Identifying the inherent mechanism of ‘suppressing depressive symptoms caused by stress’
- Trace aminergic signaling suppresses the onset of depressive symptoms caused by daily stress - Published in the international academic journal 'Nature Communications'
image: a Schematic of changes in neuronal activity of the LHb-RMTg-VTA pathway in chronic and acute stress responses. DA, dopamine; GABA, gamma-aminobutyric acid; GLU, glutamate. b, c Expression of AADC/VGLUT2 (b) and AADC/TH/TPH2 (c) in the LHb by FISH. d Pie chart of the percentage of VGLUT2-expressing AADC-positive cells in the LHb by FISH (n = 3 independent mice). e, Experimental schematic of acute tail suspension (TS)-induced stress, followed by FISH analysis. f Expression of AADC/c-Fos/VGLUT2 in the LHb of naïve and TS model mice by FISH. g–i Percentages of c-Fos-expressing AADC-positive cells (n = 8 independent Naïve mice and n = 11 independent TS mice) (g), c-Fos-expressing VGLUT2-positive cells (n = 8 independent Naïve mice and n = 11 independent TS mice) (h) and c-Fos-expressing cells in total cells in the LHb by FISH (n = 8 independent Naïve mice and n = 11 independent TS mice) (i). j Expression of c-Fos/TH in the VTA (top) and c-Fos/GAD1 in the RMTg (bottom) in naïve and TS model mice by FISH. k Percentages of c-Fos-expressing TH-positive cells in the VTA (left; n = 8 independent Naïve mice and n = 11 independent TS mice) and c-Fos-expressing GAD1-positive cells in the RMTg (right; n = 8 independent Naïve mice and n = 11 independent TS mice) of naïve and TS model mice. l Schematic of acute stress-mediated alterations in neuronal activity in the LHb-RMTg-VTA pathway. Magnified images of the regions of interest (yellow squares) are shown next to the main images in (b), (c) and (f). Unless otherwise stated, statistical comparisons were performed using a two-tailed unpaired t test. **p < 0.01 and ***p < 0.001. Data are presented as the mean values ± s.e.m. Source data are provided as a Source Data file.
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Professor Hyun Kim and his team from the Department of Anatomy, College of Medicine, Korea University, have identified the inherent mechanism that suppresses the induction of depressive symptoms caused by stress through research on the control of the neural network of trace amines in the lateral habenula and the analysis of depressive behaviors.
Continuous stress is known to induce depressive symptoms. Stress drives depression by exciting glutamatergic neurons in the lateral habenula and activating GABAergic neurons in the lateral tegmental nucleus, which silences dopaminergic neurons. However, daily stress causes activation of glutamatergic neurons in the lateral habenula, but depressive symptoms do not occur. Many researchers have suggested a theory of an inherent system that offsets the triggering of depressive symptoms, but the reason has not been clearly proven to date.
To investigate the theory, Professor Hyun Kim's research team analyzed the close relationship between trace aminergic signaling and the induction of depressive symptoms through research on the control of the neural network of trace amines in the lateral habenula and the analysis of depressive behaviors. The team observed a specific decrease in AADC (L-amino acid decarboxylase) gene expression, which produces trace amines in the lateral habenula of a stress-based depressed animal model, and the fact that artificially reducing AADC expression in the lateral habenula induces depressive symptoms. Restoring the reduced AADC gene expression alleviated depressive symptoms.
With daily stress, the lateral habenula secretes trace amines to offset the effect of glutamatergic neuron activation, and no depressive symptoms appear. But under constant stress, glutamatergic signaling is superior to trace aminergic signaling and causes depressive symptoms. This allowed the team to confirm that trace aminergic signaling acts as an inherent system that offsets the effect of glutamatergic neuron activation in everyday stress situations.
The team leader, Professor Hyun Kim, said, 'Our research has identified that trace aminergic signaling in the lateral habenula acts as an inherent system that controls the effects of glutamatergic neuron activation. This suggests a new direction for the prevention and treatment of depression.'
This research was led by the lead authors: Dr. Soo Hyun Yang and Dr. Esther Yang, as well as co-corresponding authors, Dr. Hyun Woo Lee and Hyun Kim. It was sponsored by the Ministry of Science and ICT, the Brain Science Source Technology Development Project, and the Brain Disease Overcoming Research Project of the National Research Foundation of Korea. The research results were published under the title 'Neural mechanism of acute stress regulation by trace aminergic signaling in the lateral habenula in male mice' in the online edition (April 27) of Nature Communications (IF=17.69), a sister journal of the world-renowned international academic journal Nature.