Brain from the Bottom Up: Spontaneous Birth of Synchrony in Small Neuronal Networks

More 13 July 2011: Brian Wang looks at the same research, with an emphasis on the hardware (electronic) aspect. It is fitting to look at both the neurons and the electronics, since the coming cybernetic biosingularity will be dependent upon both.

Human intelligence and consciousness are poorly understood, even by cognitive scientists, neuroscientists, and consciousness specialists. No one understands how to build a human intelligence from scratch, much less how to build a non-human intelligence capable of interacting with humans and the outside world on its own terms. But researchers at Tel Aviv University from the departments of Electrical Engineering and Physics, have taken a fascinating approach to building the basic components of brains: networks of biological neurons. Something wonderful happened when enough cultured neurons linked together in network: They spontaneously "synched up."

Background


Information processing in neuronal networks relies on the network's ability to generate temporal patterns of action potentials. Although the nature of neuronal network activity has been intensively investigated in the past several decades at the individual neuron level, the underlying principles of the collective network activity, such as the synchronization and coordination between neurons, are largely unknown. Here we focus on isolated neuronal clusters in culture and address the following simple, yet fundamental questions: What is the minimal number of cells needed to exhibit collective dynamics? What are the internal temporal characteristics of such dynamics and how do the temporal features of network activity alternate upon crossover from minimal networks to large networks?


Methodology/Principal Findings


We used network engineering techniques to induce self-organization of cultured networks into neuronal clusters of different sizes. We found that small clusters made of as few as 40 cells already exhibit spontaneous collective events characterized by innate synchronous network oscillations in the range of 25 to 100 Hz. The oscillation frequency of each network appeared to be independent of cluster size. The duration and rate of the network events scale with cluster size but converge to that of large uniform networks. Finally, the investigation of two coupled clusters revealed clear activity propagation with master/slave asymmetry.

Conclusions/Significance


The nature of the activity patterns observed in small networks, namely the consistent emergence of similar activity across networks of different size and morphology, suggests that neuronal clusters self-regulate their activity to sustain network bursts with internal oscillatory features. We therefore suggest that clusters of as few as tens of cells can serve as a minimal but sufficient functional network, capable of sustaining oscillatory activity. Interestingly, the frequencies of these oscillations are similar those observed in vivo. _PLoS

More papers by Mark Shein Idelson

Brain synchrony is an important topic of study, linked to consciousness, memory, learning, and normal function of general human brain activity. But synchronous oscillations are also programmed into the neurons themselves, at the smallest level of neuronal organisation. The challenge now, is to build "networks of networks", to discover the communications strategies which interconnected networks will evolve.

Contrast such a biological, bottom up approach with complex machine models of brain function such as the SpiNNaker project out of the University of Manchester, or the Human Brain Project (HBP) led by Henry Markram at Ecole Polytechnique de Lausanne.

Both of the above brain modeling approaches using computers, are based upon bottom-up theories of how brains work. The Lausanne project (HBP) is far more detailed -- going down to the ion channel level of neurons. The Manchester approach is impressive in its parallel computing ambitions, but it begins at the individual "neuronal spiking" level. SpiNNaker is more of a hybrid CompSci:Neurosci approach, than an actual model of the brain like the HBP.

Conventional artificial intelligence approaches do not mimic brain function closely, and are generally more "top-down" approaches, utilising conventional algorithmic concepts of mainstream computer science. Such approaches are doomed to failure before they even begin, as the last 70 years of conventional AI attempts continue to demonstrate.

In reality, brains must be grown. And new types of brains have to be evolved. Not necessarily from biological materials, but up until now the only working brains we know are biological. The first successful autonomous brains are likely to be evolved either from biological materials, or using ingenious abstractions of processes which emerge from biological mechanisms.

Al Fin cognitive scientists suggest that both the Lausanne approach and the Manchester approach are abstracted at the wrong level, to provide rapid paths to evolved intelligences. Creative human beings will have to discover the appropriate balance, but they will certainly be aided by computing systems in doing so. This is not gobbledygook nor is it AI-psychobabble. It is the genuine crux and pivot point of the problem.

What are the implications for the singularity? There will be no "uploading of consciousness" for the foreseeable future. The cyborg biosingularity is still on schedule for the decade between 2020 and 2030, if humans can avoid an extended Obama Dark Ages. The main question is how many of the cyborg components will be biological in origin, and how many will be non-biological (probably utilising nanotechnology).

Hippocampal Neurogenesis in Mice Key to New Brain Research

Scientists have found that antidepressants (sertraline and tofranil) can boost the growth of new neurons in the hippocampus of mice. This finding is important for treatment of depression, dementia, and brain trauma.

one of the ways that antidepressants work is by boosting neurogenesis in the hippocampus. Christoph Anacker and his colleagues at King's College London have now worked out how they do so.

Previous research has shown a link between some antidepressants and stress hormones called glucocorticoids. So Anacker's team decided to test whether the antidepressant sertraline acts on the glucocorticoid receptors of brain cells. They grew human hippocampal progenitor cells in a dish and added sertraline. Ten days later, the cultures showed a 25 per cent greater than expected increase in the number of new neurons.

When the researchers added a drug to block the glucocorticoid receptors before adding the antidepressant, the number of new neurons produced after 10 days was similar to that expected from natural growth. This suggests that the antidepressant does indeed exert its effect through this receptor (Molecular Psychiatry, DOI: 10.1038/mp.2011.26). _NewScientist

US researchers suspect that this neurogenic effect of antidepressants may prove useful in the treatment of brain injury.

Jason Huang, M.D., and colleagues undertook the study after noticing that patients with brain injuries who had been prescribed anti-depressants were doing better in unexpected ways than their counterparts who were not taking such medications. Not only did their depression ease; their memory also seemed improved compared to patients not on the medication.

"We saw these patients improving in multiple ways – their depression was improved, but so were their memory and cognitive functioning. We wanted to look at the issue more, so we went back to the laboratory to investigate it further," said Huang, associate professor of Neurosurgery and chief of Neurosurgery at Highland Hospital, an affiliate of the University of Rochester Medical Center.

The team's findings were published online recently in the Journal of Neurotrauma.

Huang said many patients who have a traumatic brain injury also experience depression – by some estimates, half of such patients are depressed. Doctors aren't sure whether the depression is a byproduct of the sudden, unfortunate change in circumstances that patients find themselves in, or whether the depression is a direct consequence of brain damage.

Previous research by other groups indicated that anti-depressants help generate new brain cells and keep them healthy in healthy animals. That, together with the experience of his patients, led Huang to study the effects of the anti-depressant imipramine (also known as Tofranil) on mice that had injuries to their brains.

Scientists found that imipramine boosted the number of neurons in the hippocampus, the part of the brain primarily responsible for memory. By one measure, mice treated with imipramine had approximately 70 percent more neurons after four weeks than mice that did not receive the medication.

That change was borne out on behavioral tests as well. The team tested mice by using what scientists call a novel object recognition test. Like human infants, mice tend to spend more time sizing up objects that they haven't encountered before – or don't remember encountering – than they do objects that they've seen before. This gives scientists a way to measure a mouse's memory.

The team found that mice that had been treated with imipramine had a better memory. They were more likely to remember objects they had seen previously and so spent more time exploring truly novel objects, compared to mice that did not receive the compound. _PO

Improvement of memory in mice follows naturally from the boost in neurogenesis within the hippocampus -- a part of the brain which is key to laying down new memories, among other things.

The fact that brain damaged humans also show cognitive improvement after treatment with antidepressants, points the way to new research to augment neurogenesis after brain trauma, stroke, tumour, and other forms of brain damage.

It is interesting that both tofranil -- one of the oldest antidepressants -- and sertraline, a newer antidepressant, were found to be effective in growing new hippocampal neurons. This approach may be used as a screening tool for antidepressant research, as well as a means to rank to likely effectiveness of antidepressants already on the market.

More: This PDF research article from research teams in France and the US, describes a new approach to antidepressant and anti-anxiety treatment which may take a paradoxical approach to nerve growth when compared to the antidepressants described in the above studies. Anyone who is significantly interested in understanding possible deep brain mechanisms for effective antidepressant therapy should take a look. Keep in mind that it is a research article, using mice as subjects.

Cyborg or Grobyc? You Be the Judge

Nanonerves
Human brains are amazing mental machines. As far as we know, there is nothing else quite like it in the universe. But we always wonder whether perhaps, we could build something just a bit better? Observe all the excitement and expenditure, over the past 60+ years, directed toward "artificial intelligence." What a disappointment that has been so far.

For all the different approaches that have been taken to achieve machine intelligence, most of the failures share the same feature: they rely on algorithmic digital silicon logic. This seems a bit odd, when the only proof of concept of conscious intelligence we know of -- the human brain -- utilises a distinctly and entirely different type of logic.

Here is an interesting twist on the conundrum: Why not design a neuronal scaffolding out of nanotubes made of germanium and silicon, then allow neurons to grow within the scaffolding? The neurons will naturally make networked connections with each other along the scaffold, but an added bonus may be the ability to interface the neurons with the silicon-germanium substrate of the scaffold itself.

Graduate students at the University of Wisconsin, Madison, led by Minrui Yu, have published an ACS Nano paper, "Semiconductor Nanomembrane Tubes: Three-Dimensional Confinement for Controlled Neurite Outgrowth," in which they show that they have been able to successfully coax nerve cell tendrils to grow through tiny tubes made of the semi-conductor materials silicon and germanium. While this ground-breaking research may not portend cyborgs or even human brains enmeshed with computer parts, it does open the door to the possibility of regenerating nerve cells damaged due to disease or injury.

Yu and his team, led by Justin Williams, a biomedical engineer, created tubes of varying sizes and shapes, small enough for a nerve cell to glam on to, but not so big that it could fit all the way inside. The tubes were then coated with nerve cells from mice and then watched to see how they would react. Instead of sitting idly, the nerve cells began to send tendrils through the tunnels, as if searching for a path to something or somewhere else. In some instances they actually followed the contours of the tubes, which means, in theory, that the nerves could be grown into structures. _PO

Indeed. The nerves could be grown into structures along prescribed pathways. But the possibility of a functional and powerful brain-machine interface is also being considered.

The hope of course, in this type of research, is that a way can be found to connect a computer of some sort to a group of nerve cells to reestablish communication that has been disrupted. The computer in this case could serve as a relay of sorts, allowing those who can no longer walk, for example, due to spinal injury or disease, regain their former abilities. In that regard, this particular research is even more revealing than it might at first seem, due to the fact that the tiny tubes that have been created, very closely resemble myelin, the outer insulating sheath that covers parts of normal nerve cells. _PO

This is the actual goal of the researchers in Wisconsin: to grow a nerve:computer interface. This is one approach to the brain:machine, or cyborg approach to extreme rehabilitation, or even augmentation for emergency workers or military personnel.

Another approach which is even more exotic than described above, would be to grow an intricate "nano-neural web" into the intact brain structure, to create millions of interfaces to all of the important centers of the brain. The idea behind such a grown nano-structure, besides providing an external brain:machine interface, would be to allow the conscious mind access to unconscious brain functions.

Emergent phenomena are likely to grow from the humble beginnings of such an approach. Growing a nano-neuro web interface inside an intact brain might be easier than growing one outside the brain, in some ways. The "growth front" of the web would merely need to follow pre-existing pathways, and could be assisted by internal and external feedbacks.

Alternatively, one could grow a scaffolding in vitro, according to the most advanced brain imaging, seed it with the appropriate proto-cells, and nourish it into an intricate, functioning, autopoietic neural:nano hybrid network. Any conceivable shape and combination of connections between artificially grown brain centers would be possible -- at any arbitrary and chosen level of complexity. Such an artificial -- but living -- brain could be provided with a rudimentary circulatory system, and implanted into the control structure of very sophisticated and highly connected machines and structures.

Cyborg or Grobyc? You be the judge.

Adapted from an article at Al Fin, the Next Level

Like Nothing Else We Know

The conventional view of neurons is that synaptic inputs are integrated on a timescale of milliseconds to seconds in the dendrites, with action potential initiation occurring in the axon initial segment. We found a much slower form of integration that leads to action potential initiation in the distal axon, well beyond the initial segment. In a subset of rodent hippocampal and neocortical interneurons, hundreds of spikes, evoked over minutes, resulted in persistent firing that lasted for a similar duration. Although axonal action potential firing was required to trigger persistent firing, somatic depolarization was not. In paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell. Thus, these interneurons can slowly integrate spiking, share the output across a coupled network of axons and respond with persistent firing even in the absence of input to the soma or dendrites.
_Abstract NatureNeuroSci

Cortical Network Image Source
Our brains contain about 100 billion neurons, with about 10 billion of those in the neocortex. There are perhaps 40 million neurons in the hippocampus, naturally decreasing with age. Each neuron in the brain is a computer in itself. Connected together in cortical columns and short, medium, and long-range networks, the collection of neurons in a human brain possesses complexity of behaviour beyond comprehension. Science is still learning new things about how neurons function individually and in small groups.

Spruston and his team stimulated a neuron for one to two minutes, providing a stimulus every 10 seconds. The neuron fired during this time but, when the stimulation was stopped, the neuron continued to fire for a minute.

"It's very unusual to think that a neuron could fire continually without stimuli," Spruston said. "This is something new -- that a neuron can integrate information over a long time period, longer than the typical operational speed of neurons, which is milliseconds to a second."

This unique neuronal function might be relevant to normal process, such as memory, but it also could be relevant to disease. The persistent firing of these inhibitory neurons might counteract hyperactive states in the brain, such as preventing the runaway excitation that happens during epileptic seizures.

Spruston credits the discovery of the persistent firing in normal individual neurons to the astute observation of Mark Sheffield, a graduate student in his lab. Sheffield is first author of the paper.

The researchers think that others have seen this persistent firing behavior in neurons but dismissed it as something wrong with the signal recording. When Sheffield saw the firing in the neurons he was studying, he waited until it stopped. Then he stimulated the neuron over a period of time, stopped the stimulation and then watched as the neuron fired later.

"This cellular memory is a novelty," Spruston said. "The neuron is responding to the history of what happened to it in the minute or so before."

Spruston and Sheffield found that the cellular memory is stored in the axon and the action potential is generated farther down the axon than they would have expected. Instead of being near the cell body it occurs toward the end of the axon. _PO

The real complexity does not even arise until you go up at least a couple of logical levels of brain function from the neuron. So if science is still learning basic facts about neuronal function, it is likely that there is quite a bit left to learn at multiple levels.

Mammalian brains -- particularly primate and cetacean brains -- are amazing universes where spontaneous order is created out of chaos. The most adventurous of these brains wants to not only understand itself and its world: it wants to know what else is out there.

Oligodendroglial Progenitor Cells Suddenly Sprout Neurons!

The study identified the new pyramidal neurons in a part of the brain not typically associated with neurogenesis, the piriform cortex. The piriform cortex receives not only olfactory information, but also inputs from regions of the brain that are involved in emotion regulation and memory formation. Because of its privileged access to diverse brain regions, the piriform cortex is capable of tying odor representations to other types of information that are important for a wide range of behaviors. In animals and humans, activation in the piriform cortex is linked to odor memory and the emotional qualities of odors. In rodents, activity in this region is related to sexual behavior. _HND

Source

Scientists from UC Davis have discovered that neurons are being created from non-neuron progenitor cells in the brains of mice in early adulthood. These new neurons can apparently go on to play an important role in transmitting signals to "widespread" parts of the brain.

"We used to think that the sole destiny of oligodendroglial progenitor cells was to become myelin-forming oligodendroglia," Pleasure said. "Later it was shown that they also can generate other kinds of glial cells as well. We now have demonstrated that these oligodendroglial progenitor cells, which are widely distributed in the brain, and persist throughout life, also give rise to a group of large cerebral cortical neurons. Thus, oligodendroglial progenitor cells are truly multipotent."

The researchers found that precursors of glial cells, called proteolipid promoter-expressing NG2 progenitors (PPEPs, pronounced Pee-peps), give rise to glutamatergic pyramidal neurons, an important type of brain cell that sends long-range excitatory signals. PPEPs belong to a class of glial precursor cells called oligodendroglial progenitor cells (OPCs). These cells have been discovered only recently, and they hold tremendous promise for stem-cell regenerative medicine. They are the largest proliferating population of cells in the mammalian brain and spinal cord, and they could replace or repair injured cells.

“This study shows very definitively that PPEPs generate new neurons, that these new neurons have all the morphological and structural features which suggest that they are functionally integrated into the existing circuitry,” said Fuzheng Guo, the study’s lead author and a postdoctoral fellow in the Department of Neurology in the UC Davis School of Medicine.

...The current study follows findings published in 2009 that PPEPs in the immature mouse brain generate neurons in multiple regions, including the hippocampus and piriform cortex, and that these neurons survive into adulthood. They also found that PPEPs produced GABA-ergic interneurons in the immature brain. Prior to that study, scientists had assumed that the general class of glial precursor cells, called oligodendroglial progenitor cells (OPCs), could produce only glial cells, which create insulating sheets that wrap around neuronal projections and ensure speedy and reliable signal transmission. Instead, their results showed that these cells generate all three major cell types in the brain and spinal cord.

“Whether or not OPCs could form new neurons was not at all clear until our prior study,” Pleasure said.

The researchers focused on the piriform cortex in the current study because it was found to be a “hot spot” for PPEPs in the earlier study. The study was conducted using a genetic fate-mapping technique to track the lineage, or cell fates, of OPCs in the young adult brains of genetically-engineered mice. _HND

The study was in mice, but if similar mechanisms are at play in late adolescent and early adult humans, they might explain more of the differences between the adolescent and the adult brain.

We know that pathways of the brain develop over time, and that full maturation and myelinisation does not complete until the mid-twenties or slightly later. Late development of the pre-frontal cortex is probably part of the explanation for emotional and mental maturation in adulthood, but the development in early adulthood of new pathways involved in memory formation, emotional regulation, and sexual behaviours -- as described in the above study -- may provide deeper explanations into human emotional maturation.

Scientists will now have to look more carefully -- cast a wider net -- to try to understand the many nuances of brain development and the origination of new neurons and neuronal pathways. A few new answers, a lot of new questions.