Exploring How the Nervous System Develops

Neurons Get Their Neighbors To Take Out Their Trash

Biologists have long considered cells to function like self-cleaning ovens, chewing up and recycling their own worn out parts as needed. But a new study challenges that basic principle, showing that some nerve cells found in the eye pass off their old energy-producing factories to neighboring support cells to be “eaten.” The find, which may bear on the roots of glaucoma, also has implications for Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and other diseases that involve a buildup of “garbage” in brain cells.

The study was led by Nicholas Marsh-Armstrong, Ph.D., a research scientist at the Kennedy Krieger Institute and an associate professor in the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, together with Mark H. Ellisman, Ph.D., a neuroscience professor at the University of California, San Diego. In a previous study, the two had seen hints that retinal ganglion cells, which transmit visual information from the eye to the brain, might be handing off bits of themselves to astrocytes, cells that surround and support the eye’s signal-transmitting neurons. They appeared to pass them to astrocytes at the optic nerve head, the beginning of the long tendril that connects retinal ganglion cells from the eye to the brain. Specifically, they suspected that the neuronal bits being passed on were mitochondria, which are known as the powerhouses of the cell.

To find out whether this was really the case, Marsh-Armstrong’s research group genetically modified mice so that they produced indicators that glowed in the presence of chewed up mitochondria. Ellisman’s group then used cutting-edge electron microscopy to reconstruct 3-D images of what was happening at the optic nerve head. The researchers saw that astrocytes were, indeed, breaking down large numbers of mitochondria from neighboring retinal ganglion cells.

“This was a very surprising study for us, because the findings go against the common understanding that each cell takes care of its own trash,” says Marsh-Armstrong. It is particularly interesting that the newly discovered process occurs at the optic nerve head, he notes, as that is the site thought to be at fault in glaucoma. He plans to investigate whether the mitochondria disposal process is relevant to this disease, the second leading cause of blindness worldwide.

But the implications of the results go beyond the optic nerve head, Marsh-Armstrong says, as a buildup of “garbage” inside cells causes neurodegenerative diseases such as Parkinson’s, Alzheimer’s and ALS. “By showing that this type of alternative disposal happens, we’ve opened up the door for others to investigate whether similar processes might be happening with other cell types and cellular parts other than mitochondria,” he says.

Self-repairing mechanism helps to preserve brain function in neurodegenerative diseases

New research, led by scientists at the University of Southampton, has found that neurogenesis, the self-repairing mechanism of the adult brain, can help to preserve brain function in neurodegenerative diseases such as Alzheimer’s, Prion or Parkinson’s.

The progressive degeneration and death of the brain, occurring in many neurodegenerative diseases, is often seen as an unstoppable and irrevocable process. However, the brain has some self-repairing potential that accounts for the renewal of certain neuronal populations living in the dentate gyrus, a simple cortical region that is part of the larger functional brain system controlling learning and memory, the hippocampus. This process is known as neurogenesis.

While increased neurogenesis has been reported in neurodegenerative diseases in the past, its significance is unclear. Now a research team, led by Dr Diego Gomez-Nicola from the Centre for Biological Sciences at the University of Southampton, has detected increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss.

Using a model of prion disease from mice, the research identified the time-course of the generation of these newborn neurons and how they integrate into the brain circuitry. While this self-repairing mechanism is effective in maintaining some neuronal functions at early and mid-stages of the disease, it fails at more advanced phases. This highlights a temporal window for potential therapeutic intervention, in order to preserve the beneficial effects of enhanced neurogenesis.

Dr Gomez-Nicola says: “This study highlights the latent potential of the brain to orchestrate a self-repairing response. The continuation of this line of research is opening new avenues to identify what specific signals are used to promote this increased neurogenic response, with views focused in targeting neurogenesis as a therapeutic approach to promote the regeneration of lost neurons.”

Hippocampal activity during music listening exposes the memory-boosting power of music

For the first time the hippocampus—a brain structure crucial for creating long-lasting memories—has been observed to be active in response to recurring musical phrases while listening to music. Thus, the hippocampal involvement in long-term memory may be less specific than previously thought, indicating that short and long-term memory processes may depend on each other after all.

The study was conducted at the University of Jyväskylä and the AMI Center of Aalto University, by a group of researchers led by Academy Professor Petri Toiviainen, the Finnish Centre for Interdisciplinary Music Research (CIMR) at the University of Jyväskylä, and Dr. Elvira Brattico, Aalto University and the University of Helsinki. Results of the study were published in Cortex, a journal devoted to the study of the nervous system and behaviour.

“Our study basically shows an increase of activity in the medial temporal lobe areas—best known for being essential for long term memory—when musical motifs in the piece were repeated. This means that the lobe areas are engaged in the short-term recognition of musical phrases,” explains Iballa Burunat, the leading author of the study. Dr. Brattico adds: “Importantly, this hadn’t been observed before in music neuroscience.”

A fundamental highlight of the study is the use of a setting that is more natural than those traditionally employed in neuroscience: the participants’ only task was to attentively listen to an Argentinian tango from beginning to end. This kind of music provides well-defined, salient musical motifs that are easy to follow. They can be used to study recognition processes in the brain without having to resort to sound created in a lab. By using this more realistic approach, the researchers were able to identify brain areas involved in motif tracking without having to rely on the participants’ ability to self-report, which would have constrained the study of brain processes.

“We think that our novel method allowed us to uncover this phenomenon. In other words, the identified areas may also be related to the formation of a more permanent memory trace of a musical piece, enabled precisely by the very use of a real-life stimulus (the recording of a live performance) in a realistic situation where participants just listen to the music as their brain responses are recorded,” Iballa Burunat goes on to explain. Listening to the music from beginning to end may have imprinted the participants with a long lasting memory of the tune. This might not be expected were the participants exposed to a simpler stimulus in controlled conditions, as is the case in most studies in music and memory.

Although a real-life setting may be sufficient to trigger the involvement of the hippocampus, another explanation could lie in music’s capacity to elicit emotions. “We cannot ignore music’s emotional power which is thought to be crucial for the mnemonic power of music as to how and what we remember. There is evidence on the robust integration of music, memory and emotion—take for instance autobiographical memories. So it wouldn’t be surprising that the emotional content of the music may well have been a factor in triggering these limbic responses,” she continues. This makes sense, since the chosen musical piece by Astor Piazzolla was a tribute to his father after his sudden death, and so the main purpose of the piece was to be of a deeply emotional nature”. Certainly, the hippocampus—as part of the limbic system—is connected to neural circuitry involved in emotional behavior, and ongoing research suggests that emotional events seem to be more memorable than neutral ones. The authors emphasize that these results should motivate similar approaches to study verbal or visual short term memory by tracking the themes or repetitive structures of a given stimulus. Moreover, the study has implications for neurodegenerative diseases associated with hippocampal atrophy, like Alzheimer’s. “Music may positively affect patients if used wisely to stimulate their hippocampi, and thus their memory system,” Academy Professor Petri Toiviainen indicates. A better understanding of the link between music and memory could have widespread repercussions, leading to novel interventions to rehabilitate or improve the life quality of patients with neurodegenerative conditions.

Blocking brain’s ‘internal marijuana’ may trigger early Alzheimer’s deficits

When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input — such as might accompany falling into a hole, burning one’s finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell “cat” — are firmly stored in the brain’s memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells — effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of “wet blanket” nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells’ transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance — the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

Passing along the message

But when the news is particularly significant, pyramidal cells squirt out their own “no, this is important, you shut up!” chemical — endocannabinoids — which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.

Exactly how A-beta blocks endocannabinoids’ action is not yet known. But, Madison’s group demonstrated, A-beta doesn’t stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car’s ignition switch won’t do much good if your battery is dead.)

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

Besides, flooding the brain with external cannabinoids induces tolerance — it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids’ ability to do their crucial job of opening the gates of learning and memory.

Study examines how brain ‘reboots’ itself to consciousness after anesthesia

One of the great mysteries of anesthesia is how patients can be temporarily rendered completely unresponsive during surgery and then wake up again, with all their memories and skills intact.

A new study by Dr. Andrew Hudson, an assistant professor of anesthesiology at the David Geffen School of Medicine at UCLA, and colleagues provides important clues about the processes used by structurally normal brains to navigate from unconsciousness back to consciousness. Their findings are currently available in the early online edition of Proceedings of the National Academy of Sciences.

Previous research has shown that the anesthetized brain is not “silent” under surgical levels of anesthesia but experiences certain patterns of activity, and it spontaneously changes its activity patterns over time, Hudson said.

For the current study, the research team recorded the brain’s electrical activity in a rodent model that had been administered the inhaled anesthesia isoflurane by placing electrodes in several brain areas associated with arousal and consciousness. They then slowly decreased the amount of anesthesia, as is done with patients in the operating room, monitoring how the electrical activity in the brain changed and looking for common activity patterns across all the study subjects.

The researchers found that the brain activity occurred in discrete clumps, or clusters, and that the brain did not jump between all of the clusters uniformly.

A small number of activity patterns consistently occurred in the anesthetized rodents, Hudson noted. The patterns depended on how much anesthesia the subject was receiving, and the brain would jump spontaneously from one activity pattern to another. A few activity patterns served as “hubs” on the way back to consciousness, connecting activity patterns consistent with deeper anesthesia to those observed under lighter anesthesia.

"Recovery from anesthesia, is not simply the result of the anesthetic ‘wearing off’ but also of the brain finding its way back through a maze of possible activity states to those that allow conscious experience," Hudson said. "Put simply, the brain reboots itself."

The study suggests a new way to think about the human brain under anesthesia and could encourage physicians to reexamine how they approach monitoring anesthesia in the operating room. Additionally, if the results are applicable to other disorders of consciousness — such as coma or minimally conscious states — doctors may be better able to predict functional recovery from brain injuries by looking at the spontaneously occurring jumps in brain activity.

In addition, this work provides some constraints for theories about how the brain leads to consciousness itself, Hudson said.

Going forward, the UCLA researchers will test other anesthetic agents to determine if they produce similar characteristic brain activity patterns with “hub” states. They also hope to better characterize how the brain jumps between patterns.