Creative Minds: Seeing Memories in a New Light

Steve Ramirez

Steve Ramirez/Joshua Sariñana

Whether it’s lacing up for a morning run, eating blueberry scones, or cheering on the New England Patriots, Steve Ramirez loves life and just about everything in it. As an undergraduate at Boston University, this joie de vivre actually made Ramirez anxious about choosing just one major. A serendipitous conversation helped him realize that all of the amazing man-made stuff in our world has a common source: the human brain.

So, Ramirez decided to pursue neuroscience and began exploring the nature of memory. Employing optogenetics (using light to control brain cells) in mice, he tagged specific neurons that housed fear-inducing memories, making the neurons light sensitive and amenable to being switched on at will.

In groundbreaking studies that earned him a spot in Forbes 2015 “30 Under 30” list, Ramirez showed that it’s possible to reactivate memories experimentally in a new context, recasting them in either a more negative or positive behavior-changing light [1–3]. Now, with support from a 2016 NIH Director’s Early Independence Award, Ramirez, who runs his own lab at Boston University, will explore whether activating good memories holds promise for alleviating chronic stress and psychiatric disease.

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Finding Brain Circuits Tied to Alertness

Everybody knows that it’s important to stay alert behind the wheel or while out walking on the bike path. But our ability to react appropriately to sudden dangers is influenced by whether we feel momentarily tired, distracted, or anxious. How is it that the brain can transition through such different states of consciousness while performing the same routine task, even as its basic structure and internal wiring remain unchanged?

A team of NIH-funded researchers may have found an important clue in zebrafish, a popular organism for studying how the brain works. Using a powerful new method that allowed them to find and track brain circuits tied to alertness, the researchers discovered that this mental state doesn’t work like an on/off switch. Rather, alertness involves several distinct brain circuits working together to bring the brain to attention. As shown in the video above that was taken at cellular resolution, different types of neurons (green) secrete different kinds of chemical messengers across the zebrafish brain to affect the transition to alertness. The messengers shown are: serotonin (red), acetylcholine (blue-green), and dopamine and norepinephrine (yellow).

What’s also fascinating is the researchers found that many of the same neuronal cell types and brain circuits are essential to alertness in zebrafish and mice, despite the two organisms being only distantly related. That suggests these circuits are conserved through evolution as an early fight-or-flight survival behavior essential to life, and they are therefore likely to be important for controlling alertness in people too. If correct, it would tell us where to look in the brain to learn about alertness not only while doing routine stuff but possibly for understanding dysfunctional brain states, ranging from depression to post-traumatic stress disorder (PTSD).

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Creative Minds: Modeling Neurobiological Disorders in Stem Cells

Feng Zhang

Feng Zhang

Most neurological and psychiatric disorders are profoundly complex, involving a variety of environmental and genetic factors. Researchers around the world have worked with patients and their families to identify hundreds of possible genetic leads to learn what goes wrong in autism spectrum disorder, schizophrenia, and other conditions. The great challenge now is to begin examining this growing cache of information more systematically to understand the mechanism by which these gene variants contribute to disease risk—potentially providing important information that will someday lead to methods for diagnosis and treatment.

Meeting this profoundly difficult challenge will require a special set of laboratory tools. That’s where Feng Zhang comes into the picture. Zhang, a bioengineer at the Broad Institute of MIT and Harvard, Cambridge, MA, has made significant contributions to a number of groundbreaking research technologies over the past decade, including optogenetics (using light to control brain cells), and CRISPR/Cas9, which researchers now routinely use to edit genomes in the lab [1,2].

Zhang has received a 2015 NIH Director’s Transformative Research Award to develop new tools to study multiple gene variants that might be involved in a neurological or psychiatric disorder. Zhang draws his inspiration from nature, and the microscopic molecules that various organisms have developed through the millennia to survive. CRISPR/Cas9, for instance, is a naturally occurring bacterial defense system that Zhang and others have adapted into a gene-editing tool.

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Snapshots of Life: Making the Brain Transparent

Brain webs

Credit: Ken Chan and Viviana Gradinaru Group, Caltech

What you are looking at above is something scientists couldn’t even dream of imaging less than a decade ago: bundles of neurons in the brainstem of an adult mouse. These bundles are randomly labeled with various colors that enable researchers to trace the course of each as it projects from the brainstem areas to other parts of the brain. Until recently, such a view would have been impossible because, like other organs, the brain is opaque and had to be sliced into thin, transparent sections of tissue to be examined under a light microscope. These sections forced a complex 3D structure to be visualized in 2D, losing critical detail about the connections.

But now, researchers have developed innovative approaches to make organs and other large volumes of tissue transparent when viewed with standard light microscopy [1]. This particular image was made using the Passive CLARITY Technique, or PACT, developed by the NIH-supported lab of Viviana Gradinaru at the California Institute of Technology (Caltech), Pasadena. Gradinaru has been working on turning tissues transparent since 2010, starting as a graduate student in the lab of CLARITY developer and bioengineering pioneer Karl Deisseroth at Stanford University. PACT is her latest refinement of the concept.

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Tracing the Neural Circuitry of Appetite

MC4R PVH neurons-the heart of hunger

Caption: A stylized image of the MC4R-expressing neurons (in red) within the brain’s PVH, which is the “heart of hunger”
Credit: Michael Krashes, NIDDK, NIH

If you’ve ever skipped meals for a whole day or gone on a strict, low-calorie diet, you know just how powerful the feeling of hunger can be. Your stomach may growl and rumble, but, ultimately, it’s your brain that signals when to start eating—and when to stop. So, learning more about the brain’s complex role in controlling appetite is crucial to efforts to develop better ways of helping the millions of Americans afflicted with obesity [1].

Thanks to recent technological advances that make it possible to study the brain’s complex circuitry in real-time, a team of NIH-funded researchers recently made some important progress in understanding the neural basis for appetite. In a study published in the journal Nature Neuroscience, the researchers used a variety of innovative techniques to control activity in the brains of living mice, and identified one particular circuit that appears to switch hunger off and on [2].

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