Chinese scholars discover new ideas for the treatment of mental illness
September 08, 2016 Source: WuXi PharmaTech
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In the long process of biological evolution, the fear response can make the organism effectively avoid danger. Especially the formation of fear memory, let us associate danger with specific signals, so that we can prepare in advance. On the other hand, when the danger no longer exists, the organism no longer needs to react to the above specific signals, otherwise it will waste energy. At this time, the elimination mechanism of fear memory needs to play a role.
For a long time, the amygdala and its associated pathways in the limbic system of the brain have been thought to primarily mediate fear responses, and the pathway between the amygdala and the marginal prefrontal cortex plays a key role in the elimination of fear memory. However, as far as the brain regions outside the amygdala are involved in fear reactions, little is known about them.
Recently, the research team led by Dr. Luo Minmin, a senior researcher at the Beijing Institute of Life Sciences (NIBS), has made major breakthroughs in this field. They discovered the important role of the intercondylar nucleus between the thalamus and the midbrain in the elimination of fear memory, revealing the key neurons, receptors, and neurotransmitters that accomplish this process. This achievement was published in the recent issue of Cell.
Selective inactivation of cholinergic neurons in the medial nucleus (MHb) did not significantly affect the formation of fear memory. The test method is that after a period of 20 seconds of sound stimulation, the mice are subjected to a foot shock. If the mouse forms a fearful memory of the electric shock and the previous sound, it will show a stiff behavior when it hears the sound again, that is, fear memory expression.
When the 20-second sound stimulation is no longer accompanied by a foot shock, the normal mouse will no longer be afraid of the sound and make a stiff behavior, and then the fear memory is eliminated. The researchers found that cholinergic neurons in MHb are essential for fear memory elimination, and activation of these neurons is sufficient to achieve fear memory elimination, and activation of gamma-aminobutyric acid-B (GABAB) receptors. It played a key role in this.
The GABAB receptor here can be unusual. We know that GABA receptors in neurons are usually inhibitory. Upon activation by GABA or its analog baclofen, presynaptic GABAB receptors impair excitatory postsynaptic currents (EPSC) on neurons downstream of their feet. Conversely, the cholinergic neurons in these MHbs, when activated, promote the release of the excitatory synaptic transmitters glutamate, acetylcholine, and neurokinin B, which bind immediately to the postsynaptic interneurons. The corresponding receptors have increased the amplitude of EPSC by more than 10 times! At the same time, the frequency of action potentials on the neurons between the feet also increased significantly.
Thus, the GABAB receptor is transformed into an excitatory receptor here. The researchers found that the activated GABAB receptor activates the R-type voltage-gated Cav2.3 calcium channel, causing a large influx of calcium ions, which in turn causes the release of excitatory synaptic transmitters. The release itself is enough to achieve the result of fear memory elimination. When phosphodiesterase 2A (PDE2A) is inhibited in MHb cholinergic neurons, cyclic adenosine monophosphate (cAMP), which is decomposed by the enzyme, rises, causing the release of excitatory synaptic transmitters, and Achieve fear memory elimination.
This important finding provides new ideas for the treatment of fear-related psychiatric disorders. It suggests the effect of the muscle relaxant drug baclofen on fear remission and reveals the underlying idea of eliminating specific fear excitatory synaptic transmitters to eliminate fear responses.
