline acetyltransferase and noradrenaline levels in olfactory bulbectomized rats in relation to changes in passive avoidance acquisition and open field activity. Physiol Behav 1986;37:429–34. Buron E, Bulbena A, Barrada JR, Pailhez G. EROL scale: a new behavioural olfactory measure and its relationship with anxiety and depression symptoms. Actas Esp Psiquiatr 2013;41:2–9. Cai S, Leonard BE. The effects of chronic lithium chloride administration on some behavioural and immunological changes in the bilaterally olfactory bulbectomized rat. J Psychopharmacol 1994;8:40–7. Chen D, Haviland-Jones J. Rapid mood change and human odors. Physiol Behav 1999;68: 241–50. Chen C, Shih YH, Yen DJ, Lirng JF, Guo YC, Yu HY, et al. Olfactory auras in patients with temporal lobe epilepsy. Epilepsia 2003;44:257–60. Choi GB, Stettler DD, Kallman BR, Bhaskar ST, Fleischmann A, Axel R. Driving opposing behaviors with ensembles of piriform neurons. Cell 2011;146:1004–15. Clepce M, Gossler A, Reich K, Kornhuber J, Thuerauf N. The relation between depression, anhedonia and olfactory hedonic estimates—a pilot study in major depression. Neurosci Lett 2010;471:139–43. Corthell JT, Stathopoulos AM, Watson CC, Bertram R, Trombley PQ. Olfactory bulb monoamine concentrations vary with time of day. Neuroscience 2013;247:234–41.
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