Stanford scientists reveal complexity in the brain’s wiring diagram

When Joanna Mattis started her doctoral project she expected to map how two regions of the brain connect. Instead, she got a surprise. It turns out the wiring diagram shifts depending on how you flip the switch.

"There’s a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works," Mattis said. "It turns out it’s so much more dynamic than that."

Mattis is a co-first author on a paper describing the work published August 27 in the Journal of Neuroscience. Julia Brill, then a postdoctoral scholar, was the other co-first author.

Mattis had been a graduate student in the lab of Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, where she helped work on a new technique called optogenetics. That technique allows neuroscientists to selectively turn parts of the brain on and off to see what happens. She wanted to use optogenetics to understand the wiring of a part of the brain involved in spatial memory – it’s what makes a mental map of your surroundings as you explore a new city, for example.

Scientists already knew that when an animal explores habitats, two parts of the brain are involved in the initial exploring phase and then in solidifying a map of the environment – the hippocampus and the septum.

When an animal is exploring an environment, the neurons in the hippocampus fire slow signals to the septum, essentially telling the septum that it’s busy acquiring information. Once the animal is done exploring, those same cells fire off intense signals letting the septum know that it’s now locking that information into memory. The scientists call this phase consolidation. The septum uses that information to then turn around and regulate other signals going into the hippocampus.

"I wanted to study the hippocampus because on the one hand so much was already known – there was already this baseline of knowledge to work off of. But then the question of how the hippocampus and septum communicate hadn’t been accessible before optogenetics," Mattis said.

Neurons in the hippocampus were known to fire in a rhythmic pattern, which is a particular expertise of John Huguenard, a professor of neurology. Mattis obtained an interdisciplinary fellowship through Stanford Bio-X, which allowed her to combine the Deisseroth lab’s expertise in optogenetics with the rhythmic brain network expertise of Julia Brill from the Huguenard lab.

Mattis and Brill used optogenetics to prompt neurons of the hippocampus to mimic either the slow firing characteristic of information acquisition or the rapid firing characteristic of consolidation. When they mimicked the slow firing they saw a quick reaction by cells in the septum. When they mimicked the fast consolidation firing, they saw a much slower response by completely different cells in the septum.

Same set of wires – different outcome. That’s like turning on different lights depending on how hard you flip the switch. “This illustrates how complex the brain is,” Mattis said.

Most scientific papers answer a question: What does this protein do? How does this part of the brain work? By contrast, this paper raised a whole new set of questions, Mattis said. They more or less understand the faster reaction, but what is causing the slower reaction? How widespread is this phenomenon in the brain?

"The other big picture thing that we opened up but didn’t answer is: How can you then tie this back to the circuit overall and learning memory?" Mattis said. "Those would be exciting things to follow up on for future projects."

Your brain on speed: Walking doesn’t impair thinking and multitasking

When we’re strolling down memory lane, our brains recall just as much information while walking as while standing still—findings that contradict the popular science notion that walking hinders one’s ability to think.

University of Michigan researchers at the School of Kinesiology and the College of Engineering examined how well study participants performed a very complex spatial cognitive task while walking versus standing still.

"We’re saying that at least for this task, which is fairly complicated, walking and thinking does not compromise your thinking ability at all," said Julia Kline, a U-M doctoral candidate in biomedical engineering and first author on the study, which appears online in Frontiers in Human Neuroscience.

The finding surprised researchers, who expected to see decreased thinking performance with increased walking speed, Kline said. The 2011 best-selling book “Thinking Fast and Slow” suggests that because walking requires mental effort, walking may hinder our ability to think when compared to standing still.

"Past studies that have compared mental performance at a slow walking speed and standing have not found any differences, but our study is the first to show that the walking speed doesn’t matter," said Daniel Ferris, professor of kinesiology and biomedical engineering and senior author of the paper.

"Given the health benefits of walking, we should not discourage people from walking and thinking when they want."

Ferris offered one caveat: previous research has shown that walking performance can be impaired in the elderly when they dual-task during gait.

Ferris, Kline and Katherine Poggensee of U-M’s Human Neuromechanics Laboratory measured the ability of young, healthy participants to memorize numbers and their placement on a grid, and then enter those numbers correctly with a keypad while walking different speeds and standing still.

"Think of filling numbers one through nine on a tic-tac-toe grid and then remembering where they all are," Ferris said. "At every walking speed and standing still, participants entered about half the numbers correctly."

While speed didn’t change task performance, people took wider steps when performing the task than when they were only walking, which may be to compensate and stay balanced while concentrating, Kline said.

All participants showed increased activity in areas of the brain associated with spatial relationships and short-term memory during the cognitive task. In keeping with the U-M findings, a recent Stanford study suggested that walking fueled creativity.

In addition to good news for treadmill-desk users or people who like to think on the move, the study provides a useful scientific tool by demonstrating that it’s possible to collect accurate EEG data on moving subjects, Kline said.

This is important to researchers who study the brain and are concerned about getting accurate results when the subjects aren’t perfectly still. U-M researchers achieved their EEG results by applying different signal-processing techniques to eliminate the movement “noise” from the EEG signal.

Sensing subtle differences in the environment

The hippocampus is an important region of the brain that encodes spatial memory. It consists of a number of subfields that have specialized functions in memory storage and retrieval, but the precise role of some of the subfields remains unclear. Thomas McHugh and colleagues from the Laboratory for Circuit and Behavioral Physiology at the RIKEN Brain Science Institute have now discovered that in mice, the CA2 subfield senses small changes in the environment that are at odds with their spatial memory.

McHugh and his colleagues sought to determine the role of each subfield of the hippocampus in sensing familiar and new environments through a series of mouse experiments, focusing on the often overlooked CA2 subfield. They first exposed mice to a familiar environment, and then moved them back to their home cage. The researchers then either put the mice back in the first location or moved them to a new location that the mice had never experienced. 

The research team examined similarities and differences in the way hippocampal subfields responded to the two environments by a procedure known as catFISH—cellular compartment analysis of temporal activity by fluorescence in situ hybridization. This technique allows the timing of neuronal activity to be determined and permits the assessment of contextual memory by observing changes in response to environmental manipulations.

The researchers found that in most cases, there was more overlap in the response of hippocampal neurons in all subfields when the mice were replaced in the first location after their time in the home cage compared with placement in the new location. However, in mice with a mutation in the CA3 subfield that causes CA3 neuronal activity to be uncoupled from the animal’s sensory environment, the change in CA2 response to a novel environment did not appear. The finding suggests that the CA3 inputs to CA2 modulate the ability of CA2 to sense novel environments.

In a final experiment, the researchers introduced more subtle changes to the environments during the second placement by taking objects from one location to the other. A distinct change in CA2 neuronal activity was found during these exposure intervals as a response to more subtle changes to the animals’ environment. The CA2 subfield may therefore be the most sensitive to subtle differences between existing memories and new experiences. “In future studies, we plan to use genetic approaches to control CA2 activity in order to understand its direct effect on behavior,” says McHugh.

Cockatoos know what is going on behind barriers

For investigating spatial memory and tracking in animals and human infants a number of setups have been habitually used. These can roughly be subdivided depending on what is being moved: a desired object (food reward), the hiding places for this object or the test animal itself: In the original invisible displacement tasks, designed by French psychologist Jean Piaget in the 50s, the reward is moved underneath a small cup behind one or more bigger screens and its contents is shown in between visits: if the cup is empty we know that the reward must be behind the last screen visited. Humans solve this task after about two years of age, whereas in primates only the great apes show convincing results.

Likely to be even more challenging in terms of attention, are “Transposition” tasks: the reward is hidden underneath one of several equal cups, which are interchanged one or more times. Human children struggle with this task type more than with the previous and do not solve it reliably before the age of three to four years whereas adult apes solve it but have more trouble with double than single swaps.

In “Rotation” tasks several equal cups, one bearing a reward are aligned in parallel on a rotatable platform, which is rotated at different angles. “Translocation” tasks are similar except that the cups are not rotated but the test animal is carried around the arrangement and released at different angles to the cup alignment. Children find Translocation tasks easier than Rotation tasks and solve them at two to three years of age.

A team of international Scientists tested eight Goffin cockatoos (Cacatua goffini), a conspicuously inquisitive and playful species on visible as well as invisible Piagetian object displacements and derivations of spatial transposition, rotation and translocation tasks.  Birgit Szabo, one of the experimenters from the University of Vienna, says: “The majority of our eight birds readily and spontaneously solved Transposition, Rotation and Translocation tasks whereas only two out of eight choose immediately and reliably the correct location in the original Piagetian invisible displacement task in which a smaller cup is visiting two of three bigger screens”. Alice Auersperg, the manager of the Goffin Lab who was also one of the experimenters, explains: “Interestingly and just opposite to human toddlers our cockatoos had more problems solving the Piagetian invisible displacements than the transposition task with which children struggle until the age of four. Transpositions are highly demanding in terms of attention since two occluding objects are moved simultaneously. Nevertheless, in contrast to apes, which find single swaps easier than double the cockatoos perform equally in both conditions”.

Similarly, Goffins had little complications with Rotations and Translocation tasks and some of them solved them at four different angles. Again, in contrast to children, which find Translocations easier than Rotations, the cockatoos showed no significant differences between the two tasks. Auguste von Bayern from the University of Oxford adds: ” We assume that the ability to fly and prey upon or being preyed upon from the air is likely to require pronounced spatial rotation abilities and may be a candidate trait influencing the animals’ performance in rotation and translocation tasks”.

Thomas Bugnayer from the University of Vienna concludes: “Finding that Goffins solve transposition, rotation and translocation tasks, which are likely to pose a large cognitive load on working memory, was surprising and calls for more comparative data in order to better understand the relevance of such accurate tracking abilities in terms of ecology and sociality”.

Brain imaging study reveals our brains ‘divide and conquer’

University of Queensland (UQ) researchers have found human brains ‘divide and conquer’ when people learn to navigate around new environments.

The research by UQ’s Queensland Brain Institute (QBI) could provide hope for people with spatial memory impairments.

The study found that the mental picture people create to help navigate to a new location is split into two sections.

The size of the environment is coded by one area of the brain and its complexity is coded in another.

QBI postdoctoral research fellow and lead researcher Dr Oliver Baumann said the work shed new light on how learning the layout of a new environment, and then accessing this information from memory, was represented in the brain.

“We’ve known for some time that a part of the brain called the hippocampus is important for building and maintaining cognitive maps,” he said.

“The results of our study have shown for the first time that different aspects of a learned environment – specifically its size and complexity – are represented by distinct areas within the hippocampus.”

QBI Cognitive Neuroscience Laboratory Head Professor Jason Mattingley said the findings could have important implications for people suffering from spatial memory impairments.

“This research is important for understanding how our brain normally stores and manages spatial information,” Professor Mattingley said.

“It also gives us clues as to why people with memory loss due to Alzheimer’s disease often become lost in new or previously familiar surroundings.”

Dr Baumann said 18 people navigated their way through three virtual mazes that differed either in the number of corridors through which they could travel or the length of the corridors.

After learning the task, the participants were asked to recall mental maps from each of the mazes while their brain activity was measured using functional magnetic resonance imaging.

“We found that one region in the hippocampus was more active when participants recalled a complex maze in which there were many corridors to choose from, irrespective of the overall size of the maze,” Dr Baumann said.

“Conversely, we found that a separate area of the hippocampus was more active when the overall size of the maze increased, regardless of the number of corridors.”

The study, “Dissociable representations of environmental size and complexity in the human hippocampus”, is published in The Journal of Neuroscience.

(Image: iStockphoto)

Scientists reveal drinking champagne could improve memory

New research shows that drinking one to three glasses of champagne a week may counteract the memory loss associated with ageing, and could help delay the onset of degenerative brain disorders, such as dementia.

Scientists at the University of Reading have shown that the phenolic compounds found in champagne can improve spatial memory, which is responsible for recording information about one’s environment, and storing the information for future navigation.

The compounds work by modulating signals in the hippocampus and cortex, which control memory and learning. The compounds were found to favourably alter a number of proteins linked to the effective storage of memories in the brain. Many of these are known to be depleted with age, making memory storage less efficient, and leading to poorer memory in old age and conditions such as dementia. Champagne slows these loses and therefore may help prevent the cognitive losses that occur during typical and atypical brain ageing.

Champagne has relatively high levels of phenolics compared to white wine, deriving predominantly from the two red grapes, Pinot Noir and Pinot Meunier, which are used in its production along with the white grape Chardonnay. It is these phenolic compounds which are believed to be responsible for the beneficial effects of champagne on the brain.

Professor Jeremy Spencer, Department of Food and Nutritional Sciences, University of Reading, said: “These exciting results illustrate for the first time that the moderate consumption of champagne has the potential to influence cognitive functioning, such as memory. Such observations have previously been reported with red wine, through the actions of flavonoids contained within it. 

"However, our research shows that champagne, which lacks flavonoids, is also capable of influencing brain function through the actions of smaller phenolic compounds, previously thought to lack biological activity. We encourage a responsible approach to alcohol consumption, and our results suggest that a very low intake of one to two glasses a week can be effective."

Dr. David Vauzour, the researcher on the study, added: “in the near future we will be looking to translate these findings into humans. This has been achieved successfully with other polyphenol-rich foods, such as blueberry and cocoa, and we predict similar outcomes for moderate Champagne intake on cognition in humans.”   

Previous research from the University of Reading revealed that two glasses of champagne a day may be good for your heart and circulation and could reduce the risks of suffering from cardiovascular disease and stroke.

The paper is published in Antioxidants and Redox Signalling.

(Image: Getty)

Neural Activity in Bats Measured In Flight

Animals navigate and orient themselves to survive – to find food and shelter or avoid predators, for example. Research conducted by Dr. Nachum Ulanovsky and research student Michael Yartsev of the Weizmann Institute’s Neurobiology Department, published today in Science, reveals for the first time how three-dimensional, volumetric, space is perceived in mammalian brains. The research was conducted using a unique, miniaturized neural-telemetry system developed especially for this task, which enabled the measurement of single brain cells during flight.

The question of how animals orient themselves in space has been extensively studied, but until now experiments were only conducted in two-dimensional settings. These have found, for instance, that orientation relies on “place cells” – neurons located in the hippocampus, a part of the brain involved in memory, especially spatial memory. Each place cell is responsible for a spatial area, and it sends an electrical signal when the animal is located in that area. Together, the place cells produce full representations of whole spatial environments. Unlike the laboratory experiments, however, the navigation of many animals in the real world, including humans, is carried out in three dimensions. But attempts to expand the scope of experiments from two to three dimensions had encountered difficulties.

One of the more famous efforts in this area was conducted by the University of Arizona and NASA, in which they launched rats into space (aboard a space shuttle). However, although the rats moved around in zero gravity, they ran along a set of straight, one-dimensional lines. Other experiments with three-dimensional projections onto two-dimensional surfaces did not manage to produce volumetric data, either. The conclusion was that in order to understand movement in three-dimensional, volumetric space, it is necessary to allow animals to move through all three dimensions – that is, to research animals in flight.

Ulanovsky chose to study the Egyptian fruit bat, a very common bat species in Israel. Because these are relatively large, the researchers were able to attach the wireless measuring system in a manner that did not restrict the bats’ movements. Developing this sophisticated measuring system was a several-year effort. Ulanovsky, in cooperation with a US commercial company, created a wireless, lightweight (12 g, about 7% of the weight of the bat) device containing electrodes that measure the activity of individual neurons in the bat’s brain.

The next challenge the scientists faced was adapting the behavior of their bats to the needs of the experiment. Bats naturally fly toward their destination – for example, a fruit tree – in a straight line. In other words, their normal flight patterns are one-dimensional, while the experiment required their flights to fill a three-dimensional space.

The solution was to be found in a previous study in Ulanovsky’s group, which tracked wild fruit bats using miniature GPS devices. One of the discoveries was that when bats arrive at a fruit tree, they fly around it, utilizing the full volume of space surrounding the tree. To simulate this behavior in the laboratory – an artificial cave equipped with an array of bat-monitoring devices – the team installed an artificial “tree” made of metal bars and cups filled with fruit.

Measuring the activity of hippocampus neurons in the bats’ brains revealed that the representation of three-dimensional space is similar to that in two dimensions: Each place cell is responsible for identifying a particular spatial area in the “cave” and sends an electrical signal when the bat is located in that area. Together, the population of place cells provides full coverage of the cave – left and right, up and down.

A closer examination of the areas for which individual place cells are responsible provided an answer to a highly-debated question: Does the brain perceive the three dimensions of space as “equal,” that is, does it sense the height axis in the same way as that of length or width? The findings suggest that each place cell responds to a spherical volume of space, i.e., the perception of all three dimensions is uniform. The researchers note that for those non-flying animals that essentially move in flat space, the different axes might not be perceived at the same resolution. It may be that such animals are naturally more sensitive to changes along the length and width axes than that of height. This question is of particular interest when it comes to humans because on the one hand, humans evolved from apes that moved in three-dimensional space when swinging from branch to branch, but on the other hand, modern, ground-dwelling humans generally navigate in two-dimensional space.

The findings provide new insights into some basic functions of the brain: navigation, spatial memory and spatial perception. To a large extent, this is due to the development of innovative technology that allowed the first glimpse into the brain of a flying animal. Ulanovsky believes that this trend, in which research is becoming more “natural,” is the future wave of neuroscience.

Mapping blank spots in the cheeseboard maze

IST Austria Professor Jozsef Csicsvari together with collaborators succeeds in uncovering processes in which the formation of spatial memory is manifested in a map representation • Researchers investigate timescale of map formation • Inhibitory interneurons possibly involved in selection of map

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O’Neill, postdoc in Csicsvari’s group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called “place cells”. A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations “flicker”, with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection – helping one map dominate and take over during learning, so that the relevant information is encoded.