Too much activity in certain areas of the brain is bad for memory and attention

memory deficits

Don’t Forget.

Neurons in the brain interact by sending each other neurotransmitters, of which gamma-aminobutyric acid (GABA) is the most common inhibitory one. GABA is important to restrain neural activity, preventing neurons from getting too trigger-happy and from firing too much or responding to irrelevant stimuli.

Researchers led by Dr Tobias Bast in the School of Psychology at The University of Nottingham have found that faulty inhibitory neurotransmission and abnormally increased activity in the hippocampus impairs our memory and attention.

Their latest research, published in the academic journal Cerebral Cortex, has implications for understanding cognitive deficits in a variety of brain disorders, including schizophrenia, age-related cognitive decline and Alzheimer’s, and for the treatment of cognitive deficits.

The hippocampus plays a major role in our everyday memory of events and of where and when they happen—for example remembering where we parked our car before going shopping.

This research has shown that a lack of restraint in the neural firing within the hippocampus disrupts hippocampus-dependent memory; in addition, such aberrant neuron firing within the hippocampus also disrupted attention—a cognitive function that does not normally require the hippocampus.

Increased activity can be more detrimental than reduced activity

Dr Bast, said: “Our research carried out in rats highlights the importance of GABAergic inhibition within the hippocampus for memory performance and for attention. The finding that faulty inhibition disrupts memory suggests that memory depends on well-balanced neural activity within the hippocampus, with both too much and too little causing impairments. This is an important finding because traditionally, memory impairments have mainly been associated with reduced activity or lesions of the hippocampus.

“Our second important finding is that faulty inhibition leading to increased neural activity within the hippocampus disrupts attention, a cognitive function that does not normally require the hippocampus, but depends on the prefrontal cortex. This probably reflects that there are very strong neuronal connections between hippocampus and prefrontal cortex. Our finding suggests that aberrant hippocampal activity has a knock-on effect on the prefrontal cortex, thereby disrupting attention.”

“Overall, our new findings show that increased activity of a brain region, due to faulty inhibitory neurotransmission, can be more detrimental to cognitive function than reduced activity or a lesion. Increased activity within a brain region can disrupt not only the function of the region itself—in this case hippocampus-dependent memory—but also the function of other regions to which it is connected—in this case prefrontal cortex-dependent attention.”

Adding to existing research findings

Dr Bast’s research is motivated by recent clinical findings that patients in early stages of schizophrenia, age-related cognitive decline and Alzheimer’s show faulty inhibition and increased activity within the hippocampus. The new study, where inhibition in the hippocampus of rats was disrupted before the animals took part in tests of attention and memory, revealed that such faulty inhibition and aberrant activity within the hippocampus causes the type of memory and attentional impairments seen in patients.

This research adds to the team’s recent findings, where they found that attention was disrupted by faulty inhibition and increased activity within the prefrontal cortex, a brain region important for attention.

Dr Bast, said: “Overall, these findings highlight that higher brain functions, such as attention and memory, depend on well-balanced neural activity within the underlying brain regions.”

Potential target for new treatments

This research has important implications for treating cognitive impairments.

The findings show that simply ‘boosting’ the activity of the key memory and attention centres in the brain (the hippocampus and prefrontal cortex), which has been a long-standing strategy for cognitive enhancement, will not necessarily improve memory and attention, but can actually impair these functions. What’s important is to re-balance activity within these regions.

Dr Bast, said: “One emerging idea is that early stages of cognitive disorders, such as schizophrenia and age-related cognitive decline and Alzheimer’s, are characterised by faulty inhibition and too much activity; this excess neural activity leads then to neuronal damage and the reduced brain activity characterizing later stages of these disorders. So, rebalancing aberrant activity early on may not only restore attention and memory, but also prevent further decline.

“We have new studies on the way where we aim to identify medicines that might be able to re-balance neural activity within hippocampus and prefrontal cortex and to restore memory and attention.”

Brain Researchers Discover How Retinal Neurons Claim the Best Connections

Discovery may shed light on brain disease, development of regenerative therapies

Real estate agents emphasize location, location, and – once more for good measure – location. It’s the same in a developing brain, where billions of neurons vie for premium property to make connections. Neurons that stake out early claims often land the best value, even if they don’t develop the property until later.

Scientists at the Virginia Tech Carilion Research Institute and the University of Louisville have discovered that during neurodevelopment, neurons from the brain’s cerebral cortex extend axons to the edge of the part of the brain dedicated to processing visual signals – but then stop. Instead of immediately making connections, the cortical neurons wait for two weeks while neurons from the retina connect to the brain.

Now, in a study to be published in the Nov. 14 issue of the journal Cell Reports, the scientists have discovered how. The retinal neurons stop their cortical cousins from grabbing prime real estate by controlling the abundance of a protein called aggrecan.

Understanding how aggrecan controls the formation of brain circuits could help scientists understand how to repair the injured brain or spinal cord after injury or disease.

“Usually when neuroscientists talk about repairing injured brains, they’re thinking about putting neurons, axons, and synapses back in the right place,” said Michael Fox, an associate professor at the Virginia Tech Carilion Research Institute and lead author of the study. “It may be that the most important synapses – the ones that drive excitation – need to get there first. By stalling out the other neurons, they can get the best spots. This study shows that when we think about repairing damaged neural networks, we need to consider more than just where connections need to be made. We also need to think about the timing of reinnervation.”

The researchers genetically removed the retinal neurons, which allowed the cortical axons to move into the brain earlier than they normally would.

“We were interested in what environmental molecular cues allow the retinal neurons to control the growth of cortical neurons,” said Fox, who is also an associate professor of biological sciences in Virginia Tech’s College of Science. “After years of screening potential mechanisms, we found aggrecan.”

Aggrecan is a protein that has been well studied in cartilage, bones, and the spinal cord, where it is abundant after injuries. According to Fox, aggrecan may be able to isolate damaged areas of the spinal cord to stop inflammation and prevent further destruction. The downside, however, is that aggrecan inhibits axonal growth, which prevents further repair from taking place.

Axons see this environment and either stop growing or turn around and grow in the opposite direction,” said Fox.

Although it is less studied in the developing brain, aggrecan appears in abundance there. In the new study, the researchers found that retinal neurons control aggrecan in a region that receives ascending signals from retinal cells as well as descending signals from the cerebral cortex.

Once the retinal neurons have made connections, they cause the release of enzymes that break down the aggrecan, allowing cortical neurons to move in.

Fox said it is interesting that the retinal axons can grow in this region of the developing brain, despite the high levels of aggrecan. He suspects that it may be because retinal neurons express a receptor – integrin – that cortical axons do not express.

The study, “A molecular mechanism regulating the timing of corticogeniculate innervation,” is by Fox, Jianmin Su, a research assistant professor, and Carl Levy, an undergraduate from Suffolk, Va., all with the Virginia Tech Carilion Research Institute; graduate student Justin Brooks and undergraduate Jessica Wang from Virginia Commonwealth University; and Tania Seabrook, a postdoctoral associate, and William Guido, a professor and the chair of the Department of Anatomical Sciences and Neurobiology, both with the University of Louisville School of Medicine.

Scans pinpoint moment anaesthetic puts brain under.

Anaesthetics usually knock you out like a light. But by slowing the process down so that it takes 45 minutes to become totally unresponsive, researchers have discovered a new signature for unconsciousness. The discovery could lead to more personalised methods for administering anaesthetics and cut the risks associated with being given too high or too low a dose. It also sheds new light on what happens to our brain when we go under the knife.

How much do you need? <i>(Image: Wicki58/Getty Images)</i>

Hundreds of thousands of people are anaesthetised every day, yet researchers still don’t fully understand what’s going on in the anaesthetised brain. Nor is there a direct way of measuring when someone is truly unresponsive. Instead, anaesthetists rely on indirect measures such as heart and breathing rate, and monitoring reflexes.

To investigate further, Irene Tracey and her colleagues at Oxford University slowed the anaesthesia process down. Instead of injecting the anaesthetic propofol in one go, which triggers unconsciousness in seconds, the drug was administered gradually so that it took 45 minutes for 16 volunteers to become fully anaesthetised. Their brain activity was monitored throughout using electroencephalography (EEG). The study was then repeated on 12 of these volunteers using functional magnetic resonance imaging (fMRI).

EEG recordings revealed that before the volunteers became completely unresponsive to external stimuli they progressed through a sleep-like state characterised by slow-wave oscillations – a hallmark of normal sleep, in which neurons cycle between activity and inactivity. As the dose of anaesthetic built up, more and more neurons fell into this pattern, until a plateau was reached when no more neurons were recruited, regardless of the dose administered.

Interestingly, the time it took to reach this plateau varied from individual to individual, and seemed to be determined by the number of neurons people possessed – something that decreases as we age.

Meanwhile, fMRI revealed what was happening in different regions of the brain as they lost consciousness. One theory is that an anaesthetic switches off one of the brain’s central relay hubs, the thalamus, meaning it no longer speaks to the cerebral cortex. However, Tracey’s team found that conversations between the cortex and the thalamus continued, even during deep anaesthesia – but there was no propagation of messages to wider regions of the brain.

“The thalamus is actually in a lot of dialogue with the cortex, but because it’s in this lockdown, sensory events that normally come into the cortex and would be routed out to the logical parts of the brain so that you could perceive ‘ouch that hurts’, is not happening,” says Tracey. “To have true perception you’ve got to have all the right bits active and their activity coordinated.”

Importantly, the point at which messages stopped being routed out was the same point at which the slow-wave oscillations reached a plateau. The hope is that this “saturation point” could be used as a measure of when to stop administering drugs, to reduce the risk of side effects such as headaches, dizziness and memory loss.

The next step is to monitor anaesthetised patients while they are undergoing surgery.

Journal reference: Science Translational Medicine,

Homolog of Mammalian Neocortex Found in Bird Brain.

A seemingly unique part of the human and mammalian brain is the neocortex, a layered structure on the outer surface of the organ where most higher-order processing is thought to occur. But new research at the University of Chicago has found the cells similar to those of the mammalian neocortex in the brains of birds, sitting in a vastly different anatomical structure.

he work, published in Proceedings of the National Academy of Sciences, confirms a 50-year-old hypothesis about the identity of a mysterious structure in the bird brain that has provoked decades of scientific debate. The research also sheds new light on the evolution of the brain and opens up new animal models for studying the neocortex.

“If you want to study motor neurons or dopamine cells, which are biomedically important, you can study them in mammals, in chick embryos, in zebrafish. But for these neurons of the cerebral cortex, we could only do that in mammals before,” said Clifton Ragsdale, PhD, associate professor of neurobiology at University of Chicago Biological Sciences and senior author of the study. “Now, we can take advantage of these other experimental systems to ask how they are specified, can they regenerate, and other questions.”

Both the mammalian neocortex and a structure in the bird brain called the dorsal ventricular ridge (DVR) originate from an embryonic region called the telencephalon. But the two regions mature into very different shapes, with the neocortex made up of six distinct cortical layers while the DVR contains large clusters of neurons called nuclei.

Because of this divergent anatomy, many scientists proposed that the bird DVR does not correspond to the mammalian cortex, but is analogous to another mammalian brain structure called the amygdala.

“All mammals have a neocortex, and it’s virtually identical across all of them,” said Jennifer Dugas-Ford, PhD, postdoctoral researcher at the University of Chicago and first author on the paper. “But when you go to the next closest group, the birds and reptiles, they don’t have anything that looks remotely similar to neocortex.”

But in the 1960s, neuroscientist Harvey Karten studied the neural inputs and outputs of the DVR, finding that they were remarkably similar to the pathways traveling to and from the neocortex in mammals. As a result, he proposed that the DVR performs a similar function to the neocortex despite its dramatically different anatomy.

Dugas-Ford, Ragsdale and co-author Joanna Rowell decided to test Karten’s hypothesis by using recently discovered sets of molecular markers that can identify specific layers of mammalian cortex: the layer 4 “input” neurons or layer 5 “output” neurons. The researchers then looked for whether these marker genes were expressed in the DVR nuclei.

In two different bird species — chicken and zebra finch — the level 4 and 5 markers were expressed by distinct nuclei of the DVR, supporting Karten’s hypothesis that the structure contains cells homologous to those of mammalian neocortex.

“Here was a completely different line of evidence,” Ragsdale said. “There were molecular markers that picked out specific layers of cortex; whereas the original Karten theory was based just on connections, and some people dismissed that. But in two very distant birds, all of the gene expression fits together very nicely with the connections.”

Dugas-Ford called the evidence “really incredible.”

“All of our markers were exactly where they thought they would be in the DVR when you’re comparing them to the neocortex,” she said.

A similar experiment was conducted in a species of turtle, and revealed yet another anatomical possibility for these neocortex-like cells. Instead of a six-layer neocortex or a cluster of nuclei, the turtle brain had layer 4- and 5-like cells distributed along a single layer of the species’ dorsal cortex.

“I think that’s the interesting part, that you can have all these different morphologies built with the same cell types, just in different conformations,” Rowell said. “It’s a neocortex or a big clump of nuclei, and then in reptiles they have an unusual dorsal cortex unlike either of those.”

Future experiments will test the developmental steps that shape these neurons into various structures, and the relative pros and cons of these anatomical differences. The complex language and tool-use of some bird species suggests that the nuclear organization of this pathway is also capable of supporting advanced functions — and even may offer advantages over the mammalian brain.

“If you wanted to have a special nuclear processing center in Broca’s area to carry out language processing, you can’t do that in a mammal,” Ragsdale said. “But in a bird they have these special nuclei that are involved in vocalization. It’s as if you have additional flexibility: You can have shorter circuits, longer circuits, you can have specialized processing centers.”

Beyond the structural differences, the discovery of homologous neocortex cell types will allow scientists to study cortical neurons in bird species such as the chicken, a common model used for examining embryonic development. Such research could help scientists more easily study the neurons lost in paralysis, deafness, blindness, and other neurological conditions.




Brain: Protein That Regulates Key ‘Fate’ Decision in Cortical Progenitor Cells Identified

Researchers at Cold Spring Harbor Laboratory (CSHL) have solved an important piece of one of neuroscience’s outstanding puzzles: how progenitor cells in the developing mammalian brain reproduce themselves while also giving birth to neurons that will populate the emerging cerebral cortex, the seat of cognition and executive function in the mature brain.

CSHL Professor Linda Van Aelst, Ph.D., and colleagues set out to solve a particular mystery concerning radial glial cells, or RGCs, which are progenitors of pyramidal neurons, the most common type of excitatory nerve cell in the mature mammalian cortex.

In genetically manipulated mice, Van Aelst’s team demonstrated that a protein called DOCK7 plays a central regulatory role in the process that determines how and when an RGC “decides” either to proliferate, i.e., make more progenitor cells like itself, or give rise to cells that will mature, or “differentiate,” into pyramidal neurons. The findings are reported in the September 2012 issue of Nature Neuroscience.

DOCK7 was already known to be highly expressed in various parts of the developing rodent brain, including the hippocampus and cortex. It had been shown by Van Aelst and colleagues to control the formation of axons — wiring that connects neurons.

Balancing proliferation and differentiation

In their newly published research, Van Aelst, along with Drs. Yu-Ting Yang and Chia-Lin Wang, a graduate student and postdoctoral fellow, respectively, in the Van Aelst lab, elucidate DOCK7’s regulatory role in experiments in which the protein was alternately silenced and overexpressed.

When the protein was silenced in mouse embryos, neuronal differentiation was impeded; RGCs remained in their progenitor state. When DOCK7 was overexpressed, RGCs differentiated prematurely, resulting in more neurons and fewer RGCs.

These and related experiments revealed the mechanism through which DOCK7 expression affects the two essential but contrasting functions of RGCs. “Self-renewability of RGCs must be tightly balanced with differentiation for proper cortical development,” says Van Aelst.

“The mechanism we discovered to be central in the determination of RGC fate is called interkinetic nuclear migration, or INM,” she continues, “and you can see it in action in the movies made by Drs. Wang and Yang.”

In INM, an RGC cell nucleus visibly travels over the course of the cell cycle “upward” and “downward” between opposing sides of the apical-most region of the neuroepithelium, called the ventricular zone or VZ. Nuclei move away from the apical surface during the G1 phase, undergo S phase at a basal location in the VZ, and return to the apical surface during G2 to divide at the apical location. [see diagram below]

It is DOCK7 that regulates this movement; in particular, the movement from the basal to apical location, the CSHL team has now demonstrated. On what appears to be the lower surface of the VZ, the apical surface, signals directing the RCG toward proliferation — i.e., reproduction of other RGCs — are dominant. On the upper or ‘basal’ side of the VZ, dominant signals coax the RGC to split into new intermediate progenitors or neurons.

Migration explained: DOCK7, TACC3 and centrosomes

“The cellular machinery that controls INM involves a protein complex of actin and myosin, called actomyosin, as well as microtubule-dependent systems,” notes Dr. Wang. “We show how DOCK7 exerts its effects by antagonizing the microtubule growth-promoting function of a protein called TACC3.” That protein, tellingly, is associated with the centrosome, the cellular organ that organizes microtubules, and regulates the growth of microtubules emanating from the centrosome, thereby coupling the centrosome and nucleus .

As Dr. Yang points out, DOCK7 acts by antagonizing the microtubule growth-promoting function of TACC3. Silencing of DOCK7 accelerates the movement of RGC nuclei from the basal to apical side of the VZ, resulting in extended apical residency of RGC nuclei and apical mitoses that lead to an increase in RGCs and a reduction in neurons. DOCK7 overexpression, on the other hand, leads to extended residence of RGC nuclei at basal locations and mitoses away from the apical surface, where the production of new neurons increases, at the expense of the proliferation of more progenitors.

Beyond elucidating an important mechanism of cortical development, the new research may shed light on pathologies seen in microcephaly, a condition marked by an abnormally small brain size, as well as neurodevelopmental disorders such as schizophrenia. “If DOCK7 expression is abnormal, you perturb normal neurogenesis,” says Van Aelst. “In future work we hope to explore whether an imbalance in neurogenesis caused by DOCK7 aberrations is associated with a subsequent imbalance in cortical circuitry, and various known pathologies.”

Source: science daily.