an-olfactory-preference-test-for-measuring-olfactory-hedonic-biases

An Olfactory Preference Test for Measuring Olfactory Hedonic Biases in Mouse Models of Depression

Depression is the single largest contributor to disability worldwide, affecting 280 million people annually. Beyond reduced activity and motivation, ...

Institut Pasteur, Université Paris Cité

Université de Paris Cité

GHU Paris Psychiatrie & Neuroscience

Don't forget the benefits of empathy.

Bipolar disorders are defined by recurrences of depressive and manic episodes. The pathophysiology is still unknown, and translating clinical symptoms into behaviors explorable in animal models is challenging. Animal models of bipolar disorder do not exist because cyclicity of the disease is impossible to mimic, and it is therefore necessary to study mania and depression models separately. Beyond mood, emotional biases differentiate bipolar states in humans. Mania is associated with positive biases, e.g. emotional stimuli become more rewarding and less aversive, and the opposite for depression. We propose to assess behavioral hedonic responses to innately appetitive and aversive olfactory and gustatory cues in mice as proxies for the assigned emotional valence. A mania model is therefore supposed to exhibit positive hedonic bias. Using the GBR 12909 mania model, we observed the classical hyperactivity phenotype, along with low depressive-like but high anxiety-like behaviors. Unexpectedly, GBR 12909-treated mice exhibited strong negative hedonic biases. Consequently, the GBR 12909 model of mania might not be appropriate for studying emotional disturbances associated with mania states. We propose olfactory and gustatory preference tests as crucial assessment for positive and negative valence biases, necessary for precisely characterizing animal models of bipolar disorders.

Assessing positive and negative valence systems to refine animal models of bipolar disorders: the example of GBR 12909-induced manic phenotype.

Mixed features in mood episodes: Mismatch between intensity and valence in emotional responses.

Negative bias is an essential characteristic of depressive episodes leading patients to attribute more negative valence to environmental cues. This negative bias affects all levels of information processing including emotional response, attention and memory, leading to the development and maintenance of depressive symptoms. In this context, pleasant stimuli become less attractive and unpleasant ones more aversive, yet the related neural circuits underlying this bias remain largely unknown. By studying a mice model for depression chronically receiving corticosterone (CORT), we showed a negative bias in valence attribution to olfactory stimuli that responds to antidepressant drug. This result paralleled the alterations in odor value assignment we observed in bipolar depressed patients. Given the crucial role of amygdala in valence coding and its strong link with depression, we hypothesized that basolateral amygdala (BLA) circuits alterations might support negative shift associated with depressive states. Contrary to humans, where limits in spatial resolution of imaging tools impair easy amygdala segmentation, recently unravelled specific BLA circuits implicated in negative and positive valence attribution could be studied in mice. Combining CTB and rabies-based tracing with ex vivo measurements of neuronal activity, we demonstrated that negative valence bias is supported by disrupted activity of specific BLA circuits during depressive states. Chronic CORT administration induced decreased recruitment of BLA-to-NAc neurons preferentially involved in positive valence encoding, while increasing recruitment of BLA-to-CeA neurons preferentially involved in negative valence encoding. Importantly, this dysfunction was dampened by chemogenetic hyperactivation of BLA-to-NAc neurons. Moreover, altered BLA activity correlated with durable presynaptic connectivity changes coming from the paraventricular nucleus of the thalamus, recently demonstrated as orchestrating valence assignment in the amygdala. Together, our findings suggest that specific BLA circuits alterations might support negative bias in depressive states and provide new avenues for translational research to understand the mechanisms underlying depression and treatment efficacy.

Article	Year
Don't forget the benefits of empathy. L'Encephale\| PubMed ID: 34857366	2021
Assessing positive and negative valence systems to refine animal models of bipolar disorders: the example of GBR 12909-induced manic phenotype. Scientific reports\| PubMed ID: 35513683	2022
Mixed features in mood episodes: Mismatch between intensity and valence in emotional responses. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology\| PubMed ID: 39018770	2024
Disrupted basolateral amygdala circuits supports negative valence bias in depressive states. Translational psychiatry\| PubMed ID: 39300117	2024

Chantal Henry

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