Because of the COVID-19 pandemic, many of us have been forced to be quarantined. This has meant being locked in our homes, going out in a restricted way to shop and for young people the impossibility of joining their groups of friends. Being the fundamental peer group for the construction of identity in adolescence.
We’ve been in these conditions for six months. Can you imagine if the media did not exist during a quarantine that lasts for years? Could the absence of social interaction affect our neural development? Are we beings dependent on social experience for our brain development? These questions relate to a work led by Lucy Bicks and her team at Mount Sinai Medical School, who published in the journal Nature Communications in 2020 the results of their research on the effects of social isolation on mice during a sensitive window of development, and its consequences on social interaction in adulthood. Its objective was to investigate the molecular mechanisms that regulate the maturation of a particular type of neurons and the effects on them of the absence of social interaction in adolescence and adulthood, that is, how social isolation during a key window of development changes our brain chemistry. This is relevant, as many of the psychiatric disorders have in common alterations in social behavior, so discovering the molecular bases would allow researchers to design specific drugs that could help with these problems.
Previous research in mice showed that social isolation during a critical period of development results in lasting behavioral disorders for these animals. This period ranges from day 21 to 35 from the birth of the mouse (which is equivalent in humans from weed to adolescence) and is a moment more sensitive to experiences that promote the establishment of connections between neurons, modifying the communication capacity between them.
Social isolation and its implications in the brain
An important precedent is that an area of the brain called the middle prefrontal dorsal cortex (dmPFC) is involved in complex behaviors related to behavioral regulation that we will hereinafter call behavioral area. Additionally, this area matures during this same sensitive period between 21 and 35 days after birth. In the behavioral area, as in other parts of the brain, there is a type of special neuron called «interneurons», which are responsible for regulating communication between different brain regions. The information they transmit is vital to the development and functioning of our brain, as incommunicado neurons, apart from serving little, tend to die quickly. In order to detect the activity of interneurons, that is, when they are sending messages to other neurons, a technique that joins them to a parvalbumin protein (hereinafter PV interneurons) is used, which when activated release calcium. In this way, in this technique what is observed is the release of calcium.
Previous background told Lucy Bicks and her team that there is a critical period that affects social isolation, and a specific brain area that regulates complex behaviors. They also suspected that this group of PV interneurons could be involved in the negative impact of social isolation on development.
The first challenge was to demonstrate that this subgroup of PV interneurons is effectively involved in social interaction. For this, the researchers made four live measurements of the activity of this neural subgroup: an observation of the resting state of the animal, a measurement of the neural activity of a mouse next to an object, an evaluation during a passive social interaction and finally another during an active interaction.
How did you make live observation of neural activity? They used a technique called photometry, which measures and visualizes changes in calcium levels in neurons, when they communicate. For this, the study animal is genetically modified so that its neurons emit a small light signal when their calcium levels vary. These changes can be recorded by an optical fiber located in the part of the brain that interests us, which is the behavioral area.
To better understand the experiments performed, imagine a square space that has inside a mouse connected to a fiber optic cable (A), to measure changes in neural activity in PV interneurons. Another mouse (B) is entered in this space. If the latter approaches the first one, we are in the presence of an example of passive interaction. On the other hand, if animal A approaches B, it is an active encounter.
PV interneurons, indispensable for social interaction
What results did you get in all four situations? First, they observed that: when the animal is alone, the RVs are not activated. On the other hand, when the animal is in the company of an inanimate object, the activation of PV interneurons is similar to when alone. In the experiments in which another mouse was incorporated into the box it was observed that when an active interaction occurs, there is a pattern of activation of the interneurons in the brain area that we are studying, moments before the encounter. On the contrary, prior to passive encounter, neural activity decreases. With these experiments the researchers found that these interneurons are involved in active social interaction.
However, someone might argue that the activation of interneurons in the area of behavior, prior to social encounter, is caused by another factor and not necessarily by social interaction. Therefore, the second challenge was to prove that there is a cause-and-effect relationship between the activation of interneurons and social encounter. For this, they used a technique called optogenetics in which a genetic modification of specific neurons is combined, with the use of an LED-like light. However, in the case of optogenetics, instead of passively observing what happens to neurons, genetic modification causes neurons to make a light-sensitive protein. In practice this means that we can increase the activity of the neurons that interest us by exposing them to light, so, if the light is turned on, the neurons are activated.
With the help of this technique the most relevant behavioral test was done, which took place in a box with three compartments arranged in series: in the compartment on the left, the researchers left a mouse and on the right a novel object (the mice are curious). In the center compartment they deposited the genetically modified mouse and measured its neural activity when it was heading to the right or left. Where do you think the mouse went when by applying light for a short period of time they activated their PV interneurons? Precisely to the left, to look for your peer. With this, they concluded that a brief neural activation of behavioral zone is associated with the active initiation of a social interaction.
As mentioned above, the researcher and her team found that the behavioral area is involved. They also demonstrated that PV interneurons were not only part of the process, but were indispensable for social interaction, and without their activity it is inhibited.
In one last experimental series, they compared two groups of animals, some «solitary» that had been isolated during the p21-p35 youth period, and other «control» that had coexisted with other mice during that period. In solitary mice, the neural network studied decreased its activity during active encounters, unlike in control mice.
Subsequently, they measured the electrical activity of PV neurons after the postnatal day 35 (p35-p60) in both groups, in the area of our interest. In control mice, a progressive increase in the rate of shots of interneurons (increased «communication») was observed over the course of days. However, no change was observed in solitary mice. The lack of activity of these interneurons indicates that they are not adequately performing their work of creating and maintaining the connections between different groups of developing neurons, which could affect the correct formation of the circuits in which they intervene, which in this case we know are circuits involved in socialization functions. This might suggest a kind of ‘arrest’ of the development of these interneurons.
Consequently, Bicks and his team demonstrated that youthful social experience is required to develop ‘healthy’ neural activity in the area of behavior in adulthood. This neural activity happens only if the initiative is taken to seek social interaction. This means that socialization in adolescence is indispensable for adulthood to «activate the brain» to drive a social experience. If nor, isolation behaviors in adulthood or «antisocial» as noted in the article could be promoted. At the same time, it is common to find deficiencies in the functioning of interneurons in neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) and schizophrenia, both with deficits in social interaction.
What is novel about this study in mice is that they demonstrated how an alteration in a specific period of youth development has consequences for socialization during adulthood. Presenting ‘adolescence’ as a sensitive window of development, unique, where peer-to-peer social experiences are fundamental to the structuring of neural networks in mammals.
Finally, as a product of the pandemic we have reduced the number of social experiences, especially adolescents are more often interacting with a screen, rather than sharing with friends. It may be important for these developing people, as well as for the study mouses, to share experiences in person with other teens their age and try to reduce their reliance on technological devices as much as possible.
Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior. https://www.nature.com/articles/s41467-020-14740-z
This article arises from the agreement with the Interdisciplinary Center for Neuroscience of the University of Valparaiso