Mice have more synapses connecting neurons than primates


Primates are generally thought to be “smarter” than mice, but in a surprising finding, researchers found that mice actually have more synapses connecting neurons in their brains.

In a study comparing the brains of macaques and mice at the synaptic level, researchers found that primates had significantly fewer synapses per neuron than rodents.

Using artificial recurrent neural network modeling, the team was further able to determine that the metabolic cost of building and maintaining synapses likely makes larger neural networks more sparse, as seen. in primates compared to mouse neurons.

“This raises interesting questions, such as what are the ramifications of building a larger neural network, like those seen in primates? “

The researchers took advantage of recent advances in electron microscopy, as well as existing publicly available datasets, to compare connectivity in the two species. They chose to look at both excitatory and inhibitory synapses because most previous research had focused only on excitatory synapses. Focusing on the 2/3 layer neurons in the adult primary visual cortex facilitated the comparison between species, as these neurons have distinct morphologies that are similar in primates and mice.

After reconstructing the microscopy images and measuring the shapes of 107 macaque neurons and 81 mouse neurons, the researchers identified nearly 6,000 synapses in the macaque samples and more than 9,700 synapses in the mouse samples. By comparing the data sets, they found that neurons from primates receive two to five times fewer excitatory and inhibitory synaptic connections than neurons from similar mice.

“The reason it’s surprising is that there’s this kind of quiet assumption among neuroscientists and, I think, people in general that having more neural connections means you’re smarter, says Gregg. Wildenberg, a scientist from the Narayanan lab. “Bobby” Kasthuri from the Argonne National Laboratory.

“This work clearly shows that while there are more total connections in the brain of primates as a whole because there are more neurons, if you look by neuron, primates actually have fewer synapses.

“But we do know that primate neurons can perform calculations that mouse neurons cannot. This raises interesting questions, such as what are the ramifications of building a larger neural network, like those seen in primates? “

What is behind synapse mismatch?

After discovering this startling discovery, Wildenberg connected with Matt Rosen, a graduate student at the David Freedman lab at the University of Chicago, hoping Rosen could bring his computer expertise to better understand the gap in synapse numbers and its possible cause.

“We have always expected the density of synapses in primates to be similar to that seen in rodents, or maybe even higher because there is more space and more neurons in the primate brain.” , explains Rosen. “In light of Gregg’s surprising discovery, we reflected on why primate neurons make fewer connections than expected. And we thought maybe this was driven by evolutionary forces – that maybe the energy costs associated with maintaining a brain could be causing this difference.

“The brain makes up only about 2.5% of our total body mass, but requires about 20% of the body’s total energy. It is a very expensive organ.

“So we developed models of artificial neural networks and trained them to perform tasks while giving them constraints inspired by the metabolic costs that real brains face, to see how this affects the connectivity that occurs in networks that result. “

The modeling considered two potential metabolic costs: the cost of individual electrical signals sent by neurons, called action potentials, which are energetically very expensive, and the cost of building and maintaining synapses between different cells. What they found was that as the number of neurons increased in the network, increasing metabolic stresses made it more difficult to create and maintain connections between cells, resulting in reduced synapse density. .

“The brain only makes up about 2.5% of our total body mass, but requires about 20% of the body’s total energy,” says Wildenberg. “It’s a very expensive organ. It is believed that the majority of this energy is spent on synapses, both in energy to communicate through synapses but also to build and maintain them. As the brain gets bigger, with more neurons, there will likely be tradeoffs, metabolically speaking. “

Develop different types of brains

The results, the researchers say, will help inform future research on primates and mice, as well as comparisons between the two.

“Basically I think all neuroscientists want to understand what makes us humans, what separates us from other primates and mice,” says Wildenberg. “We are working on connectomics, which focuses on understanding neuroanatomy at the level of individual connections. Before that, it had not been well described if there were any differences in the connections that might give us clues as to how evolution builds different types of brains.

“Every brain is made up of neurons, and every neuron connects and communicates with other neurons in a stereotypical way. How does evolution work within these constraints to build different types of brains? You have to study mice, primates, and a bunch of other species to really start to understand what’s going on here.

Rosen also points out that understanding the differences between species can help clarify general brain principles to better understand behavior.

“The comparative approach allows us to think carefully about the anatomy of the brain in the context of the specific behaviors of an organism,” he says. “No one treats a mouse and a primate the same; they behave differently. These fundamental observations of the anatomical differences between the two can allow us to extract general principles that can be applied to all species, as well as what is unique for each animal.

For example, understanding synaptic density, and in particular the relationship between excitatory and inhibitory synapses, may inform research on neurological disorders such as Parkinson’s disease and autism.

“If we only measure the excitatory / inhibitor ratio in mice and assume it’s the same for all species, how does that affect our understanding of the disease?” Said Wildenberg. “We found differences in the excitatory / inhibitor ratio in primates compared to mice; what are the implications for how we translate these patterns for humans? “

Future research will include examining similar questions during brain development, working to understand how the number and density of synapses affect the network over time, and how this development differs between mice and primates.

The results appear in Cell reports.

Funding for the work came from the McKnight Foundation, the National Institutes of Health, and the National Science Foundation.

Source: University of Chicago

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