Neurobiology

Scientists create new system to study effects of drugs and disease on brain

The human brain needs extra protection as our brain is the most complex and delicate part of our body. Hence blood vessels are highly selective in nature transporting oxygen and nutrition to the brain and blocking the passage of harmful toxic and chemicals from blood to the brain and vice-versa.

The highly selective nature of the blood vessel is mainly due to a unique network called the blood-brain barrier (BBB) which comprises mainly of pericyte and astrocyte cells. if the BBB is disrupted or damaged it can cause harmful damage to neurons.

This is Your Brain on Chips from Wyss Institute.

According to previous studies, BBB is thought to have other function i.e. it directly linked with brain and helping it to carry out it various function. But scientists were unable to study BBB  because culturing cells in the laboratory is simplified and fails to be the right model for the detailed study while natural brain tissues are too complex to study the interaction between brain and BBC.

The team of researchers from the Wyss Institute has created a “just right” model of BBB and brain interface which can help to study the effect of drugs on brain and blood vesicles.  This new BBB-brain interface created using microfluidically linked Organ Chips that reacts to meth like the human brain and allows an unprecedented look into how the brain’s vasculature influences and regulates its metabolic function detail structure of how brain vasculatures influences and regulate its metabolic function.

“Most of today’s research on Organ Chips is focused on trying to increase the complexity of cell types on each chip, but we realized that the brain is already so complex that we couldn’t analyze it on one chip, so we did the opposite and divided one organ onto multiple chips,” said first author Ben Maoz, Ph.D., a former Technology Development Fellow at the Wyss Institute who is currently an Assistant Professor at Tel Aviv University, Israel. “The beauty of this work is that Organ Chips were able to open up another dimension for neurological research that no other method could; decoupling a very dense organ to unveil new interactions between the different structures within the brain.”

Methamphetamine (“meth,” left) is known to disrupt the tight junctions – shown here in green – between the cells of the blood-brain barrier (BBB), letting toxic substances enter the brain. When the researchers added meth to healthy BBB cells (middle), it caused the junctions to become leaky (right), confirming that the BBB-Brain Chip system can be used to study the effects of drugs on the human brain. Credit: Wyss Institute at Harvard University

The BBB-Brain Chip system is made up of mainly three chips which are“influx” BBB Chip, a Brain Chip, and “efflux” BBB Chip.. these chips are separated physically but are connected through microfluidic channels. The function of microfluidic channel is similar to blood vessel i.e. to allow the exchange of chemicals and other substances between them physically distinct from each other but all connected with microfluidic channels to allow the exchange of chemicals and other substances between them.


In the laboratory, the scientist exposed the cultured human cells linked with BBB-Brain Chips to methamphetamine (“meth”) which is a drug that can make neurons susceptible to harmful damage. On exposure, this drug disrupts the junctions between the cells of the BBB in vivo and cause it to leakage of molecules that normally wouldn’t be able to cross the BBB into the Brain Chip. During their study, they found that the model worked, and established that it could be used in research to better understand drugs’ effects on the human brain and develop treatments.

“Blood vessels are frequently thought to just be a barrier or a transporter of chemicals. But when we looked at the linked BBB-Brain Chips, we noticed that there seemed to be some crosstalk between the endothelial cells and the neurons,” explained co-author Anna Herland, Ph.D., a former Postdoctoral Fellow at the Wyss Institute who is now an Associate Professor at the Royal Institute of Technology and the Karolinska Institute in Stockholm, Sweden. “We also know from studies of long-term meth abusers that this drug affects the brain’s metabolism, so we started to dig deeper to see if we could characterize the metabolic link between the BBB and the brain.”

In the light of this newly created  BBB-Brain Chip system, researchers were able to analyze all of the molecules secreted by the individual cell populations alone followed by connecting the chips to trace where those substances traveled. Researchers also noticed that the chemicals secreted by the cells on the uncoupled BBB Chip were largely related to neuron maintenance and protection, showing BBB provide chemical cues to neurons by producing molecules.

The next step of the study was to determine the influence of the endothelium on metabolites in the brain. Their finding demonstrated that products of vascular endothelial cell metabolism become substrates for the production of neurotransmitters that mediate neuronal cell information processing in the brain, suggesting that the health of our blood vessels could have a direct impact on mental function.

“The big breakthrough here is that we have teased out communication networks between cells in a way that never could have been done with traditional brain research techniques. We are seeing here an unanticipated level of complexity that raises the bar in terms of what it will mean to successfully map the brain’s connectome.”- Kit Parker

“The big breakthrough here is that we have teased out communication networks between cells in a way that never could have been done with traditional brain research techniques. We are seeing here an unanticipated level of complexity that raises the bar in terms of what it will mean to successfully map the brain’s connectome”, said corresponding author Kit Parker, Ph.D., a Core Faculty member of the Wyss Institute and the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

Using this system, scientists will be able to do a highly multiplexed, massively parallel metabolomic analysis of many different chemicals produced by different cell types, all on these tiny chips.

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