At Brookhaven, researchers combined light-activated proteins that stimulate specific brain cells, a technique known as optogenetics, with positron emission tomography (PET) to observe the effects of stimulation throughout the entire brain. Their paper in the Journal of Neuroscience describes this method, which will allow researchers to map exactly which neurological pathways are activated or deactivated downstream by stimulation in specific brain areas. Hopefully, following these pathways will enable researchers to correlate the brain activity with observed behaviors or certain symptoms of disease.

Three markers on the head of a mouse enable the AwakeSPECT system to obtain functional images of the brain of a conscious mouse as it moves around. (Credit: Image courtesy of DOE/Thomas Jefferson National Accelerator Facility)

Scientists at Oak Ridge used dynamic imaging in mice to examine changes in brain chemistry caused by disease or application of a drug. They hope this research tool will be used to develop better disease diagnostics as well as better treatments. The newest aspect of this study, however, is that unlike most nuclear imaging studies where laboratory mice are drugged or kept in place so that their brains can be studied, the new technique allows for moving subjects. The researchers from Jefferson Lab, Oak Ridge, Johns Hopkins and Maryland used their new system to obtain functional images of the brains of conscious mice that were free to move. The system, called AwakeSPECT (Awake Single-Photon Emission Computed Tomography),  was then used to examine the effects of anesthesia on the action of a dopamine transporter in the mouse brain for the first time. These types of dopamine transporter imaging compounds are used for Alzheimer’s, dementia and Parkinson’s disease studies. The technique entails injection of a radionuclide, which gathers in targeted areas of the brain. The radionuclide emits gamma rays that are detected in separate scans from many different angles, all of which are combined by an algorithm to produce a three-dimensional image.

Martin Pomper led a group of researchers at Johns Hopkins Medical School to conduct the first mouse imaging studies with the new system. Their study showed that AwakeSPECT can be used to obtain detailed, functional images of the brain in a conscious mouse that was able to move freely around in an enclosed space. “We’ve shown the technology works. Now, you just have to make it a tool that more people will readily use” says Jefferson Lab’s Drew Weisenberger, who led the multi-institutional collaboration that created the novel technique.

One area of active research that would benefit from such imaging techniques is the question of how animals orient themselves in space. Existing experiments have all looked at how animals move around in two-dimensional settings and they have made the important discovery of place cells, neurons located in the hippocampus responsive to spatial orientation. Populations of place cells working together can produce full representations of an animal’s environment, the only problem being that in the real world animals have to navigate in three dimensions unlike the laboratory experiments. That’s why Dr. Nachum Ulanovsky of the Weizmann’s Institute’s Neurobiology Department chose to study the Egyptian fruit bat to look at how three-dimensional space is perceived in mammalian brains for the first time. His research used a miniaturized neural-telemetry system developed especially for this task, which enabled the measurement of single brain cells during flight. The activity of the  hippocampal neurons in the bats’ brains showed that the representation of three-dimensional space is just like in two dimensions: each place cell is responsible for identifying a particular spatial area in space and sends an electrical signal when the bat is located in that area. The population of place cells provides full coverage of the particular area, say a cave, left, right, forward, back, up and down.

These results give new insights into navigation, spatial memory and spatial perception, all basic functions of the mammalian brain. The study’s success is due to the development of the technology that allowed looking into the brain of a flying animal. Single cell measurement is only the first step, looking at neural circuits can reveal much more about how these place cell representations are then used in conjunction with other brain areas resulting in the behavior we see. Development of new brain imaging techniques continues to provide a more complete understanding of basic human and animal behaviors, and hopefully one day will lead to a full understanding of the human brain.

-Leo Shapiro

Sources:

Lights, Chemistry, Action: New Method for Mapping Brain Activity – ScienceDaily

System Provides Clear Brain Scans of Awake, Unrestrained Mice – ScienceDaily

Neural Activity in Bats Measured In-Flight – ScienceDaily

Inside of you there are 10¹³ human cells and 10¹⁴ bacteria cells.

In other words, for every one cell of you there are ten that are not you…Wait, what? The first question this recent discovery may fuel is a stumbled WHAT? But lets digress for a moment and ask, why?

The initial visceral curiosity here arises from one major assumption that the Western psyche makes about the world, that I am an individual and am derived in my current form from the process of competitive selection. The reality however, is that none of us are individuals and we are all derived not just from natural selection, but from collaborative efforts between tens of thousands of species of organisms acting in symphony to produce the emergent concert that is: us. That may be a bit heavy. Let me explain.

Again, there are ten times the number of bacterial cells throughout the human body and they are mostly centralized to the digestive tract. This internal ecosystem of microbial flora is referred to as one’s “microbiome”. Each person’s microbiome is different, in a similar way that we are all different. The distribution of species in the digestive tract reflects one’s life experiences, adventures and location of upbringing. For example, the typical gut flora of a person raised in the United States has more bacteria specialized in processing fat and protein. This is in part why people immigrating to the United States often have problems with gaining weight in the first few years, because their microbial counterparts are ill-equipped at handling the amount of fat in American foods.

Another astonishing example of this “microbial footprinting” is in the microbiomes of people who have lived their entire lives in Japan where seaweed is a dietary staple. Throughout the world the microbe Bacteroides plebeius has been observed in the gut of various people. Curiously however, the B. plebeius microbe in some Japanese people has incorporated a gene passed to it, via horizontal gene transfer, from Zobellia galactanivorans, a marine bacterium. The gene in the Japanese form of B. plebeius expresses enzymes specializing in the degradation of certain polysaccharides found in seaweed. Implications for the exhausted “Nature vs. Nurture” debate abound, these findings are Earth-shattering in more ways than the hands can hold. Oh, by the way, this doesn’t stop at digestion.

Bacteria Are Everywhere in the Human Body

The real sexy aspect of this new vein of research is the implications for the behavioral sciences. In 2011, a series of papers came out linking a lack of adequate gut microbial populations to an anxiety disorder. Researchers raised a brood of mice in a germ-free environment, i.e. from birth they had little to no exposure to the typical microbial populations they may encounter, and the results were a bit unsettling. The researchers noted significant defects in the development of the Amygdala which subsequently showed in behavioral studies that the sterile mice had major issues with anxiety and depression. In another similar study, it was shown that feeding normal mice probiotic bacteria significantly reduces depression-like behavior.

Right now, this is the biggest emerging area of research worldwide. Finally, the notion that we are not individuals, but emergent structures of ecosystems is taking hold. The result of such novel understanding is entirely uninformed and preemptive attempts at targeting this new world to cure and change. Currently, probiotic medicines are starting to crop up, each of which will soon be shown to have more “side effects” than efficacy in the expected. When we make a discovery, we immediately assume we understand how to manipulate the system, unaware of how the vastly complex structures we are changing. We are always confidently overzealous. These recent discoveries are awesome, they really are, but I want to stress that we cannot let our zeal overtake us. This time around, we must admit a lack of understanding and re-realize the feeling of awe. Again, upwards of 40,000 different species of bacteria, right inside of you, are talking to one another; buffering carcinogens and reward hormones, digesting cellulose, fermenting, interacting in ways we really will never know although they may be helping “us”!

“We” would not be alive if it were not for our microbial brethren. Let me pose this question: Is taking the step to understand this internal ecosystem the next step in consciousness. Until now, we have had a very elementary understanding of who we are and why we are who we are. Is this the next step?

- Jesse Bryant

Animals in a microbial world, a new imperative for the life sciences – McFall-Ngai et al. 2012 PNAS

Mood and gut feelings – Forsythe et al. 2009 Elsevier

An ecological and evolutionary perspective on human-microbe mutualism and disease – Dethlefsen et al. 2007 Nature

“Man had always assumed that he was more intelligent than dolphins because he had achieved so much — the wheel, New York, wars and so on — whilst all the dolphins had ever done was muck about in the water having a good time. But conversely, the dolphins had always believed that they were far more intelligent than man — for precisely the same reasons….In fact there was only one species on the planet more intelligent than dolphins, and they spent a lot of their time in behavioural research laboratories running round inside wheels and conducting frighteningly elegant and subtle experiments on man. The fact that once again man completely misinterpreted this relationship was entirely according to these creatures’ plans.” – Douglas Adams, The Hitchhiker’s Guide to the Galaxy

As tempting as it may be to believe the science fiction version of the intelligence rankings, real-life science has spoken and suggests (much to my displeasure) that humans may actually be the highest on the intelligence scale.

Glia are non-neuronal cells found in the brain mainly described as performing “housekeeping” functions, for example, providing structural support to neurons, and providing them with nutrients. Astrocytes are a specific type of glia, and as one might hypothesize, they are bigger in humans than in mice. Was this just a consequence of humans having more complex brains, or do these astrocytes have different functions in humans beyond the basic housekeeping functions? To test this, scientists grafted human astrocyte progenitor cells into developing mouse brains to create chimeric mice.

Human astrocyte (green) and mouse astrocyte (red)

The human astrocytes that matured successfully matured as human cells; characteristics such as their size were unaffected by being in a mouse environment. But they did not remain completely foreign – they successfully formed electrical connections with the mouse cells. Their differing cellular properties were thus propagated into the mouse neural networks. Of particular interest is the hippocampus, the brain region important for learning and memory. Chimeric hippocampal slices had a higher level of baseline excitatory activity, and long-term potentiation (LTP), or synapse strengthening, was much greater. At the molecular level, this can be explained because the human cells express higher levels of a protein that promotes an increased number of glutamate receptors at the synapse.

There were also clear differences in the behavior of chimeric mice. Experiments were performed to test learning and memory abilities to corroborate the cellular results observed in the hippocampus. A classic fear conditioning experiment involves pairing a tone with a foot shock; mice learn to associate the two and exhibit freezing behavior after hearing a tone. Chimeras learned the association after only one tone/shock pairing. The learning persisted for several days, during which time control animals did not learn the initial association. The experiment was repeated as context fear conditioning, meaning that the mice were placed in different chambers that had varying floors and odors. Chimeric mice were able to differentiate between chambers significantly better than their control counterparts. In other learning and memory tasks, these mice learned their way through mazes faster and were better at familiar object recognition in novel contexts.

The results of this study show that glial cells have much more function beyond their basic housekeeping properties. A single cell graft manipulation was enough to significantly improve mouse performance on learning and memory tasks. Complexity of these cells has evolved with the brain, and this provides important new insight on how exactly this complexity has come to be. Future experiments could involve grafting chimpanzee or macaque glia, any differences observed could be key in outlining how our processing abilities evolved from our monkey fathers (I additionally support research with dolphin glia grafts, keeping on the theme of the three most intelligent species). Unfortunately, without the higher processing abilities made possible by human cells, mice likely cannot achieve the tasks and level of status they exhibit in the science fiction. It seems as though man has indeed correctly interpreted his relationship with the mouse.

So long, and thanks for all the fish.

-Reena Clements

References:

Human Brain Cells Boost Mouse Memory – ScienceNOW

Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice – Cell Stem Cell