Loneliness and social isolation are known to cause several mental health issues, as the COVID-19 pandemic reminded us. This can cause long-term difficulties and seriously impact the brain and overall brain function.
By studying the different biological and behavioural effects of social isolation on mice, Dr Jing Liang and her team have recently identified a promising therapeutic with the power to reverse these changes, a major development in this field.
Read the original research: https://www.nature.com/articles/s41598-022-09814-5
Read the Research Outreach article here
Image source: Adobe Stock / Maridav
Hello and welcome to Research Pod! Thank you for listening and joining us today.
In this episode, we will be looking at the innovative research of Dr Jing Liang and their team at the University of Southern California Mann School of Pharmacy and Pharmaceutical Sciences, USA, who have been studying the different biological and behavioural effects of social isolation on mice. The team have recently identified a promising therapeutic with the power to reverse these changes, a major development in this field.
Loneliness and social isolation are known to cause several mental health issues including anxiety, depression, insomnia, and suicidal tendencies. In the long run, these can lead to cognitive decline, an early sign of Alzheimer’s disease and related dementias (ADRDs). This was quite evident during and after the COVID-19 pandemic which immensely affected the mental health of millions of people worldwide: we saw an increased number of cases of anxiety/depression and acute stress disorder in people that had to be socially isolated for several weeks.
Although previous studies have shown that anxiety can lead to cognitive decline, the mechanisms behind this connection have not yet been fully understood. Dr Jing Liang and her team at the USC Mann School of Pharmacy in the USA have been working on better understanding the impact of social isolation on the brain. Through their research, the team hopes to find new ways to prevent its catastrophic effects from happening.
Social isolation has been shown to cause changes to specific areas in the brain such as the hippocampus, a complex brain structure that is not only responsible for emotional control, including fear, anxiety, and depression, but also regulates long-term memory formation. The dysfunction of the hippocampus is believed to be associated with conditions such as anxiety, depression, cognitive decline, and memory loss.
Another finding in the brain of cognitively impaired people is the loss of previously made connections between nerve cells, called neurons. Neurons connect to each other and transfer signals through the tips of dendrites, called synapses. The dendrites can be thought of as the ‘arms’ of neurons, with synapses being the ‘hands’. Healthy and well-functioning synapses are necessary for normal brain function, and their absence leads to cognitive decline and memory loss. Liang and her team have previously studied an Alzheimer’s disease animal model. They showed that there is a reduced activity of a specific type of synapses in the brain, called GABAergic, or gamma-aminobutyric acid synapses, which are responsible for regulating cognitive functions and emotions such as anxiety through special receptors, or GABAARs.
But it’s not only the neurons in the brain that get affected. Astrocytes are the star-shaped structural cells of the immune system in the brain. Their role is to support the neurosynapses, form tripartite synapses with GABAergic synapses, and keep them in an optimal functional state. Astrocytes also provide nutrients to neurons, protect neuro-synapses, and create an environment for optimal functioning of neuro-synapses. Therefore, any damage to the astrocytes can directly affect the function of the neuro-synapses.
It has been shown before that in cognitively impaired brains such as those of patients with Alzheimer’s disease, the astrocytes are fewer in numbers, smaller, and dysfunctional. The fact that similar changes were identified in the astrocytes of animals that had been socially isolated for the purpose of experimentation, known as the social isolation model, makes the researchers confident that cognitive decline associated with social isolation is caused by the damaged connections between astrocytes and the neurons – the tripartite-synapse theory.
Liang’s team decided to create a social isolation animal model and study its impact on mice brains. They found that socially isolated mice exhibited more anxious or aggressive behaviours compared to the ones that were housed in groups and had daily social interactions. Just like in previous experiments, they decided to examine the effects of a substance called dihydromyricetin, or DHM for short, in mice. DHM is a natural compound extracted from the Japanese raisin tree with cell protective properties. Amongst others, DHM was previously shown to have great potential in improving alcohol-related behaviours and mental disorders. In addition, Liang and her team have previously demonstrated its role in improving social isolation-related cognitive impairment and memory loss in the same model of mice.
To better understand how social isolation affects the mammal brain, Liang and her team aimed to use their animal model to further investigate the mechanisms that lead to cognitive decline through stress and anxiety. They also identified the structural changes in the brain and examined whether these can be reversed using DHM.
For their experiment, Liang’s team used 6-week-old adult mice that were exposed to a 12-hour light/dark cycle and had free access to bed, food, and water. The researchers then created different groups of mice, with some of them being housed in cages together in groups of two or three. The remaining mice – the social isolation group – were placed in an opaque cage, each mouse on their own to help completely isolate them from the others. All mice were housed under the above conditions for four weeks in total. Over the last two weeks of the experiment, the mice were either given a treatment with DHM or were given a dummy drug, known as a vehicle, containing just agar to create a control group to which the treated group would be compared against. This created four groups of mice: the DHM social isolation group, the vehicle social isolation group, the DHM group housing group and the vehicle group housing group.
Next, all mice underwent behavioural tests to evaluate their cognitive abilities. These included object recognition testing, where the mice were tested on whether they could tell the difference between familiar and new objects, and context recognition tests, where the animals were tested on their ability to remember the setting a specific object was initially found in and identify any changes that were implemented by the researchers. The latter is associated with relevant regulation centres on the hippocampus and is an indirect method to evaluate the structure’s functionality and health.
Brain tissues from all four groups were extracted and treated with immunohistochemistry stains, a technique that enabled the researchers to identify specific proteins in the brain tissues. The proteins that they looked for were markers related to astrocyte function and health. Next, the team studied the stained tissues under the microscope and all results were analysed using statistical methods, with the results for each of the four teams compared to one another.
The researchers were surprised to find that even this short period of isolation caused significant changes in the mice’s brain, resulting in memory deficits and impaired cognitive function. They also discovered that the isolated mice that hadn’t received DHM treatment had atrophied astrocytes with smaller branches compared to the group housing mice, suggesting their functionality was impaired. These findings were less evident in isolated mice treated with DHM, which demonstrated improved object recognition abilities compared to their non-treated peers and less negative changes in the structure and functionality of their astrocytes as well.
Liang’s team confirmed with this latest study that social isolation made cognitive and memory abilities worse in mice. They also observed the relevant changes in astrocytes and synapses formation in the areas of the brain responsible for emotional regulation and long-term memory.
Dihydromyricetin, an herbal substance that had previously shown promising results in improving cognition and memory loss in mice, was able to reverse these effects. It improved memory, cognitive function and it induced regeneration of the damaged astrocytes.
The findings of Liang and her team are crucial not only because they clearly demonstrate the impact of short-term social isolation on the brain, but because they also showcase a new potential preventative treatment for its consequences on mental health and brain function. These impressive results make the researchers hopeful that DHM could potentially be used in the future not only to prevent social isolation related cognitive decline and permanent brain damage, but also as a component of new therapeutic strategies against dementia and Alzheimer’s disease.
The results of this study showed that even two weeks of social isolation led to changes in the brain, which worsened after four weeks. Fortunately, these changes could be reversed with DHM treatment. This is why the team is already planning future studies with an aim to identify the maximum length of social isolation period that allows for timely intervention with DHM, before any permanent brain damage occurs.
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