Studies from Dr. Minmin Luo’s lab revealed a new neural circuit that regulates fear memory expression through surprising cellular mechanisms

On July 14, 2016. Dr. Minmin Luo's lab published a research article entitled "Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression"in the journal Cell.

When an environmental cue predicts threat, we respond with fear. When that cue ceases to predict threat, our fear response gradually extinguishes. Excessive fear or fear that persists in the absence of threat is dysfunctional as in phobias and post-traumatic stress disorder. Studies so far have focused on the roles of the extended amygdala and its connected brain areas in fear behaviors. Here, the authors report that the habenulo-interpeduncular pathway, a neural circuit outside of the amygdala, regulates fear memory expression and extinction through a surprising cellular mechanism. The authors found that killing cholinergic neurons in the medial habenula or inactivating their GABA_B receptors causes prolonged fear response even when a cue no longer predicts danger, whereas activating the cells or their GABA_B receptors suppresses fear responses. These findings lead the authors to conclude that the habenulo-interpeduncular pathway, which is evolutionarily conserved in all vertebrates, plays a crucial role in regulating fear responses.

The authors further discovered that, in contrast to the traditional view that GABA_B receptors are exclusively inhibitory, GABA_B receptors in the habenula cholinergic neurons mediates their behavioral effect by strongly enhancing the corelease of multiple neurotransmitters, including glutamate, acetylcholine, and neurokinin B. Another twist in the tale: although GABA_B receptors often close calcium channels, the receptors here excite the cells by facilitating the opening of a peculiar R -type calcium channels. Based on the newly identified mechanisms, the authors identified several compounds, including a PDE2A inhibitor, that activate the neural pathway and speed up the extinction of fear memory. These findings thus substantially expand our understanding of the signaling capacity of GABA and GABA_B receptors. Moreover, it suggests alternative therapeutic approaches to treating fear disorders.