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Combining a Breath-Synchronized Olfactometer with Brain Simulation to Study the Impact of Odors on Corticospinal Excitability and Effective Connectivity

It is widely accepted that olfactory stimulation elicits motor behaviors, such as approaching pleasant odorants and avoiding unpleasant ones, in animals ...

Université Claude Bernard Lyon 1

Cellular imagery using histology sections is one of the most common techniques used in Neuroscience. However, this inescapable technique has severe limitations due to the need to delineate regions of interest on each brain, which is time consuming and variable across experimenters.

Non-imaged based method for matching brains in a common anatomical space for cellular imagery.

Anxiety disorders represent 1 of the most common classes of psychiatric disorders. In the aging population and for patients with age-related pathology, the percentage of people suffering of anxiety is significantly elevated. Furthermore, anxiety carries with it an increased risk for a variety of age-related medical conditions, including cardiovascular disease, stroke, cognitive decline, and increased severity of motor symptoms in Parkinson's disease. A variety of anxiolytic compounds are available but often carry with them disturbing side effects that impact quality of life. Among nonmedicinal approaches to reducing anxiety, odor diffusion and aromatherapy are the most popular. In this review, we highlight the emerging perspective that the use of odorants may reduce anxiety symptoms or at least potentiate the effect of other anxiolytic approaches and may serve as an alternative form of therapy to deal with anxiety symptoms. Such approaches may be particularly beneficial in aging populations with elevated risk for these disorders. We also discuss potential neural mechanisms underlying the anxiolytic effects of odorants based on work in animal models.

Odorants: a tool to provide nonpharmacological intervention to reduce anxiety during normal and pathological aging.

Adult olfactory neurogenesis provides waves of new neurons involved in memory encoding. However, how the olfactory bulb deals with neuronal renewal to ensure the persistence of pertinent memories and the flexibility to integrate new events remains unanswered. To address this issue, mice performed two successive olfactory discrimination learning tasks with varying times between tasks. We show that with a short time between tasks, adult-born neurons supporting the first learning task appear to be highly sensitive to interference. Furthermore, targeting these neurons using selective light-induced inhibition altered memory of this first task without affecting that of the second, suggesting that neurons in their critical period of integration may only support one memory trace. A longer period between the two tasks allowed for an increased resilience to interference. Hence, newly formed adult-born neurons regulate the transience or persistence of a memory as a function of information relevance and retrograde interference.

Short-term availability of adult-born neurons for memory encoding.

Pleasant odorants are represented in the posterior olfactory bulb (pOB) in mice. How does this hedonic information generate odor-motivated behaviors? Using optogenetics, we report here that stimulating the representation of pleasant odorants in a sensory structure, the pOB, can be rewarding, self-motivating, and is accompanied by ventral tegmental area activation. To explore the underlying neural circuitry downstream of the olfactory bulb (OB), we use 3D high-resolution imaging and optogenetics and determine that the pOB preferentially projects to the olfactory tubercle, whose increased activity is related to odorant attraction. We further show that attractive odorants act as reinforcers in dopamine-dependent place preference learning. Finally, we extend those findings to humans, who exhibit place preference learning and an increase BOLD signal in the olfactory tubercle in response to attractive odorants. Thus, strong and persistent attraction induced by some odorants is due to a direct gateway from the pOB to the reward system.

Neural processing of the reward value of pleasant odorants.

Although transcranial direct current stimulation (tDCS) shows promise as a treatment for auditory verbal hallucinations in patients with schizophrenia, mechanisms through which tDCS may induce beneficial effects remain unclear. Evidence points to the involvement of neuronal plasticity mechanisms that are underpinned, amongst others, by brain-derived neurotrophic factor (BDNF) in its two main forms: pro and mature peptides. Here, we aimed to investigate whether tDCS modulates neural plasticity by measuring the acute effects of tDCS on peripheral mature BDNF levels in patients with schizophrenia. Blood samples were collected in 24 patients with schizophrenia before and after they received a single session of either active (20 min, 2 mA,  = 13) or sham ( = 11) frontotemporal tDCS with the anode over the left prefrontal cortex and the cathode over the left temporoparietal junction. We compared the tDCS-induced changes in serum mature BDNF (mBDNF) levels adjusted for baseline values between the two groups. The results showed that active tDCS was associated with a significantly larger decrease in mBDNF levels (mean -20% ± standard deviation 14) than sham tDCS (-8% ± 21) (F = 5.387;  = 0.030; η = 0.205). Thus, mature BDNF may be involved in the beneficial effects of frontotemporal tDCS observed in patients with schizophrenia.

Frontotemporal Transcranial Direct Current Stimulation Decreases Serum Mature Brain-Derived Neurotrophic Factor in Schizophrenia.

When you smell an odorant, your first reaction will certainly be either I like it or I dislike it. This primary reaction is a reflection of what is called the "hedonic value" of the odor. Very often, this hedonic value dominates the olfactory percept, more than olfactory identification or intensity. This component of olfactory perception is of primary importance for guiding behavior: avoiding danger (the smell of smoke, gas, etc.), consuming food, or seduction. Olfactory hedonics can be assessed using a large number of methods in humans, including psychophysical measures, autonomic responses, measurement of facial expressions or peripheral nervous activity. All of these techniques have their limitations: subjectivity, invasiveness, need for expertise, etc. A NEW METHOD: The olfactory system is closely linked to the reward system, the role of which is to mediate motivated behavior. In this context, we propose that the capacity odorants have of recruiting the reward system and thus inducing motivated behavior can be used to identify new behavioral parameters to assess odor hedonic value in humans.

Identification of new behavioral parameters to assess odorant hedonic value in humans: A naturalistic approach.

The search for a biological marker predicting the future failure or success of electroconvulsive therapy (ECT) remains highly challenging for patients with treatment-resistant depression. Evidence suggests that Brain-Derived Neurotrophic Factor (BDNF), a protein known to be involved in brain plasticity mechanisms, can play a key role in both the clinical efficacy of ECT and the pathophysiology of depressive disorders. We hypothesized that mature BDNF (mBDNF), an isoform of BDNF involved in the neural plasticity and survival of neural networks, might be a good candidate for predicting the efficacy of ECT. Total BDNF (tBDNF) and mBDNF levels were measured in 23 patients with severe treatment-resistant depression before (baseline) they received a course of ECT. More precisely, tBDNF and mBDNF measured before ECT were compared between patients who achieved the criteria of remission after the ECT course (remitters,  = 7) and those who did not (non-remitters,  = 16). We found that at baseline, future remitters displayed significantly higher mBDNF levels than future non-remitters ( = 0.04). No differences were observed regarding tBDNF levels at baseline. The multiple logistic regression model controlled for age and sex revealed that having a higher baseline mBDNF level was significantly associated with future remission after ECT sessions (odd ratio = 1.38; 95% confidence interval = 1.07-2.02,  = 0.04). Despite the limitations of the study, current findings provide additional elements regarding the major role of BDNF and especially the mBDNF isoform in the clinical response to ECT in major depression.

Serum Mature BDNF Level Is Associated with Remission Following ECT in Treatment-Resistant Depression.

Experiencing chronic stress significantly increases the risk for depression. Depression is a complex disorder with varied symptoms across patients. However, feeling of sadness and decreased motivation, and diminished feeling of pleasure (anhedonia) appear to be core to most depressive pathology. Odorants are potent signals that serve a critical role in social interactions, avoiding danger, and consummatory behaviors. Diminished quality of olfactory function is associated with negative effects on quality of life leading to and aggravating the symptoms of depression. Odor hedonic value (I like or I dislike this smell) is a dominant feature of olfaction and guides approach or avoidance behavior of the odor source. The neural representation of the hedonic value of odorants is carried by the granule cells in the olfactory bulb, which functions to modulate the cortical relay of olfactory information. The granule cells of the olfactory bulb and those of the dentate gyrus are the two major populations of cells in the adult brain with continued neurogenesis into adulthood. In hippocampus, decreased neurogenesis has been linked to development or maintenance of depression symptoms. Here, we hypothesize that chronic mild stress can alter olfactory hedonics through effects on the olfactory bulb neurogenesis, contributing to the broader anhedonia phenotype in stress-associated depression. To test this, mice were subjected to chronic unpredictable mild stress and then tested on measures of depressive-like behaviors, odor hedonics, and measures of olfactory neurogenesis. Chronic unpredictable mild stress led to a selective effect on odor hedonics, diminishing attraction to pleasant but not unpleasant odorants, an effect that was accompanied by a specific decrease in adult neurogenesis and of the percentage of adult-born cells responding to pleasant odorants in the olfactory bulb.

Article	Year
Non-imaged based method for matching brains in a common anatomical space for cellular imagery. Journal of neuroscience methods\| PubMed ID: 29684463	2018
Odorants: a tool to provide nonpharmacological intervention to reduce anxiety during normal and pathological aging. Neurobiology of aging\| PubMed ID: 31377537	2019
Short-term availability of adult-born neurons for memory encoding. Nature communications\| PubMed ID: 31811134	2019
Neural processing of the reward value of pleasant odorants. Current biology : CB\| PubMed ID: 33607032	2021
Frontotemporal Transcranial Direct Current Stimulation Decreases Serum Mature Brain-Derived Neurotrophic Factor in Schizophrenia. Brain sciences\| PubMed ID: 34069556	2021
Identification of new behavioral parameters to assess odorant hedonic value in humans: A naturalistic approach. Journal of neuroscience methods\| PubMed ID: 34826503	2022
Serum Mature BDNF Level Is Associated with Remission Following ECT in Treatment-Resistant Depression. Brain sciences\| PubMed ID: 35203890	2022
Chronic unpredictable mild stress alters odor hedonics and adult olfactory neurogenesis in mice. Frontiers in neuroscience\| PubMed ID: 37600017	2023

Nathalie Mandairon

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