No more neuronal gibberish: How 100 billion nerve cells produce a clear thought or an action

Intracellular filled hippocampal basket cells (magenta) and granule cells (green) with a schematic illustration of the distance-dependent inhibition.

We have approximately 100 billion nerve cells in our brains, all of which communicate with one another. Why do they lead to clear thoughts or purposeful actions instead of mere gibberish? The reason lies, among other things, in a small group of inhibitory nerve cells that can use the messenger GABA to curb the activity of other nerve cells. The neuroscientists Dr. Michael Strüber and Prof. Dr. Marlene Bartos from the University of Freiburg and their colleague from Vienna Prof. Dr. Peter Jonas have discovered that the distances between communicating cells play a part in the regulation of brain networks. The team presents this approach in the current issue of the journal Proceedings of the National Academy of Sciences (PNAS).

GABA is released at special contact points, synapses, from a projection of the inhibitory cells that serves precisely this purpose, the axon. The messenger causes an electrical inhibitory current in the target cells. A special subtype of the GABA-releasing cells is the so-called basket cell. It is known to have a strongly inhibitory effect on brain circuits. A reason for this is the fact that basket cells have a long and widely branching axon, with which they can control hundreds to thousands of target cells scattered over a broad area. Up to now it was not clear whether all of these target cells are subject to the same inhibitory current or whether target cells that are more distant from the GABA-releasing basket cell are more difficult to keep under precise control.

With the help of the patch-clamp technique for measuring the inhibitory currents of individual cells, the team discovered that the farther away a target cell is, the smaller and longer are their inhibitory currents. In pharmacological and electrophysiological experiments and by means of detailed microscopic studies, the neuroscientists demonstrated that the basket cell axon with more distant target cells forms less synapses and that other proteins capable of sensing GABA are found in these synapses.

What could be the reason for such a complex structure? While this question cannot be answered in its entirety, the scientists investigated the consequences of a distance-dependent inhibition in computer simulations of neuronal networks. Contrary to expectations, the weakening inhibition enables the basket cells to precisely control the activity of a large number of nerve cells and thus to synchronize them. The synchronization of entire brain areas leads to rhythmic brain activities like gamma oscillations, which serve a crucial function in higher mental processes. The new approach of distance-dependent inhibition could be an important component in the regulation of brain networks that enables the brain to orchestrate the activity of 100 billion individual yet connected nerve cells to produce a thought.

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That smartphone is giving your thumbs superpowers

While neuroscientists have long studied brain plasticity in expert groups--musicians or video gamers, for instance--smartphones present an opportunity to understand how regular life shapes the brains of regular people.

When people spend time interacting with their smartphones via touchscreen, it actually changes the way their thumbs and brains work together, according to a report in the Cell Press journal Current Biology on December 23. More touchscreen use in the recent past translates directly into greater brain activity when the thumbs and other fingertips are touched, the study shows.

"I was really surprised by the scale of the changes introduced by the use of smartphones," says Arko Ghosh of the University of Zurich and ETH Zurich in Switzerland. "I was also struck by how much of the inter-individual variations in the fingertip-associated brain signals could be simply explained by evaluating the smartphone logs."

It all started when Ghosh and his colleagues realized that our newfound obsession with smartphones could be a grand opportunity to explore the everyday plasticity of the human brain. Not only are people suddenly using their fingertips, and especially their thumbs, in a new way, but many of us are also doing it an awful lot, day after day. Not only that, but our phones are also keeping track of our digital histories to provide a readymade source of data on those behaviors.

Ghosh explains it this way: "I think first we must appreciate how common personal digital devices are and how densely people use them. What this means for us neuroscientists is that the digital history we carry in our pockets has an enormous amount of information on how we use our fingertips (and more)."

While neuroscientists have long studied brain plasticity in expert groups--musicians or video gamers, for instance--smartphones present an opportunity to understand how regular life shapes the brains of regular people.

To link digital footprints to brain activity in the new study, Ghosh and his team used electroencephalography (EEG) to record the brain response to mechanical touch on the thumb, index, and middle fingertips of touchscreen phone users in comparison to people who still haven't given up their old-school mobile phones.

The researchers found that the electrical activity in the brains of smartphone users was enhanced when all three fingertips were touched. In fact, the amount of activity in the cortex of the brain associated with the thumb and index fingertips was directly proportional to the intensity of phone use, as quantified by built-in battery logs. The thumb tip was even sensitive to day-to-day fluctuations: the shorter the time elapsed from an episode of intense phone use, the researchers report, the larger was the cortical potential associated with it.

The results suggest to the researchers that repetitive movements over the smooth touchscreen surface reshape sensory processing from the hand, with daily updates in the brain's representation of the fingertips. And that leads to a pretty remarkable idea: "We propose that cortical sensory processing in the contemporary brain is continuously shaped by personal digital technology," Ghosh and his colleagues write.

What exactly this influence of digital technology means for us in other areas of our lives is a question for another day. The news might not be so good, Ghosh and colleagues say, noting evidence linking excessive phone use with motor dysfunctions and pain.

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Broad receptive field responsible for differentiated neuronal activity

Billions of neurons process signals in our brain. In the sensory part of our cerebral cortex, which is responsible for perceptions of the outside world, not all neurons are equally active: even neurons positioned directly next to each other can be differentially active. If there is input of a stimulus, some neurons respond more than their neighbors. Until now, the reason for this remained elusive. Are the more active neurons perhaps more strongly connected within the cortex? Or do they get more information from upstream areas of the brain?

To clarify this, the researchers stimulated the whiskers of mice and investigated how different neurons in the brain react. For this purpose, they measured the activity of two neurons simultaneously. The active cells are characterized by a high concentration of the protein cFos. Since this was coupled to the green fluorescent protein (GFP), the researchers were able to distinguish more active cells from less active ones.

First they stimulated only one central whisker. Surprisingly, no differences showed up between the two neurons. However, if the researchers stimulated many whiskers at the same time with a short airpuff, the response of the GFP-labeled neuron was significantly earlier and larger. Apparently, the more active neurons are distinguished by the fact that they respond to a wider receptive field. But where does this information come from?

Before we perceive a stimulus from our environment, it must pass through the thalamus in the brain. This area is therefore also called "the gateway to consciousness." In mice, the signals from the whiskers are processed in two areas of the thalamus, the so-called ventral posteromedial nucleus (VPM) and the area of the posteromedial nucleus (POm). Using optogenetic stimulation, the team led by James Poulet determined which of these two nuclei is responsible for the enhanced response of specific neurons. By means of light impulses in the brain, they could specifically activate the thalamic nuclei and thus selectively simulate a flow of information through one of the two nuclei.

If the scientists activated the VPM, both types of neurons showed an equally strong response. They behaved exactly as if only a single whisker was touched. This specific reaction is thus apparently mediated by the VPM. The POm, by contrast, elicited -- just like the stimulation of several whiskers -- a stronger and faster response of the GFP-labeled neurons.

The POm is known for covering a broad receptive field and for transmitting the signals to widely distributed areas in the cerebrum. According to current research, the most active neurons in the somatosensory (touch-sensitive) cortex are characterized by the fact that they not only get specific information from the VPM, but can also draw on the wide receptive field of the POm. This parallel processing of specific and large-scale stimulus information by separate groups of neurons could be a fundamental mechanism of sensory perception. The more active neurons may have a particularly important role in sensory perception.

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Neuronal circuits filter out distractions in brain

Cold Spring Harbor Laboratory scientists have identified neural connections between the cortex, thalamus, and TRN (TRN neurons shown in red, left and right panels) that help filter out distractions. Loss of a single protein in the TRN (shown here in green, middle and right panels) dramatically affects the function of the neural circuit and changes how mice focus.

The next time you are in a crowded room, or a meeting, or even at the park with your kids, take a look around. How many people are on their phone? Distractions invade every aspect of our lives. Status updates, text messages, email notifications all threaten to steal our attention away from the moment. While we fight the urge to check the phone, our brains are making constant judgment calls about where to focus attention. The brain must continually filter important information from irrelevant interference.

Scientists have hypothesized for decades about how the brain might accomplish this, but it has been challenging to find evidence to support the theories. Now, researchers at Cold Spring Harbor Laboratory (CSHL) have identified a neural circuit in the mouse brain that controls attention and sensory processing, providing insight into how the brain filters out distractions. The work has implications for devastating psychiatric disorders such as schizophrenia that are characterized at least in part by significant attention deficits.

The cortex is the region of the brain where most cognitive function happens. It is there that information is processed and interpreted, and decisions are made. But sensory information must pass through a neuronal gate, called the thalamus, on its way to the cortex. The thalamus, a ball-shaped bundle of neurons, is coated in a thin neuronal skin called the thalamic reticular nucleus, or TRN. As early as 1984, Nobel laureate Francis Crick hypothesized that the TRN might function like a guardian of the gate, regulating precisely which information is worthy of being passed on through the thalamus to the cortex for further analysis.

Researchers were intrigued by the hypothesis but faced technical struggles to prove that it was correct. Given the unique anatomical structure of the TRN -- analogous to the skin on an apple -- scientists were unable to target those neurons specifically. Still, evidence began to mount that the theory could be correct. Dysfunction of the TRN has been implicated in schizophrenia, and activity in the TRN correlates with sensory detection and attention.

Now, nearly 30 years after Crick's hypothesis, a team of CSHL scientists led by Associate Professor Bo Li has been able to provide the elusive evidence that the TRN regulates signaling between the cortex and thalamus. Together, the three structures form a circuit that controls attention and sensory processing in the mouse brain.

Using new viral technology combined with mouse models developed by CSHL Professor Josh Huang, Li and his team found a way to precisely target the TRN. They inactivated a single protein, called ErbB4, specifically in the TRN. Mutations in ErbB4 have been associated in prior studies with schizophrenia and other attention deficit disorders. The protein is found in large amounts in the TRN.

The team found that loss of ErbB4 in the TRN greatly affects the animal's ability to focus amid distractions. "When ErbB4 is absent, we saw that the connections between the cortex and the TRN become much stronger," explains Li. "This perturbs the role of the TRN as a guardian of the thalamus 'gate,' and provides a mechanism for the hypothesis that Crick proposed so long ago."

Beyond offering new insights into the neuronal basis of attention, the research suggests possible targets for therapeutics to treat attention deficit disorders as well as attention problems in broader illnesses including schizophrenia. According to Li, the next step is "to understand how loss of ErbB4 enhances the connections between the cortex and the TRN, which will hopefully enable us to pinpoint more drug targets in the future."

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