Time Magazine: Mice With OCD Can Mean New Hope for Humans



Optogenetics cover scene.


A new study of mouse brains leads to new insights — and perhaps new treatments — for a common disorder

by Jeffrey Kluger ,June 07, 2013

There may be no torment quite like the sublime looniness that is obsessive-compulsive disorder (OCD).

Your hands are clean, the door is locked, you didn’t insult a colleague at work or drive over someone on the way home or mishear the 17 doctors you’ve seen in the past month who told you that no, you really, truly don’t have whatever disease you think you’ve got. And yet you keep washing or locking or checking or worrying.

Most people think they understand OCD — and most people are wrong.

It’s not just tidiness, it’s not just fretfulness, and it’s not a glib adjective (“You should see how neat my desk is. I’m so OCD!”). It is, instead, a profound malfunction in various regions of the brain — principally the amygdala, which processes fear, anxiety and other primal emotions — and the mere fact that it is exceedingly treatable with cognitive-behavioral therapy, medication or both does not make it any less awful if you’ve got a real case of it.

Now, thanks to a new study just published in Science, people suffering with OCD have at least a little more hope of recovery than they did before — and people studying the disorder have a lot more insight into what causes it in the first place.

The fact that OCD can be expressed in so many different ways has always suggested that it is caused by idiosyncratic interactions among several different brain regions. The amygdala likely plays a role in all of them, but the best-known forms of OCD — contamination anxiety and the excessive washing that can follow — are thought to be governed by the orbital frontal cortex (OFC) and the ventromedial striatum (VMS). The OFC governs decisionmaking and volitional activity; the VMS governs how we experience fear and risk. It’s not hard to see how an alarm set off by the VMS can lead to a decision to wash by the OFC — even if that decision defies reason.

To explore that circuitry — and the way it goes haywire — a team of researchers led by Dr. Susanne Ahmari, assistant professor of clinical psychiatry at Columbia University, turned to a new technology called optogenetics.

The researchers first engineered a common adenovirus — usually associated with upper-respiratory infections — to carry the genetic coding for a light-sensitive pigment known as rhodopsin. They then injected the virus into the OFC of lab mice, where it could enter brain cells carrying its rhodopsin payload with it.

That caused the otherwise normal cells to become light sensitive. Finally, the scientists inserted fiber optic strands into the mice’s brains and stimulated them with pulses of light. What they expected to see was an increase in grooming behavior, which is common among mice — and in their species-specific way is similar to hand washing in humans. But when they flicked the light on in the mice’s brains what they got was pretty much nothing — at least at first.

“When we hyperstimulated this specific circuit, we thought we were going to see an increase in abnormal behaviors,” Ahmari said in a video released along with the Science paper. “That stimulation did not lead directly to repetitive behavior, but if we repeatedly stimulated for several days in a row for just five minutes a day, what we got was the progressive evolution of grooming behavior.”

The mice, in effect, had been neurologically nudged to a full-blown case of OCD, and even when the researchers quit the stimulation, the behavior stuck around for at least a week. In some of the mice, small doses of fluoxetine — the generic form of Prozac and other selective serotonin reuptake inhibitors — hastened the disappearance of the behavior.

All that reveals a lot. For one thing, it may help explain why some OCD patients can go for years or decades without the disorder and then experience a single traumatic event — a near accident on a highway, a legitimate disease scare that turns out to be nothing — and shortly after, develop OCD symptoms related to the experience.

They may have been born with a predisposition to the disorder (the genetic roots of OCD are still not completely understood), but the triggering event, like the few days of light stimulation in the mice, tips them fully into it.

More important, the research maps the underlying neural wiring behind the disorder and could help in the development of better, more precisely targeted drugs.

For people with intractable cases of OCD that resist both behavioral and pharmacological therapy, other researchers have looked at deep-brain stimulation (DBS), using fine wires to activate or deactivate trouble spots. This is already being used successfully to treat the tremors associated with Parkinson’s disease. What science learns from studying mice could eventually lead to improved DBS.

None of this fully explains the mysteries of OCD, and drilling into the heads of human patients to insert wires is clearly a last therapeutic resort, especially since the large majority of cases do respond so well to less invasive treatment.

Still, for sufferers who long castigated themselves as weak-willed or otherwise responsible for their own suffering, it can be a relief to know that OCD is just a sickness like any other — and as with so many sicknesses, relief is increasingly possible.

Gary Marcus: The New Yorker "Obama's Brain" Excerpt

Magnified 400 times, this is a 2-Photon fluorescence image of glial cells in the cerebellum. Glial cells provide support for the brain's neurons. This image was made by Thomas Deerinck of the National Center for Microscopy and Imaging Research, University of California, San Diego.

At some level, the brain is a kind of computer. It takes in information, combines new information with previously acquired information, and performs actions based on the results of those computations.

Yet we know remarkably little about how the brain performs its computations and how those computations relate to behavior, especially in comparison to what we know about computers.

Computers are, for all practical purposes, entirely understood. We know what they’re made of, we know how electrons move inside of them, and we know how their basic logical functions (such as “and,” “or,” and “not”) combine to form more complex operations, such as arithmetic and control (e.g., performing process X if a password is entered correctly and process Y if the password is entered incorrectly).

 In turn, programming languages relate machine language to more abstract sets of instructions that are more readily understood by human beings. An unbroken chain of inference connects the plans of the programmer to the actions of the electrons that ultimately implement them.

When it comes to the brain, we know comparatively little, in part because the brain is considerably less straightforward. By some counts (though the exact number remains elusive), there are hundreds of different kinds of neurons, each with different physical properties and ways of interacting with other neurons.

We don’t, for example, even know whether the basic unit of computational currency in the brain is digital (e.g., a set of zeroes and ones, like in virtually all modern computers) or analog (like the continuously moving second hand in an old-fashioned clock, an approach that was commonly used in some pre-Second World War computers).

Likewise, although we know something about which brain regions participate in the processing and storage of memories, we still don’t understand how the brain encodes those memories. And we know very little about how the brain’s basic units organize into larger-scale circuits, and how those circuits, often in physically disparate parts of the brain, work together to produce unified behavior.

Modern biology was launched in large part by three discoveries: Oswald Avery’s discovery of DNA; Watson and Crick’s deciphering of the physical structure of the DNA; and the discovery, by several researchers in the early nineteen sixties, of the code by which different triples of RNA nucleotides are turned into amino acids. All three of these discoveries were made possible in part by Mendel’s experiments with peas, in which he identified what we now know as genes.

The brain will finally give up its secrets when we do something similar, by constructing an inventory of the brain’s basic elements—the neural analogs to transistors, logic gates, and microprocessors — and relating those basic elements to broader-scale cognitive computations.

To connect brain to behavior, we don’t need to build a whole brain, as the E.U. aims to do; we need to understand how the brain’s parts work together.

And new techniques, like optogenetics (which allow experimenters to control brain activity—and hence an animal’s behavior—by exposing neurons to light) and fluorescent imaging (which makes it possible to monitor the responses of thousands of neurons simultaneously in awake, behaving animals), make addressing such questions potentially feasible for the first time.

Read more: http://www.newyorker.com/online/blogs/newsdesk/2013/02/obamas-brain.html#ixzz2LwNwZm7I

Rebel Scientist Gary Lynch's Quest for Memory

Thanks to a two-day weekend (somewhat scarce for me), I manged to finish Joseph Ledoux's The Synaptic Self, and also start and finish Terry McDermott's 101 Theory Drive A Neuroscientist's Quest for Memory. I'm feeling pretty darn smart right now.

McDermott's book about neuroscientist's Gary Lynch's decades long research into Long-Term Poteniation. LTP is the strengthening of connections between brain cells that occures when they communicate, making subsequent communication more likely. The book gives the reader an keen appreciation on just how arduous and uncertain biological lab research is. It seems the brain's placiticity allows the growth of new "spines" on the dendrites of neurons, and these changes may be behind how memories are made and stored and even how thought is manufactured.

Lynch's quest is to find the actual structual changes in the celluar circuits that encode memory. Along the way he discovers ampakine, a class of drugs designed to enhance communication between brain cells. If they work as envisioned, the drugs, still in development, would enhance almost all cognitive activities. They may be a new drug to treat memory loss and perhaps even mood disorders.

101 Theory Drive: A Neuroscientist's Quest for Memory by Terry McDermott 

It's not fiction: Gary Lynch is the real thing, the epitome of the rebel scientist -- malnourished, contentious, inspiring, explosive, remarkably ambitious, consistently brilliant. He is one of the foremost figures of contemporary neuroscience, and his decades-long quest to understand the inner workings of the brain's memory machine has begun to pay off.Award-winning journalist Terry McDermott spent nearly two years observing Lynch at work and now gives us a fascinating and dramatic account of daily life in Lynch's lab-the highs and lows, the drudgery and eureka moments, the agonizing failures. He provides detailed, lucid explanations of the cutting-edge science that enabled Lynch to reveal the inner workings of the molecular machine that manufactures memory. And he explains where Lynch's sights are now set: on drugs that could fix that machine when it breaks, drugs that would enhance brain function during the memory process and that hold out the possibility of cures for a wide range of neurological conditions, including Alzheimer's, Parkinson's, and Attention Deficit Hyperactivity Disorder. Here is an essential story of science, scientists, and scientific achievement-galvanizing in the telling and thrilling in its far-reaching implications.

Dr. Gary Lynch is one of the most cited neuroscientists in the world and author of more than 550 scientific articles. He is Professor of Psychiatry at the University of California at Irvine. He is the co-author of Big Brain: The Origins and Future of Human Intelligence.

Brain Circuits and Addiction

What is the nature of addiction?

Amy Winehouse was a terrific talent and one of the favorite recording artists of all time. She also struggled with substance abuse. To what extent remains largely unknown but her death has fueled debate as to the precise nature of drug addiction and how it should be addressed by society as a whole.

In other words, why do some people behave in the often self-destructive manner in which they do? And why are people addicted to drugs in the first place?  How, if at all, might they be helped?

Now, you might think that this is a spectacularly hard task to delve into the neuroscience of addiction try to shed some light. Surely, drugs of abuse (such as amphetamines, cocaine, opiates, alcohol and nicotine) have a broad range of actions that are wholly dissimilar from each other? Well, that is partly true, but when it comes to their addictive properties, they have more in common than you might think.

What constitutes addiction?

Addiction, as most will know, develops as a result of chronic exposure to a particular substance. People who are addicted to a drug show similar patterns of behaviour. These include:

1. A compulsion to seek the drug

2. An inability to control the amount of drug consumption

3. A negative emotional state when subjected to periods of withdrawal

Neuroscientists have sought to understand the neural mechanisms underlying these behaviours for generations and emerging from these studies is the concept of the ‘reward circuit’ that seems to be involved in the development and maintenance of drug addiction.  In fact, research on the medial forebrain pleasure circuit may be entering a golden age of discovery.

Now, a lot of neuroscience (indeed any science) is about gradually building up a picture from fragments of information. In most cases, that information may not even come from human subjects but from animal models. That means that current ideas regarding drug addiction are far from unequivocal, but from looking at the correlations between how the rodent brain and human brain are altered during the development of drug addiction, we can make careful assumptions about what might be the general rule.
You see, the brain behaves a little bit like a factory, with different departments responsible for producing a certain sort of feeling or behaviour. This means that there are anatomically distinct areas that are concerned with happiness, memory, movement and so on. This is (as ever) an oversimplification, as it is usually the concerted action of several brain regions that lead to emergence of a particular thought or action. However, it is useful to think of the brain in this way, particularly when analysing how brain circuits are altered in drug users.

The reward circuit

The reward circuit consists of several brain regions that are heavily interconnected; each with distinct – but related – functionality. These include the nucleus accumbens (a brain region that is extremely well documented for its involvement in drug addiction), the ventral tegmental area, the amygdala, the prefrontal cortex, the hippocampus and the insula, among others.

Dysfunction in each of these areas has been implicated in the onset and maintenance of drug-addiction, each area being responsible for a slightly different facet of the drug-addicted mental state.

The nucleus accumbens: pleasure

Now, the nucleus accumbens is known as the reward center of the brain. Largely because in various different experimental paradigms, subjects that report that they are experiencing reward show increased activity in this area. This can be whilst taking drugs of abuse or simply eating, engaging in sexual activity or indeed anything associated with pleasurable reward.

All drugs of abuse raise the level of a chemical known as dopamine in the nucleus accumbens and it is this elevation in dopamine (initiated in different ways by different drugs) that is responsible for the feeling of euphoria associated with drug intake.

However, persistent activation of the nucleus accumbens leads to the development of drug addiction, primarily due to persistent changes in the level of dopamine, which leads to an alteration in how people respond to otherwise rewarding stimuli. Put simply, after disruption of the dopamine levels in the nucleus accumbens, people get less satisfied with things that aren’t their drugs of choice. Furthermore, people derive progressively more pleasure from the drug in question, exacerbating the effect.

The amygdala: fear

On the flip side of the coin, the amygdala is a region of the brain situated right next to the nucleus accumbens but is often associated with feelings of fear and anxiety.
As opposed to the positive reinforcement created by the nucleus accumbens, it is during withdrawal that the amygdala seems to have its largest role. Basically, as access to the drug is taken away, stress-related hormones are increased in the amygdala which can lead (at least partially) to the negative feeling associated with withdrawal.

The hippocampus: memory

The hippocampus is an area of the brain that is associated with learning and memory as well as the ability to perform tasks requiring spatial navigation, such as finding your way around a building. It is also important for ‘contextual-conditioning’, meaning that it enables the mind to establish links between an environmental cue (a nightclub, for example) and a memory (such as taking a drug.)

Activation of the hippocampus is implicated in initiating cue-induced drug-seeking behaviour. Indeed, it has been shown that cue-induced craving of drugs (eg. the feeling of needing a drink in a pub or a cigarette with a cup of coffee) is associated with an increase in activity in the hippocampus (as well as the amygdala) in humans, indicating that normal memory function may be being encroached upon by drugs of abuse.

The prefrontal cortex: decision

The prefrontal cortex consists of several subdivisions including the orbitofrontal cortex and dorsolateral prefrontal cortex. These areas have a variety of different functions but are often described as being imperative in carrying out decision-making processes in response to internal/external-cues, a process known as executive function.

It is believed that the activity of the prefrontal cortex is disrupted in subjects who are addicted to drugs. This may go some way to explaining why drug users often make poor decisions regarding drug intake (ie. pursuing a drug whilst fully aware of the negative impact drug intake will have on them and the people around them.)

What goes on in the brain of a drug addict

So…
As complicated as that may have sounded, it represents a gross oversimplification of what actually goes on in the mind of a drug addict. I simply wanted to introduce you to some of the concepts that are emerging as a result of neuroscientific research and give you a flavor of what is to come in future posts. As I move through my journey into drug addiction, I will make constant references to the reward circuit and its components and so an introduction was necessary to familiarise you with the brain’s machinery. -- Dr. Paul

Dr. Paul is a graduate from the University of Bristol and the author of Dr Paul’s Brain Talk, a neuroscience-related magazine. Dr. Paul believes that over the coming decades, neuroscience research will begin to have a greater impact on our lives and he aims to bring the findings of this fascinating field to the general public, in words they can understand.

Whole-Brain Circuit Map

Mapping the mammalian brain circuits

Thirty-seven researchers from Cold Spring Harbor Laboratory (CSHL) and 20 other major research institutions in the U.S. and Europe have issued a major challenge to the neuroscience community. At long last, the time has come, they argue in a just-published paper, to assemble a comprehensive map of the major neural circuits in the mammalian brain.

In an age in which the genomes of a number of organisms, including that of humans, have been fully sequenced and can be accessed instantly by anyone with a computer, anywhere in the world, it is astonishing to consider that "we have, as yet, not been able to compile a whole-brain map of the circuitry that underlies the functioning of our own brains," notes Professor Partha P. Mitra, Ph.D., senior author of the paper and leader of the ongoing Brain Architecture Project at CSHL, funded by the WM Keck Foundation. To help address this knowledge gap, Mitra organized a series of meetings at the CSHL Banbury Center in 2007 and 2008, from which this proposal grew.

The neuroscience community's "sparse knowledge" of mammalian neuroanatomical circuitry is "perhaps the largest lacuna in our knowledge about nervous system structure," Mitra and his colleagues observe in their paper, which appears in the recent issue of PLoS Computational Biology

Map the brain circuits of the mouse.

The case for committing resources to assembly of a whole-brain circuit map is especially strong, they say, because it almost certainly will provide insights about what goes wrong in brain dysfunctions spanning a range of neurodevelopmental illnesses including autism, schizophrenia, and perhaps mood disorders such as depression, bipolar illness, and obsessive-compulsive disorder (OCD). Further, the authors argue that technological advances along with decreasing computational and data-storage costs have made such an effort feasible now, when it could only be dreamt of even in the recent past.

A community-wide project to prepare a 'first draft'.
Mitra and his co-authors therefore advocate for "a concerted effort" to complete a first-draft circuit map of the entire mouse brain within two to three years, as a first step to mapping vertebrate brain architecture across species. The proposed project would ideally be pursued simultaneously by neuroresearchers at multiple institutions as per standardized protocols. "In this respect," says Jason Bohland, Ph.D., a postdoctoral neuroscience researcher at CSHL and the paper's main author, "it would be analogous to the multi-institution effort to sequence the human genome, with the important distinction that our brain-circuit map could be completed much more rapidly and would cost a small fraction of the genome project as little as a few million dollars ranging up to perhaps $20 million, depending on the redundancy in coverage that we commit to." 

To date, research on the brains of mammals typically, rodents and non-human primates has described, using a multitude of different techniques, only a small fraction of the total set of neuronal pathways, in an unsystematic manner. Even though spectacular advances have been made in neuroscientists' ability to examine and measure the output of individual neurons in the brains of living animals, such studies have shed little light on how the brain as a whole is wired together. In much the same way that the study of the genome has shifted to emphasize networks of interacting genes, neuroresearchers are beginning to understand the importance of circuit-level properties in the normal and dysfunctional brain.

This, says Mitra, is notable in part because "the defining architectural feature of the nervous system is precisely that it forms a circuit." One critical question, therefore, is at what level of resolution to attempt a whole-brain circuit diagram. Mitra and co-authors are proposing to map the circuit in the mouse brain at what they call a "mesoscopic scale." Somewhere between the micro- and macroscopic, this intermediate level corresponds with the basic architectural organization of the mouse brain, in terms of its observed cellular, chemical, and genetic makeup. Most importantly, the authors expect this to be the level at which the pattern of connections in individual animals will have a significant degree of commonality, ultimately providing a meaningful and tractable description of the brain's structure.

Tracing the inputs and outputs of each area. Brain organization at the macroscopic level the level of entire structural-functional systems and major nerve-fiber bundles is somewhat understood, but provides an insufficient level of description of the overall wiring diagram. Some researchers have argued that it would be best to map mouse brain structure at the micro-level of individual synapses the myriad gaps across which individual neurons communicate, with the help of neurotransmitters and modulators such as glutamate, GABA, acetylcholine, dopamine and serotonin. But this isn't technologically feasible to do on a brain-wide scale for a mouse, let alone larger vertebrate brains. Data storage at such a scale, which would involve storing nanometer-resolution images made with electron microscopes, could cost as much as one billion dollars, Mitra says.

In contrast, the proposed project is "both technologically and economically practical, involving techniques that are well proven," as per Mitra. All measurements will be made in standard lab mice of precisely the same developmental age 56 days, as in the Allen Brain Atlas project; each mouse will be injected in one brain area with one or more tracers, which are actively transported within individual nerve cells. These tracers appears to be "conventional" molecules that have been used by neuroanatomists over the last several decades, or engineered viruses that infect cells at the injection site, marking their extent through the expression of a fluorescent protein. The utility of these techniques is in tracing projection neurons either from axon terminals to potentially distant cell bodies or vice-versa.

Together, the tracers will provide a view of the pattern of inputs and outputs for a given site in the brain. These patterns will be mapped from images of thinly sectioned brain slices obtained using light microscopy, taking advantage of recently available technologies to rapidly and automatically scan and digitize a set of slides.

Extracting and combining the results across individual mice will be a computational challenge that requires automating a number of of the steps that neuroanatomists now perform by hand. Bohland is aware of these challenges. "Solving these problems in general is difficult because the circumstances of individual experiments can be wildly different," he acknowledges, "But in the systematic, standardized protocols we call for, finding solutions becomes considerably easier." .

The full dataset will comprise hundreds of terabytes a very modest data-storage burden, as per Mitra. "That will give us about twofold coverage of the entire brain circuit in a first draft, and could be accomplished in two or three years, with cooperation from the neuroscience community. At more robust funding levels, we could attempt 10-fold coverage over, perhaps, a five-year period." In the spirit of genome projects, all data from the proposed program would be made rapidly available over the web to the entire research community.

While the immediate focus now is to bring a mouse connectivity project to fruition, the authors also make the case for cataloging and digitizing results from existing studies in other species, and for filling key gaps with targeted studies. Moreover, there is an important need, they argue, for further development and validation of experimental techniques that can be used directly in the human brain.

Comparing circuits in healthy brain vs. the brain in autism or schizophrenia. Perhaps the most exciting aspect of such a brain mapping project is its likelihood to deepen our understanding of what goes awry at the circuit level in neuropsychiatric illnesses. At present, researchers are lacking data of this type with which to work on theories of disease causation and mechanism. "In recent years," Mitra observes, "a number of researchers have made mouse models of various complex disorders, such as schizophrenia or autism. But so far no one has been able to pinpoint what goes wrong in brain circuitry when you have one of these devastating illnesses.
"It has been hypothesized, at least for neurodevelopmental disorders, that the circuit is altered during the developmental process, in some manner fundamentally changing the circuit. Once we have succeeded in fully mapping the brain in the healthy mouse, we will be able to measure, objectively, how the whole-brain circuit differs in mice that model various aspects of behaviors or known genetic alterations linked to human illnesses like autism or schizophrenia. "I think this would be a crucial missing piece in any effort to understand comparatively, not at the level of observed behavior, or at the level of the genome, but at the level of the brain circuit, how healthy individuals differ from those with illness," Mitra says. "With a circuit map we will be able to hypothesize disease-circuit phenotypes for neurodevelopmental illnesses, which, in turn, should lead to new understanding of disease causation and mechanism, and to the development of new therapeutic approaches.

"Our first challenge, however, is to engage our neuroscience colleagues and enlist them in the project to get a first draft of the healthy mouse brain. That's the necessary first step before we can begin looking at brain circuits in disease and making comparisons."