Posts tagged cerebral cortex
Articles and news from the latest research reports.
Manipulating memory with light
Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.
Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.
Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories — memories about specific places and events — involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.
"The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event," Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.
But this model has been difficult to test directly, until the arrival of optogenetics.
Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.
They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a “fear response.”
Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.
"The cortex can’t do it alone, it needs input from the hippocampus," Wiltgen said. "This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true."
They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.
Sensory Sensitivity: Stimulation and deprivation alter vascular structure in the brain
Nerves and blood vessels lead intimately entwined lives. They grow up together, following similar cues as they spread throughout the body. Blood vessels supply nerves with oxygen and nutrients, while nerves control blood vessel dilation and heart rate.
Neurovascular relationships are especially important in the brain. Studies have shown that when neurons work hard, blood flow increases to keep them nourished. Scientists have been asking whether neural activity also changes the structure of local vascular networks.
According to new research published in the Sept. 3 issue of Neuron, the answer is yes.
(Source: hms.harvard.edu)
Neurons in human skin perform advanced calculations
A fundamental characteristic of neurons that extend into the skin and record touch, so-called first-order neurons in the tactile system, is that they branch in the skin so that each neuron reports touch from many highly-sensitive zones on the skin.
According to researchers at the Department of Integrative Medical Biology, IMB, Umeå University, this branching allows first-order tactile neurons not only to send signals to the brain that something has touched the skin, but also process geometric data about the object touching the skin.
Our work has shown that two types of first-order tactile neurons that supply the sensitive skin at our fingertips not only signal information about when and how intensely an object is touched, but also information about the touched object’s shape, says Andrew Pruszynski, who is one of the researchers behind the study.
The study also shows that the sensitivity of individual neurons to the shape of an object depends on the layout of the neuron’s highly-sensitive zones in the skin.
Perhaps the most surprising result of our study is that these peripheral neurons, which are engaged when a fingertip examines an object, perform the same type of calculations done by neurons in the cerebral cortex. Somewhat simplified, it means that our touch experiences are already processed by neurons in the skin before they reach the brain for further processing, says Andrew Pruszynski.
When we learn, we associate a sensory experience either with other stimuli or with a certain type of behaviour. The neurons in the cerebral cortex that transmit the information modify the synaptic connections that they have with the other neurons. According to a generally-accepted model of synaptic plasticity, a neuron that communicates with others of the same kind emits an electrical impulse as well as activating its synapses transiently. This electrical pulse, combined with the signal received from other neurons, acts to stimulate the synapses. How is it that some neurons are caught up in the communication interplay even when they are barely connected? This is the crucial chicken-or-egg puzzle of synaptic plasticity that a team led by Anthony Holtmaat, professor in the Department of Basic Neurosciences in the Faculty of Medicine at UNIGE, is aiming to solve. The results of their research into memory in silent neurons can be found in the latest edition of Nature.
Learning and memory are governed by a mechanism of sustainable synaptic strengthening. When we embark on a learning experience, our brain associates a sensory experience either with other stimuli or with a certain form of behaviour. The neurons in the cerebral cortex responsible for ensuring the transmission of the relevant information, then modify the synaptic connections that they have with other neurons. This is the very arrangement that subsequently enables the brain to optimise the way information is processed when it is met again, as well as predicting its consequences.
Neuroscientists typically induce electrical pulses in the neurons artificially in order to perform research on synaptic mechanisms.
The neuroscientists from UNIGE, however, chose a different approach in their attempt to discover what happens naturally in the neurons when they receive sensory stimuli. They observed the cerebral cortices of mice whose whiskers were repeatedly stimulated mechanically without an artificially-induced electrical pulse. The rodents use their whiskers as a sensor for navigating and interacting; they are, therefore, a key element for perception in mice.
An extremely low signal is enough
By observing these natural stimuli, professor Holtmaat’s team was able to demonstrate that sensory stimulus alone can generate long-term synaptic strengthening without the neuron discharging either an induced or natural electrical pulse. As a result – and contrary to what was previously believed – the synapses will be strengthened even when the neurons involved in a stimulus remain silent.In addition, if the sensory stimulation lasts over time, the synapses become so strong that the neuron in turn is activated and becomes fully engaged in the neural network. Once activated, the neuron can then further strengthen the synapses in a forwards and backwards movement. These findings could solve the brain’s “What came first?” mystery, as they make it possible to examine all the synaptic pathways that contribute to memory, rather than focusing on whether it is the synapsis or the neuron that activates the other.
The entire brain is mobilised
A second discovery lay in store for the researchers. During the same experiment, they were also able to establish that the stimuli that were most effective in strengthening the synapses came from secondary, non-cortical brain regions rather than major cortical pathways (which convey actual sensory information). Accordingly, storing information would simply require the co-activation of several synaptic pathways in the neuron, even if the latter remains silent. These findings may also have important implications both for the way we understand learning mechanisms and for therapeutic possibilities, in particular for rehabilitation following a stroke or in neurodegenerative disorders. As professor Holtmaat explains: “It is possible that sensory stimulation, when combined with another activity (motor activity, for example), works better for strengthening synaptic connections”. The professor concludes: “In the context of therapy, you could combine two different stimuli as a way of enhancing the effectiveness.”
Contradictory findings on how the full moon affect our sleep
A Swiss research study conducted last year showed that the full moon affects sleep. The findings demonstrated that people average 20 minutes less sleep, take five minutes longer to fall asleep and experience 30 minutes more of REM sleep, during which most dreaming is believed to occur.
Different outcome
Numerous studies through the years have attempted to prove or disprove the hypothesis that lunar phases affect human sleep. But results have been hard to repeat. A group of researchers at the famed Max Planck Institute and elsewhere analyzed data from more than 1,000 people and 26,000 nights of sleep, only to find no correlation.
International researchers are being urged to publish their results in hopes of getting to the bottom of the question. Michael Smith and his co-researchers at Sahlgrenska Academy have analyzed data generated by a previous sleep study and compared them with the lunar cycle.
20 minutes less sleep
Based on a study of 47 healthy 18-30 year-olds and published in Current Biology, the results support the theory that a correlation exists.
“Our study generated findings similar to the Swiss project,” Michael Smith says. “Subjects slept an average of 20 minutes less and had more trouble falling asleep during the full moon phase. However, the greatest impact on REM sleep appeared to be during the new moon.”
More susceptible brain
The retrospective study by the Gothenburg researchers suggests that the brain is more susceptible to external disturbances when the moon is full.
“The purpose of our original study was to examine the way that noise disturbs sleep,” Mr. Smith continues. “Re-analysis of our data showed that sensitivity, measured as reactivity of the cerebral cortex, is greatest during the full moon.”
Greater cortical reactivity was found in both women and men, whereas only men had more trouble falling asleep and slept less when the moon was full. Skeptics warn that both age and gender differences may be a source of error, not to mention more subtle factors such as physical condition and exposure to light during the day.
Need for more studies
Though fully aware of the issues, Mr. Smith is not prepared to dismiss the results of the Gothenburg study.
“The rooms in our sleep laboratories do not have any windows,” he says. “So the effect we found cannot be attributable to increased nocturnal light during full moon. Thus, there may be a built-in biological clock that is affected by the moon, similar to the one that regulates the circadian rhythm. But all this is mere speculation – additionally, more highly controlled studies that target these mechanisms are needed before more definitive conclusions can be drawn.”
The article Human sleep and cortical reactivity are influenced by lunar phase is published in Current Biology.
Neural Transplant Reduces Absence Epilepsy Seizures in Mice
New research from North Carolina State University pinpoints the areas of the cerebral cortex that are affected in mice with absence epilepsy and shows that transplanting embryonic neural cells into these areas can alleviate symptoms of the disease by reducing seizure activity. The work may help identify the areas of the human brain affected in absence epilepsy and lead to new therapies for sufferers.
Absence epilepsy primarily affects children. These seizures differ from “clonic-tonic” seizures in that they don’t cause muscle spasms; rather, patients “zone out” or stare into space for a period of time, with no memory of the episode afterward. Around one-third of patients with absence epilepsy fail to respond to medication, demonstrating the complexity of the disease.
NC State neurobiology professor Troy Ghashghaei and colleagues looked at a genetic mouse model for absence epilepsy to determine what was happening in their brains during these seizures. They found that the seizures were accompanied by hyperactivity in the areas of the brain associated with vision and touch – areas referred to as primary visual and primary somatosensory cortices in the occipital and parietal lobes, respectively.
“There are neurons that excite brain activity, and neurons that inhibit activity,” Ghashghaei says. “The inhibitory neurons work by secreting an inhibitory neurotransmitter called gamma-aminobutyric acid, or GABA. The ‘GABAergic’ interneurons were recently shown by others to be defective in the mice with absence seizures, and we surmised that these malfunctioning neurons might be part of the problem, especially in the visual and somatosensory cortical areas.”
Ghashghaei’s team took embryonic neural stem cells from a part of the developing brain that generates GABAergic interneurons for the cerebral cortex. They harvested these cells from normal mouse embryos and transplanted them into the occipital cortex of the genetic mice with absence seizures. Absence seizure activity in treated animals decreased dramatically, and the mice gained more weight and survived longer than untreated mice.
“This is a profound and remarkably effective first result, and adds to the recent body of evidence that these transplantation treatments can work in mouse models of epilepsy. But we still don’t understand the mechanisms behind what the normal inhibitory cells are doing in areas of the visual cortex of absence epileptic mice,” Ghashghaei says. “We know that you can get positive results even when a small number of transplanted neurons actually integrate into the cortex of affected mice, which is very interesting. But we don’t know how the transplanted cells are connecting with other cells in the cortex and how they alleviate the absence seizures in the mouse model we employed.
“Our next steps will be to explore these questions. In addition, we are very interested in methods being devised by multiple labs around the world to ‘reprogram’ cells from transplantation patients to generate normal GABAergic and other types of neurons. Once established, this would eliminate the need for embryonic stem cells for this type of treatment. The ultimate goal is to develop new therapies for humans suffering from various forms of epilepsies, especially those for whom drugs do not work.”
Isolating the Circuits that Control Voluntary Movement
Extraordinarily complex networks of circuits that transmit signals from the brain to the spinal cord control voluntary movements. Researchers have been challenged to identify the controlling circuits, but they lacked the tools needed to dissect, at the neural level, the way the brain produces voluntary movements.
Recently, Dr. John Martin, medical professor in City College’s Sophie Davis School of Biomedical Education, postdoctoral fellow Dr. Najet Serradi and other colleagues employed a sensitive genetic technique that eliminated a particular gene in the cerebral cortex and, in the process, changed the circuitry.
The team hypothesized that the corticospinal tract, which stretches from cerebral cortex to the spinal cord, is important for voluntary reaching movements, but not for more routine and stereotypic walking movements. “We reasoned that if we genetically altered the corticospinal tract we would affect voluntary reaching movements, but not walking.” Professor Martin said.
In genetically intact mice, corticospinal tract signals are transmitted from one side of the cerebral cortex to the opposite side of the spinal cord. Such mice reach with one arm, or the other – but not both arms together.
Professor Martin and colleagues used specially bred mice, i.e. knockout mice, with the gene EphA4 removed from the cerebral cortex. These mice reached with both forelimbs together, rather than with one. This happened because the genetic manipulation changed the circuit; it caused the signal to move to be transmitted from one side of the cerebral cortex to both sides of the spinal cord.
However, their stereotypic walking was unaffected. Professor Martin said this shows that while voluntary movements depend on the corticospinal tract walking depends on circuits in other parts of the brain and spinal cord, which are not affected by the gene manipulation.
The findings, he added, “etch away at the vexing problem of achieving a deeper understanding of how the brain functions in voluntary movement.” In addition greater knowledge of how voluntary circuits function could lead to new understanding of cerebral palsy, a condition in which the corticospinal tract is injured around the time of birth and people often make “mirror movements” of both arms when they intend to move only one, he said.
The research, which is funded by the National Institute of Neurological Diseases and Stroke, aims to understand the brain and spinal cord circuits for voluntary movement. Using similar genetic tools, his team hopes to further dissect the connections and functions of the corticospinal tract movement circuits in ways to restore movements after brain or spinal cord injury.
(Source: www1.cuny.edu)
Seeking the Causes of Hyperactivity
The 60 trillion cells that comprise our bodies communicate constantly. Information travels when chemical compounds released by some cells are received by receptors in the membrane of another cell. In a paper published in the Journal of Neuroscience, the OIST Cell Signal Unit, led by Professor Tadashi Yamamoto, reported that mice lacking an intracellular trafficking protein called LMTK3, are hyperactive. Hyperactivity is a behavioral disorder that shows symptoms including restlessness, lack of coordination, and aggressive behavior. Identifying the genetic factors that contribute to such behaviors may help to explain the pathological mechanisms underlying autism and Attention Deficit Hyperactivity Disorder, ADHD, in humans.
LMTK3 is abundant in two brain regions: the cerebral cortex, which coordinates perception, movement, and thought, and the hippocampus, which governs memory and learning. In the brain, neurons communicate via connections called synapses. To send a message, a nerve terminus in the pre-synapse releases neurotransmitters to be received by the post-synaptic receptors. Yamamoto’s team discovered that LMTK3 regulates trafficking of neurotransmitter receptors at synapses. In neurons of mice deficient in LMTK3, internalization of receptors are augmented in the post-synapse, suggesting that synaptic communication is impaired. The LMTK3-deficient mice exhibited various hyperactive behaviors such as restlessness and hypersensitivity to sound. Interestingly, their dopamine levels were elevated. Dopamine is a neurotransmitter known to be involved in regulation of movement and hormone levels, motivation, learning, and expression of emotion. Excessive dopamine secretion results in schizophrenia, causing a loss of integrity of neuronal activity, and abnormal thoughts and emotions. The relationships between regulation of neurotransmitter receptor expression by LMTK3, dopamine turnover, and the biochemical pathways that induce hyperactivity, remain unknown.
Functions of many human proteins are still not understood. The Cell Signal Unit continues genetic studies of intracellular proteins that maintain and regulate complex functions such as behaviors, through their activities inside cells. “We hope to advance our research in order to elucidate genetic defects that result in behavioral abnormalities,” Yamamoto said.
Genetic legacy from the Ottoman Empire: Single mutation causes rare brain disorder
An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the height of the Ottoman Empire in Turkey about 16 generations ago.
(Image caption: An fMRI scan of the brain of a patient with CLP1 mutation reveals severe atrophy of the brainstem (red line) and cerebellum (blue) as well as lack of formation of the corpus callosum (green), which connects both sides of the cerebrum (yellow), which is also atrophied. The lines outline approximately the expected sizes of the brain areas. A study traced the mutation to a single individual born in Turkey during the Ottoman Empire, some 16 generations ago.)
The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.
“The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer’s or Lou Gehrig’s Disease,” said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.
Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson’s group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells’ protein-making machinery.
The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.
Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.
The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.
Gunel said that the high prevalence of consanguineous marriages [between closely related people] in Turkey and the Middle East leads to these rare recessive genetic neurodegenerative disorders. Affected children inherit mutations in the same gene from both of their parents, who are closely related to each other, such as first cousins. Without consanguinity between parents, children are very unlikely to inherit two mutations in the same gene.
“By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function” Gunel said. “We learn a lot about normal biology by studying what happens when things go wrong.”
(Source: news.yale.edu)
Life Stressors Trigger Neurological Disorders
When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.
Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.
Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.
Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”
Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.
Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.
While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.
Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.
Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.