Dr Gabriel Uguru
We are living in a highly competitive and resource-scarce world. This means that we live and work under lots of pressures – pressure from home, work, society, peer pressure, financial and health pressures, etc.
Many people no doubt, succumb to any one of these pressures while some are resistant. Pressure generates stress and those that succumb to stress are said to be susceptible, while those that are resistant are considered as resilient.
Join our WhatsApp ChannelStress can trigger joylessness or lack of interest in things we previously found entertaining. Some people who are susceptible to stress may be incapable of experiencing joy or pleasure. This medical condition is known as anhedonia and is a common symptom of depression. Anhedonia is often seen in people with neurological and psychiatric conditions, especially people suffering from severe depression, Parkinson’s, schizophrenia, etc.
In the December 2024 edition of the journal, Nature, Mazen Kheirbek and coworkers explored the link between the brain and anhedonia and identified plausible treatment options. They took advantage of the fact that mice like most human beings have “sweet tooth” (i.e. a liking for sugary or sweet-tasting foods). The researchers found that mice that succumb to traumatic social stress become withdrawn, socially inactive, and anhedonic.
The basolateral amygdala (BLA) is that part of the brain associated with emotional, reward, and anxiety-related behaviours. The ventral hippocampus, which projects into the amygdala, is also associated with emotional and anxiety behaviours. The BLA informs decision-making by generating reward representations tailored to outcomes, while the ventral hippocampal neurones encode stimuli that are predictive of rewards and drive reward-related behaviours.
The amygdala and the ventral hippocampus are interconnected and play a reciprocal role in generating emotional and motivated behaviour. How these two nodes associated with reward-related functions are affected by stress is not clear.
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The neurologists, therefore, subjected mice to a stressful condition by placing them together with larger and more aggressive mice before letting them have a drink of either sugary water or only plain water. Those who preferred plain water were classified as having anhedonia while those who preferred sugary water were classified as resilient (i.e. resistant to stress). Control mice were not subjected to stress, and they preferred sugary water as normal.
To identify the neural signatures of the intention to switch or stay on the same reward choice as in earlier trial, the mice were exposed to four different sequences of consecutive rewards: water–water; water–sucrose; sucrose–water; sucrose–sucrose. The tests show anhedonic mice switching more from sucrose to water and repeatedly making water choices while resilient and control mice stuck to sugar choices.
Neuronal monitoring of the amygdala and hippocampus by Neuropixels recordings, showed patchy communication in anhedonic mice. But in resilient mice the communication between the two brain areas associated with emotional behaviour was robust.
Muscarinic acetylcholine M3 (hM3) receptors are found in different parts of the body, including the brain, lungs, and pancreas. hM3Dq is a modified form of this receptor and is activated by a compound called clozapine-n-oxide. Mice expressing hM3Dq were given clozapine-n-oxide to increase neurone firing rates and thereby enhance communication between the amygdala and hippocampus.
Treated anhedonic mice showed preference for sugary water more often than they did before the treatment. Also, their brain activity was improved so that the neuronal firing pattern looked similar to that of the resilient mice. This in effect shows that there is a difference between anhedonic and resilient mice on how they process information about rewards.
In a resting-state, individuals with severe depressive disorder show a change in functional connectivity between the amygdala and hippocampus. Anhedonic mice showed such spontaneous activity patterns in a specific region of the amygdala, which was interpreted as a sign of trauma. This predictive stress signature could be more accurate and reliable than using behavioural changes in appetite as a biomarker for stress.
A replication of the mice model experiment in humans may require more complex decision-making tasks than the simple water vs sugar choices presented to the mice.
The study highlights the importance of the amygdala-hippocampus circuit as a potential target for neuromodulation when treating mood disorder patients. The study also opens the possibility of studying other areas of the brain (e.g. the hypothalamus and prefrontal cortex) involved in emotional behaviour for potential solutions to stress-induced depression.
