Brain cells activated, reactivated in learning and memory

Memories are made of this, the song says. Now neuroscientists have for the first time shown individual mouse brain cells being switched on during learning and later reactivated during memory recall. The results are published Dec. 13 in the journal Current Biology.

We store episodic memories about events in our lives in a part of a brain called the hippocampus, said Brian Wiltgen, now an assistant professor at the Center for Neuroscience and Department of Psychology at the University of California, Davis. (Most of the work was conducted while Wiltgen was working at the University of Virginia.) In animals, the hippocampus is important for navigation and storing memories about places.

"The exciting part is that we are now in a position to answer a fundamental question about memory," Wiltgen said. "It’s been assumed for a long time that the hippocampus is essential for memory because it drives reactivation of neurons (nerve cells) in the cortex. The reason you can remember an event from your life is because the hippocampus is able to recreate the pattern of cortical activity that was there at the time."

According to this model, patients with damage to the hippocampus lose their memories because they can’t recreate the activity in the cortex from when the memory was made. Wiltgen’s mouse experiment makes it possible to test this model for the first time.

Rhesus monkeys cannot hear beat in music

Beat induction, the ability to pick up regularity – the beat – from a varying rhythm, is not an ability that rhesus monkeys possess. These are the findings of researchers from the University of Amsterdam (UvA) and the National Autonomous University of Mexico (UNAM), which have recently been published in the scientific journal PLOS ONE.

The research conducted by Henkjan Honing, professor of Music Cognition at the UvA, and a team of neurobiologists headed by Hugo Merchant from the UNAM, shows that rhesus monkeys cannot detect the beat in music, although they are able to detect rhythmic groups in music. The results of this research support the view that beat induction is a uniquely human, cognitive skill and contribute to a further understanding of the biology and evolution of human music.

(Photograph by Shane Moore)

The nematode worm (scientific name C. elegans) is a simple-minded animal: it has exactly 302 neurons (compare that to a human’s roughly 100 billion). The pattern of connections between these neurons was painstakingly mapped out decades ago using electron microscopy, but it turns out that knowledge of the connections is not sufficient to understand (or even replicate) the information processor they represent. For example, some connections are inhibitory while others are excitatory, but this map doesn’t say which is which.

In order to learn how one neuron affects another, we need to see what happens when the first neuron is activated. NEMALOAD (“nematode upload”) is a project to integrate a number of recent technologies that should make this feasible, at least in C. elegans, and using this capability to replicate the information processing structure that governs the worm’s behavior in a digital model.

Fragile X Protein Linked to Nearly 100 Genes Involved in Autism

Doctors have known for many years that patients with fragile X syndrome, the most common form of inherited intellectual disability, are often also diagnosed with autism. But little has been known about how the two diagnoses are related.

Now a collaborative research effort at Duke University Medical Center and Rockefeller University has pinpointed the precise genetic footprint that links the two. The findings, published online in the journal Nature on Dec. 12, 2012, point the way toward new genetic testing that could more precisely diagnose and categorize the spectrum of autism-related disorders.

Fragile X syndrome is the most well understood single-gene cause of autism. It results from defects on a small part of the genetic code for a protein that researchers have dubbed the fragile X mental retardation protein, or FMRP.

Normally, FMRP plays an important role controlling production of other proteins in the brain and other organs. It does this by looking for specific genetic patterns located on the messages encoding proteins. When it locates these genetic flags, it attaches to them and, along with other signals, controls where and when protein is made.

In fragile X syndrome, this process breaks down because a defect in the gene causes the body to produce too little, or in some cases, none of the FMRP protein. As a result, additional proteins it would normally regulate are made in the wrong place and at the wrong time. Until now, little was known about how this process worked in people with the autism.

Using a combination of laboratory experiments and advanced bioinformatics, the research team, led by Thomas Tuschl, PhD, a Howard Hughes Medical Institute investigator at Rockefeller University, and Uwe Ohler, PhD, an associate professor in Biostatistics and Bioinformatics at the Duke Institute for Genome Sciences & Policy, identified both the genetic flags that FMRP is looking for and the genes it targets.

(Image courtesy of www.sueblimely.com)

Stress-Resilience/Susceptibility Traced to Neurons in Reward Circuit

A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking – they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient.

“For the first time, we have shown that split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light,” explained Ming-Hu Han, Ph.D., of the Mount Sinai School of Medicine, New York City, a grantee of NIH’s National Institute of Mental Health (NIMH). “These results add to mounting clues about the mechanism of fast-acting antidepressant responses.” Han, Eric Nestler, M.D., Ph.D., of Mount Sinai, and colleagues, report on their study online, Dec. 12, 2012, in the journal Nature.

In a companion article, NIMH grantees Kay Tye, Ph.D., of the Massachusetts Institute of Technology, Cambridge, Mass., and Karl Deisseroth, M.D., Ph.D., of Stanford University, Stanford, Calif., used the same cutting-edge technique to control mouse brain activity in real time. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by daily presentations of chronic, unpredictable mild physical stressors, instead of by shorter-term exposure to severe social stress.

Prior to the new studies, Han’s team suspected that a telltale pattern – rapid firing of neurons that secrete the chemical messenger dopamine in a key circuit hub – makes an animal vulnerable to the depression-like effects of acute severe stress, and that slower firing supports resilience. But they lacked direct, real-time evidence.

To pinpoint cause-and-effect, they turned to a research technology pioneered by Deisseroth, called optogenetics. It melds fiber optics and genetic engineering to precisely control the activity of a specific brain circuit in a living, behaving animal. Genetically modified viruses are used to inject light-reactive proteins, borrowed from primitive organisms like algae, to make the circuitry similarly light-responsive.

Researchers both induce, relieve depression symptoms in mice by stimulating single brain region with light

Researchers at Stanford University have successfully induced and relieved depression-like deficiencies in both pleasure and motivation in mice by controlling just a single area of the brain known as the ventral tegmental area. It is the first time that well-defined types of neurons within a specific brain region have been directly tied to the control of myriad symptoms of major depressive illness.

In the paper published in Nature on Dec. 12, Stanford bioengineer Karl Deisseroth, MD, PhD, and a team including postdoctoral scholars Kay Tye, PhD, and Melissa Warden, PhD, and research assistant Julie Mirzabekov have used a technique known as optogenetics to pinpoint a specific brain location that produces multiple depression-like symptoms. The region in question is the ventral tegmental area, or VTA, a source of dopamine and a central player in the brain’s internal motivation and reward systems.

“We have for the first time directly tied dopamine neurons in the VTA to controlling and relieving these very different and diverse symptoms,” said Deisseroth, the study’s senior author and a professor of bioengineering and of psychiatry and behavioral sciences. “While depression is a complex disease with still many unknowns, this knowledge may help launch new kinds of investigation into the pathways of depression in the brain, and develop concepts to help people suffering from depression.”

Deisseroth’s team was able to both induce and relieve multiple depression-like symptoms in laboratory mice by genetically modifying the dopamine neurons in the VTA to be sensitive to light. Using fiber optic cables inserted in rodents’ brains, they could then instantaneously produce and inhibit the depression-like symptoms by turning the light on and off. This research technique, developed by Deisseroth at Stanford in 2005, is known as optogenetics.

Study Details Brain Damage Triggered by Mini-Strokes

A new study appearing today in the Journal of Neuroscience details for the first time how “mini-strokes” cause prolonged periods of brain damage and result in cognitive impairment. These strokes, which are often imperceptible, are common in older adults and are believed to contribute to dementia. 

“Our research indicates that neurons are being lost as a result of delayed processes following a mini-strokes that may differ fundamentally from those of acute ischemic events,” said Maiken Nedergaard, M.D., D.M.Sc., the lead author of the study and professor of Neurosurgery at the University of Rochester Medical Center (URMC). “This observation suggests that the therapeutic window to protect cells after these tiny strokes may extend to days and weeks after the initial injury.”

The prevalence of mini-strokes, or microinfarcts, has only been recently appreciated because common imaging techniques, such as MRI, are typically not sensitive enough to detect these microscopic injuries.

Similar to severe ischemic strokes, mini-strokes are caused when blood flow is blocked to a small area of the brain, usually by particle that travelled there from another part of the body. But unlike acute ischemic strokes – which bring about immediate symptoms such as numbness, blurry vision, and slurred speech – mini-strokes usually pass without notice. However, it is increasingly appreciated that these smaller strokes have a lasting impact on neurological function.

Microinfarcts are far more common than previously understood; it is believed that about 50 percent of individuals over the age of 60 have experienced at least one mini-stroke. Studies have also correlated the presence of mini-strokes with the symptoms of dementia. An estimated 55 percent of individuals with mild dementia and upwards of 70 percent of individuals with more severe symptoms show evidence of past mini-strokes. This association has led researchers to believe that these mini-strokes may be key contributors to age-related cognitive decline and dementia.

Nedergaard and her colleagues were the first to develop an animal model in which the complex progression and, ultimately, the cognitive impact of mini-strokes could be observed. Her team found that, in most instances, these strokes result in a prolonged period of damage to the brain.