Barring a few lucky or enlightened ones who've learnt to slay this dragon, stress affects virtually everyone, in acute or chronic way, at some point in life. In this process, as the last 30 years of research shows, our brain is affected in many ways. One of the fascinating and evolving stories of stress is the contrasting effect it has in the two neighbouring parts of the brain —the hippocampus and the amygdala. It’s a story that is also, albeit very slowly, throwing crucial light on why most anti-depressants are not effective and why the world today is staring at a mental illness epidemic.
It’s been established that stress not only shrinks the hippocampus, the seat of factual memory and learning in the brain, in volume but even reduces synaptic plasticity, or long term potentiation (LTP). A synapse is a junction that allows a neuron to pass electrical signal to another neuron or any other cell. When there’s a rapid and long-lasting enhancement of the response of a synapse to one of its inputs, it is called LTP which allows spatial memories to be formed in the hippocampus.
Decreased hippocampal volume has been linked to cognitive deficits, which are common in post-traumatic stress disorders. In fact, a shrinking hippocampus is also a risk factor for the development of such disorders.
In all these years stress has been extensively studied to show that it impairs LTP in the hippocampus. Neurons themselves lose dendrites, synapses, and their capacity for LTP. Together these explain why following chronic stress factual memory and cognition decline.
But all these studies fail to explain why when everything (volume and synaptic plasticity) is going down in the hippocampus; emotional response and anxiety are going up in the neighbouring part of the brain, that is, the amygdala. While scientists understand the former, they have little clue about the latter. Now, in the 40th year of the publication of the landmark paper on LTP that transformed the understanding of memory and stress, neuroscientist Sumantra Chatterji and his colleagues at the National Centre for Biological Sciences in Bangalore provide some scientific evidence. The mystery of exaggerated emotional response in stress disorders rests in the electrical activity of amygdala, part of the brain which is responsible for anxiety, fear and aggression.
We have shown that the same LTP which reduces memory in the hippocampus gives rise to enhanced fear and anxiety in amygdala, says Chattarji. “The same plasticity mechanism that is shown to decrease in the hippocampus is seen to be going up in amygdala. We know that LTP is pivotal for forming fear memories and we show that LTP goes up in amygdala during stress.”
Looking at the basic cellular mechanism, the NMDA receptors -- the molecular substrate that is responsible for LTP to happen -- are seen to pass double the current in the amygdala. In their earlier work Chattarji and his colleagues have shown that stress creates new synapses in this part of the brain. This, again, is in contrast to the hippocampus where synapses are lost during stress. In experiments on animal models, Chattarji has showed that it’s the new synapses – formed during stress—that pass extra electrical current, not the old synapses.
It turns out the new synapses, or the silent synapses as they are called, are loaded with memory-making molecules or the NMDA receptors. If you look at the cells at rest, says Chattarji, you can’t tell any difference. But if the cells get activated, such as during the formation of fear memory, then the silent synapses open up and create stronger memories.
This explains why stress, which in most cases makes us forget facts of life, elicits strong, many times exaggerated, emotional response in us.
Chattarji is reporting his finding at a stellar Royal Society gathering in London on Dec 2-3. Scientists have gathered to celebrate, as it were, the 40th anniversary of the unraveling of the LTP. It is convened by Timothy Bliss, the scientist who discovered in the 1970s how a few seconds of high frequency electrical stimulation can increase synaptic transmission in the rabbit hippocampus for days. He published his landmark paper in 1973 in the Journal of Physiology.
It’d be fair to say Chattarji’s work turns the entire hippocampus-stress-memory framework on its head.
Much as neuroscience has advanced, the correlation of mice model to humans remains as relevant as it was decades ago, except of course that the models are getting more sophisticated. Nearly 95 percent of neurobiology research even today is based on rats and mice, he says. Even if you consider the current LTP contrast in hippocampus and amygdala, animal and human studies complement each other beautifully.
For the last 5-10 years, clinicians have seen through brain imaging that in stress disorder patients, while hippocampus becomes less active amygdala becomes hyperactive. But they did not have a molecular basis for that. “What they’ve seen in humans actually bears out in animals now. And the fact that nothing invasive can be done in humans, the two together can now explain the mystery,” says Chattarji.
Fascinating as this aspect of brain may be, the findings raise a very common sense challenge. How do you design a drug that does opposite things in two adjacent parts of the brain. The reality is most anti-depressants are developed with just one model—of the hippocampus—in mind. This also explains why in recent times the US and UK carry warning labels on the most popular anti-depressant drugs (the selective serotonin reuptake inhibitors or SSRIs) like Prozac, Zoloft or Paxil because they create enhanced anxiety and suicidal tendencies in young patients, at least in the first few weeks of the treatment..
Chattarji, who in the last few years has made a systematic effort to bring psychiatrists closer to neuroscience by conducting week-end sessions at NCBS, says practitioners rarely care for the mounting scientific data and its implication in everyday practice. He says most clinicians are concerned about prescribing a drug and assuaging the symptoms of their patients rather than understanding how brain works and why their treatment may not be effective in the medium to long term.
It’ll take some time before the drug design community begins to take the double model—hippocampus and amygdala — into consideration. The world of psychiatric drugs has long rested on serendipity and marketing tactics, but this time the science looks convincing.
The thoughts and opinions shared here are of the author.
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