Measuring all neurons in the brain

Try to contemplate a future device that allows registering in minute detail the behaviors of a cheetah and a gazelle during a chase, including all muscle and skeletal movements. At the same time, we’re capable of recording billions of neurons across the two nervous systems while the entire chase unfolds from before the cheetah initiates the pursuit until its dramatic conclusion.


What would we discover? How much of our textbooks would have to be altered?

A radical rethinking might be needed, and a lot would have to be rewritten. An alternative possibility is that many of the experimental paradigms employed to date are quite effective in isolating critical mechanisms that reflect the brain’s functioning in general settings. True, novel findings would be made with new devices and techniques, but they would extend current neuroscience by building naturally upon current knowledge. The first scenario is not idle speculation, however.

So-called naturalistic experimental paradigms are starting to paint a different picture of amygdala function, for example. In one study, a rat was placed at one end of an elongated enclosure and a piece of food was placed midway between the rat and a potential predator, a lego-plus-motor device called a “Robogator.” To successfully obtain the food pellet, the rat had to retrieve it before being caught by the Robogator (don’t worry, capture didn’t occur in practice). The findings[1] were inconsistent with the standard “threat-coding model” that says that amygdala responses reflect fear-like or other related defensive states. During foraging (when approaching the pellet), neurons reduced their firing rate and were nearly silent near the predator. Clearly, responses did not reflect threat per se.

From: Choi, J. S., & Kim, J. J. (2010). Amygdala regulates risk of predation in rats foraging in a dynamic fear environment. Proceedings of the National Academy of Sciences, 107(50), 21773-21777.

Another study recorded from neurons in the amygdala over multiple days, as mice were exposed to different conditions[2]. Mice were exposed to a small open field and were free to explore it. These creatures don’t like to feel exposed, so in the experiment they frequently stayed at the corners of the box a good amount of time. But they also ventured out in the open for periods and navigated around the center of the box with some frequency. The researchers discovered two groups of cells: one that was engaged when the mouse was being more defensive in the corners (these “corner” cells fired more vigorously at these locations), another when the mouse was in an exploratory mode visiting the center of the space (“center” cells fired more strongly when the animal was around the middle of the field). The researchers also managed to record from the exact same cells during more standard paradigms, including fear conditioning and extinction. They then tested the idea that the firing of amygdala neurons tracks “global anxiety”; for instance, they should increase their responses when the animal entered the center of the field in the open-field condition, as well as when they heard the CS tone used in the conditioning part of the experiment. Surprisingly, cells did not respond in this way. Instead, neuronal firing reflected moment-to-moment changes in the exploratory state of the animal, such as during the time window when the animal transitioned from exploratory (for example, navigating in the open field) to non-exploratory behaviors (for example, when starting to freeze).

The above two examples provide tantalizing inklings that there’s a lot to discover – and revise – about the brain. It’s too early to tell, but given the technological advances neuroscience is witnessing, examples are popping up all over the place. For example, a study by Karl Deisseroth and colleagues[3] recorded activity of ~24,000 neurons throughout 34 brain regions (cortical and subcortical). Whereas measuring electrical activity with implanted electrodes typically measures a few cells at a time, or maybe ~100 by using state-of-the-art electrode grids, the study capitalized on new techniques that record calcium fluorescence instead. When cells change their activity, including when they spike, they rely on calcium-dependent mechanisms. In genetically-engineered mice, neurons literally glow based on their calcium concentration. By building specialized microscopes, it is possible to detect neuronal signaling across small patches of gray matter. When mice smelled a “go” stimulus, a licking response produced water as a reward. The animals were highly motivated to perform this simple task as the experimenters kept them in a water-restricted state. Water-predicting sensory stimuli (the “go” odor) elicited activity that rapidly spread throughout the brain of thirsty animals. The wave of activity began in olfactory regions and was disseminated within ~300 ms to neurons in every one of the 34 regions they recorded from! Such propagation of information triggered by the “go” stimulus was not detected in animals allowed to freely consume water. Thus, the initial water-predicting stimulus initiates a cascade of firing throughout the brain only when the animal is in the right state – thirsty.

In another breakthrough study, Kenneth Harris, Mateo Carandini and colleagues[4] used calcium imaging techniques to record from more than 10,000 neurons in the visual cortex of the mouse. At the same time, facial movements were recorded in minute detail. They found that information in visual cortex neurons reflects more than a dozen features of motor information (related to facial movements, including whiskers and other facial features), in line with emerging evidence. These results are remarkable because traditional thinking is that motor and visual signals are only merged later in so-called “higher-order” cortical areas; definitely not in primary visual cortex. But the surprises didn’t stop there. The researchers also recorded signals across the forebrain, including other cortical areas, as well as subcortical regions. Surprisingly, information about the animal’s behavior (at least as conveyed by motor actions visible on the mouse’s face) was observed nearly everywhere they recorded. In considering the benefit of this ubiquitous mixing of sensory and motor information, the investigators ventured that effective behaviors depend on the combination of sensory data, ongoing motor actions, and internal variables such as motivational drives. This seems to be happening pretty much everywhere in the brain, including in primary sensory cortex. The examples above hint that much is to change in neuroscience in the coming decades. And these results come from fairly constrained settings. The amygdala study used a 40 x 40 x 40 plastic box; the thirst study probed mice with their heads fixed in placed; and the facial movement study employed an “air-floating ball” that allowed mice to “run”. Imagine what we’ll discover in the future.

[1] Recordings in the basolateral amygdala. Amir, A., Kyriazi, P., Lee, S. C., Headley, D. B., & Pare, D. (2019). Basolateral amygdala neurons are activated during threat expectation. Journal of Neurophysiology, 121(5), 1761-1777.

[2] Recordings in the basal amygdala: Gründemann, J., Bitterman, Y., Lu, T., Krabbe, S., Grewe, B. F., Schnitzer, M. J., & Lüthi, A. (2019). Amygdala ensembles encode behavioral states. Science, 364(6437), eaav8736.

[3] Allen, W. E., Chen, M. Z., Pichamoorthy, N., Tien, R. H., Pachitariu, M., Luo, L., & Deisseroth, K. (2019). Thirst regulates motivated behavior through modulation of brainwide neural population dynamics. Science, 364(6437), 253-253.

[4] Stringer, C., Pachitariu, M., Steinmetz, N., Reddy, C. B., Carandini, M., & Harris, K. D. (2019). Spontaneous behaviors drive multidimensional, brainwide activity. Science, 364(6437), 255-255.

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