5HT-DREADD · In vivo pharmacogenetic investigation of 5-HT mechanisms in emotional learning
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-07-01 → 2018-06-30
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
In vivo pharmacogenetic investigation of 5-HT mechanisms in emotional learning
Serotonin is critical for mood regulation in health and disease and strongly implicated in the vulnerability to anxiety and depression. Importantly, accumulating evidence suggests that the main influence of serotonin is upon emotional learning rather than on mood directly. The objective of this project was to determine the neural mechanisms through which changes in serotonin levels, within defined neuronal circuits, affect learning and memory for aversive emotional experiences. However, the neuronal circuitry involved and how serotonin activity translates into behaviour are yet to be fully elucidated. To explore the effect of specifically manipulating serotonin circuitry on emotionality, I have utilised a chemogenetic approach. This involves inserting new genetic code into certain neurons that leads to the expression of new receptors only in those specific cells. These receptors do not respond to any chemical in the brain but instead are only activated by a drug I then deliver weeks later. These are therefore called DREADDs; Designer Receptors Exclusively Activated by Designer Drugs. In this project, I introduced these receptors to serotonin cells in the dorsal raphe nucleus (DRN), the key source of serotonin innervation in the brain. However, these are not the only cells in that area as they are controlled by local inhibitory gamma aminobutyric acid (GABA) neurons. I therefore also explored how expressing these receptors and selectively activating these local GABA neurons affected the functionality of the serotonin system and the subsequent effect on behaviour. This selectivity is achieved by delivering the new genetic code to the DRN with viruses containing the information for these receptors (hM3Dq) as well as a fluorescent “tag”, or just this “tag” (mCherry) to act as a control. Different lines of mice then allow for this to either be expressed only in serotonin neurons (SERT-Cre mice) or the GABA neurons (vGAT-Cre mice).
Data: CORDIS, © European Union
Project objective
Emotional health and well-being is widely accepted to be crucial for healthy life and the success of societies. Anxiety and depression are two common and debilitating emotional disorders, with highly negative social and financial implications. Serotonin (5-hydroxytryptamine; 5-HT) is thought to be critical to the healthy mood regulation and strongly implicated in the vulnerability to anxiety and depression. Importantly, accumulating evidence suggests that 5-HT’s main influence is upon emotional learning rather than on mood directly. The objective of this proposal is to determine the neural mechanisms through which changes in 5-HT levels, within defined neuronal circuits, affect learning and memory for aversive emotional experiences. New pharmacogenetic techniques will be developed that allow the selective triggering of 5-HT neuron activation and then inhibition in the same animal. We will use this technology to stimulate or inhibit 5-HT release in the basolateral amygdala, a brain area that is crucial for aversive learning, whilst an animal is engaged in an emotional processing task. Through this we will learn how 5-HT modulates neuronal activity in the amygdala at critical time-points during the encoding and retrieval of aversive memories. The results from these studies will provide entirely new insights into how 5-HT modulates amygdala information processing and aversive learning. Understanding how 5-HT affects emotional learning will ultimately lead to a deeper understanding of healthy mood states and the biological mechanisms underlying vulnerability to disorders such as anxiety and depression.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union