It is known that adversity in early life can have long-term effects on mental health of adults. Now, a study using mice led by scientists from Tata Institute of Fundamental Research, Mumbai, finds that stimulating a particular pathway in the brain in early life can cause anxiety, depression and even schizophrenia-like symptoms later in life. This does not happen if the stimulation is carried out in adolescent or adult mice. The study has been published in the journal eLife.
Engineering the mice
Using genetic engineering the researchers modulated a specific pathway in the brains of mice which is known to stimulate the excitatory neurons in the forebrain region. When they carried out prolonged stimulation in two-week old mice and observed them when they grew into adults, the researchers found that the adult mice exhibited signs of increased anxiety, depression-like behaviour and even symptoms of schizophrenia-like behaviour. Such behaviour was not observed in mice that had been subjected to the stimulation as adolescents or adults.
The group used bigenic mouse models that were engineered to express Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in excitatory neurons of the forebrain. Vidita Vaidya of TIFR who led the research says, “The DREADD in question results in increased Gq signalling when it is stimulated by [specific] drugs…” This increased Gq signalling stimulates the excitatory neurons in the forebrain.
Prof. Vaidya further explains the observation of schizophrenia-like behaviour thus: Usually when someone is surprised by a sudden, loud sound, they show a startled response. But if the loud sound is preceded by a softer sound of lower volume, they show inhibition of the startled response. This is called pre-pulse inhibition.
In the case of individuals with schizophrenia, the pre-pulse inhibition does not happen. The behaviour of the experimental mice that had been subjected to stimulation of excitatory neurons in their infancy was interesting. “We study the pre-pulse inhibition behaviour which is a hallmark of a behavioural change noted in patients of schizophrenia. Animals in which we have stimulated Gq signalling in forebrain excitatory neurons go on to exhibit pre-pulse inhibition deficits in adulthood,” she explains.
The entire study took nearly six years, with major participation by Sthitaprajnya Pati, a PhD student with Prof. Vaidya. Collaborators James Chelliah at JNCASR, Bengaluru and Anant Patel at CCMB provided key support for electrophysiology experiments and NMR experiments, respectively.
The researchers had several controls for different aspects of the experiment: “We checked whether the genetic strategy itself has behavioural effects which it didn’t. We tested the effects of DREADD activation in adolescent and adult mice and that also had no effect,” says Prof. Vaidya. Thus, there is a “tight time-window in early life” when animals are highly sensitive to this perturbation.
The study throws open several interesting questions. “If we can mimic the effects of early stress using these chemogenetic strategies, can we also reverse the effects of early stress? If so, is there a restricted window of time in which reversal would work?” says Prof. Vaidya.