| Author: | Lei, Ting |
| Title: | Sonogenetic modulation to reverse depression-related behaviors |
| Advisors: | Sun, Lei (BME) |
| Degree: | Ph.D. |
| Year: | 2025 |
| Department: | Department of Biomedical Engineering |
| Pages: | viii, 124 pages : color illustrations |
| Language: | English |
| Abstract: | Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics' potential in a mouse depression model, targeting excitatory medial prefrontal cortex (mPFC) neurons that project to its downstream brain area - dorsal raphe nucleus (DRN). Projecting neurons were induced to express a mechanosensitive ion channel, ultrasound was applied, and alterations in patterns of neuronal activation and depressive behaviors were evaluated. Sonogenetics selectively activated targeted excitatory mPFC neurons projecting to the DRN, enhancing real-time DRN neuronal activity and serotonin release, with no observed tissue damage or astrocytic/microglial activation. Tail suspension and forced swim tests revealed that sonogenetically activating this pathway rapidly reversed despair-like behaviors in stressed mice, whereas antidepressant effects observed upon mPFC sonication were abrogated by functionally silencing the downstream DRN neurons. Subsequently, we investigated the direct manipulation of sonogenetic modulation of DRN serotoninergic (5-HTDRN) neurons. We found that sonogenetic modulation of 5-HTDRN neurons significantly increased the neuronal activity and the level of serotonin in the DRN, and alleviated despair-like phenotypes in a real-time manner. There was also no sign of tissue damage or abnormal activation of microglia and astrocytes. Collectively, this study constitutes the first demonstration of the potential for a circuit-targeted sonogenetic therapeutic approach for depression. |
| Rights: | All rights reserved |
| Access: | open access |
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