Affiliations : The Douglas Institute, McGill, Canada
Journal reference: doi: 10.15252/embr.201948097
Summary: The habenula is a small well connected structure in our brains. This article reveals that the habenula is implicated in mood and anxiety disorders as it affects anxiety-like behavior and social interactions. This will help us better understand anxiety disorders and improve on relevant treatments.
Anxiety in a small brain region called the habenula
“Small in size but large in impact” perfectly reflects the tiny brain structure (about 5 to 9 mm in diameter in humans) that is the habenula (Hb). Highly conserved across species, this structure holds a strategic central position in the brain, connecting the front and back areas.
The habenula’s success story began about ten years ago when a study on monkeys demonstrated that it is activated in anticipation of aversive consequences such as failure to obtain an expected reward. The habenula was further broken down into two subdivisions: the lateral (LHb) and the medial (MHb) habenula. While the lateral part is involved in a large network and different cognitive and affective functions, the medial part follows a very specific pathway in the brain and has been shown to be involved mainly in negative events such as fear memory, mood disorders and anxiety.
Anxiety, a widespread syndrome that is particularly exacerbated by the current global pandemic, is experienced by many individuals at some point in time. Anxiety is defined as a psychological and physiological state characterized by cognitive, emotional and behavioral responses to various stressors. It manifests itself through a variety of somatic symptoms that may result from a perception of inevitable and uncontrollable threats. People with anxiety disorders experience difficulties coping with potential threats. It is therefore essential to identify targets for effective treatments and due to its involvement in anxiety the medial habenula might present a promising target.
Genetically removing chloride channels in cholinergic neurons reduced habenula activity
A recent study published by Cho et al. in the prestigious EMBO journal examined the role of cholinergic neurons of the medial habenula in symptoms of anxiety. Cholinergic neurons are a type of neurons that mainly use the acetylcholine neurotransmitter to communicate with other brain cells. More precisely, the authors observed that a chloride channel called TMEM16A was present in this neuron population. TMEM16A chloride channels are known, among other things, to regulate brain activity by controlling the membrane potential and excitability of various cell types including neurons. The researchers in the study genetically developed a mouse model (called knock-out transgenic mice) that lacks this channel (TMEM16A KO mouse) specifically in cholinergic neurons of the medial habenula. They thus demonstrated that the removal of this channel significantly reduced the spontaneous activity of medial habenula, resulting in a reduction in the frequency of neuron activation (also called firing). Also, it appeared that this reduction was not only observable in the habenula but also in its main target region, the interpenuncular nucleus.
Genetically removing chloride channels in cholinergic neurons increased anxiety and decreased social interactions
The researchers then examined the effects of this ablation on anxiety via two standardized behavioral tests: the raised cross maze and the light/dark box. These tests are based on the rodent’s preference for dark enclosed areas, as opposed to light, open areas. Generally speaking, a more anxious animal will tend to spend more time in a dark and enclosed area. Thus, because TMEM16A KO mice spent more time the dark and enclosed area than control mice, the authors concluded that genetically modified mice had increased anxiety. As there is a close relationship between anxiety levels and social behaviors in rodents and in humans, the levels of social interactions were examined in TMEM16A KO mice, revealing with no surprise a significant decrease in social interactions compared to control mice. Overall, these results suggest that, by reducing neuronal activity in the medial habenula, removal of the channel would lead to increased anxiety behavior and social interaction disorders in these KO mice.
DREADDING the results
In order to examine whether the decrease in the medial habenula activity alone mediates observed anxiogenic and social changes, Cho et al. employed a technique called DREADD (Designer Receptors exclusively activated by Designer Drugs). This technique is based on the injection of synthetic receptors in the brain region of interest, here the medial habenula. The receptors are specifically expressed in relevant neurons, here cholinergic neurons from the MHb. The receptors are exclusively activated by synthetic drugs, here clozapine. When administered, clozapine reacts with the DREADDs to activate or inhibit targeted neurons, allowing to determine their behavioral impact. In other words, the authors used the DREADD technique to inhibit MHb cholinergic neurons of mice still possessing their TMEM16A channels. This resulted in a significant reduction of habenular activity, increased anxiety and altered social behaviors. Overall, these results confirm that reduced activity of the medial habenula is at the origin of anxiety and social deficiencies.
Take home message
The puzzle that is the medial habenula is taking shape as more evidence is consolidated. Other studies have reported results that support these findings. For example, it has been shown that cholinergic neurons are implicated in the anxiety experienced during nicotine withdrawal. In addition, genetically modified mice with an abnormal medial habenular pathway also exhibit dysfunctional social interaction patterns. Thus, the idea that the medial habenula could be a tiny area with enormous potential as a therapeutic target in the field of anxiety disorders is gradually emerging in the scientific sphere. It will nevertheless take a few more years before this research knowledge reaches the clinic to be transferred and applied to humans.