Scientists at the Allen Institute have generated a new high-resolution view of the connections that form the neuronal wiring of the mouse brain. Their study, published in Nature, traced thousands of connections between brain areas, and provides a foundation for researchers to better understand how abnormal or damaged brain circuitry is associated with disorders such as Alzheimer’s disease and schizophrenia. The results offer a high-resolution expansion of the Allen Mouse Brain Connectivity Atlas, a publicly available resource that in its original form captured the brain-wide wiring diagram of the mouse, its “connectome,” at a medium (or mesoscale) level of resolution.

“These connections are the primary way neurons communicate with each other,” said Hongkui Zeng, PhD, executive director of structured science at the Allen Institute for Brain Science, a division of the Allen Institute, and senior author of the study. “The elaborate and complicated networks in the brain, their different pathways and subsystems, process everything we see, our movements, memories, and feelings.”


This video shows axon pathways originating from five different neuron types located across the cortical layers. Each neuron type is false-colored in the movie. [Allen Institute]
 

The upgraded resource, which includes about a thousand new experiments, represents possibly the most detailed map of connections in a mammalian brain to date, tracing neural wiring within and between the thalamus and cortex, the outermost region of the mammalian brain that is responsible for higher level functions like memory, decision making, and how we make sense of the world around us. Analyzing all their data, the researchers uncovered an underlying “org chart” of wiring among the different areas that comprise the thalamus and cortex. This chart showed a defined order to the connections that underpin how our brains function. “Understanding the connectivity of the brain is fundamental for understanding how the brain works,” Zeng commented. The researchers report their work in a paper titled, “Hierarchical organization of cortical and thalamic connectivity.”

“The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown,” the authors reported. “Cognitive processes and voluntary control of behavior originate in the cortex. To understand how incoming sensory information is processed and integrated with past experiences and current states in order to generate appropriate behavior requires knowledge of the anatomical patterns and rules of connectivity between cortical areas.”

The original iteration of the Allen Mouse Brain Connectivity Atlas dataset, which was first made available in 2014, captured connections between brain regions. To derive a more detailed view of how the mammalian brain is wired the researchers studied connections between specific classes of neurons across the cortex and thalamus. The experiments exploited a modified virus that traces neurons’ paths, effectively lighting up the brain’s information routes. “We used a genetic viral tracing approach, building on our previously established whole-brain imaging and informatics pipeline, to map projections originating from unique cell populations in the same cortical area, and from distinct projection classes in the thalamus,” the investigators commented.

If the first iteration of the map captured the equivalent of railroad tracks in the brain’s transit system, this new expansion adds the specific routes from one point to another, using special labels to light up five different kinds of neurons that reside in different layers of the cortex. “Our findings follow analyses of projection patterns spanning nearly the entire mouse cortex and thalamus, and show how these patterns relate to layer and cell class,” the researchers explained.

The mouse brain has approximately 85 million neurons that make roughly 100 billion connections, or synapses. A complete synapse-by-synapse connectome of a mammalian brain hasn’t yet been generated, but capturing the connections made by different classes of cells allowed the researchers to uncover new information about how the wiring is organized. “Our results show that the mouse cortex and thalamus form an integrated hierarchical organization,” the investigators reported.

“This is another landmark, tour-de-force study from the Allen Institute for Brain Science that addresses fundamental issues of brain organization in the mouse,” said David Van Essen, PhD, alumni endowed professor of neuroscience at Washington University School of Medicine in St. Louis and a scientific advisor to the Allen Institute for Brain Science. “The team has acquired, analyzed, and freely shared a vast amount of high-quality anatomical connectivity data, thereby providing the most extensive ‘meso-connectome’ description to date for the wiring of any mammalian brain.”

The image shows a single section from a mouse brain. Neurons in one layer of sensory cortex (the very dense yellow color on the right) were labeled with green fluorescence to trace all the pathways arising from these cells across the brain. When these axons reach their cortical targets, they form synapses across the layers of the cortex with distinct patterns associated with the direction of information routing. [Allen Institute]
Alterations in brain connections have been seen in Alzheimer’s disease, Parkinson’s disease, and several other brain diseases and disorders. Julie Harris, PhD, associate director of neuroanatomy at the Allen Institute for Brain Science, who led the connectivity study, is now heading an effort to examine a similar map of connections in a mouse model of Alzheimer’s disease, with a view to better understanding how the wiring diagram—and its underlying organization—might change with disease.

“What came out of these data was a big mess of connections, and at first glance it looked like everything is connected to everything,” said Harris, who is co-first author on the Nature article, along with Stefan Mihalas, PhD, associate investigator at the Allen Institute for Brain Science. “The big question for us was, how do you make sense of these patterns? Is there any logic behind it?”

Using a computational approach, the researchers found that different sections of the cortex and thalamus can be mapped into a hierarchy. Parts of the cortex that are specialized for information gathered via our senses, such as vision and smell, are on the bottom “rungs,” and regions that handle more complicated input—say, a memory that is triggered by a familiar scent—sit at the top. Connections flow both up and down the brain’s org chart, but the connections moving up are different than those moving down.

The results also showed that not all connections respect hierarchical laws. There are hints that the human cortex uses the same organizational system, and a previous study led by Van Essen showed a similar hierarchy in visual regions of the primate brain. “… we have substantially expanded the Allen Mouse Brain Connectivity Atlas resource (http://connectivity.brain-map.org), adding 1,256 new tracing experiments,” the authors stated. “Our findings follow analyses of projection patterns spanning nearly the entire mouse cortex and thalamus, and show how these patterns relate to layer and cell class.”

“This is not a simple hierarchy, like a one-way sequence of ascending steps,” commented Christof Koch, PhD, chief scientist and president of the Allen Institute for Brain Science and one of the study co-authors. “There are a lot of connections that do not follow the strict hierarchical rules. But this tells us something about the likely flow of information in these parts of the mammalian brain. The next step will be to look directly at how neurons pass information through their electrical activity to confirm that this pattern matters.”

 

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