Animal study highlights potential new target for treating anxiety disorders
Increasing acidity in the brain’s emotional control center reduces anxiety, according to an animal study published February 26 in The Journal of Neuroscience. The findings suggest a new mechanism for the body’s control of fear and anxiety, and point to a new target for the treatment of anxiety disorders.
Anxiety disorders, which are characterized by an inability to control feelings of fear and uncertainty, are the most prevalent group of psychiatric diseases. At the cellular level, these disorders are associated with heightened activity in the basolateral amygdala (BLA), which is known to play a central role in emotional behavior.
Many cells in the BLA possess acid-sensing ion channels called ASIC1a, which respond to pH changes in the environment outside of the cell. Maria Braga, DDS, PhD, and colleagues at the Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, found that activating ASIC1a decreased the activity of nearby cells and reduced anxiety-like behavior in animals. These findings add to previous evidence implicating the role of ASIC1a in anxiety.
“These findings suggest that activating these channels, specifically in fear-related areas such as the amygdala, may be a key to regulating anxiety,” explained Anantha Shekhar, MD, PhD, who studies panic disorders at Indiana University and was not involved in this study. “Developing specific drugs that can stimulate these channels could provide a new way to treat anxiety and fear disorders such a post-traumatic stress and panic disorders.”
To determine the effect ASIC1a activation has on neighboring cells, Braga’s group bathed BLA cells in an acidic solution in the laboratory and measured the signals sent to nearby cells. Lowering the pH of the solution decreased the activity of cells in the BLA.
Activating ASIC1a also affected animal behavior. When the researchers administered a drug that blocks ASIC1a directly into the BLA of rats, the rats displayed more anxiety-like behavior than animals that did not receive the drug. In contrast, when rats received a drug designed to increase the activity of ASIC1a channels in the BLA, the animals displayed less anxiety-like behavior.
“Our study emphasizes the importance of identifying and elucidating mechanisms involved in the regulation of brain function for the development of more efficacious therapies for treating psychiatric and neurological illnesses,” Braga said. While the findings suggest that drugs targeting ASICs may one day lead to novel therapies for anxiety disorders, Braga noted that “more research is needed to understand the roles that ASIC1a channels play in the brain.”
Link to the article:
Cognitive neuroscience constantly works to find the appropriate level of description (or, in the case of computational modeling, implementation) for the topic being studied. The goal of this post is to elaborate on this point a bit and then illustrate it with an interesting recent example from neurophysiology.
As neuroscientists, we can often choose to talk about the brain at any of a number of levels: atoms/molecules, ion channels and other proteins, cell compartments, neurons, networks, columns, modules, systems, dynamic equations, and algorithms.
However, a description at too low a level might be too detailed, causing one to lose the forest for the trees. Alternatively, a description at too high a level might miss valuable information and is less likely to generalize to different situations.
For example, one might theorize that cars work by propelling gases from their exhaust pipes. Although this might be consistent with all of the observed data, by looking “under the hood” one would find evidence that this model of a car’s function is incorrect.
On the other hand, a model may be formulated at too low a level. For example, a description of the interactions between molecules of wood and atoms of metal is not essential for a complete, thorough understanding of how a door works.
One particularly exciting aspect of multi-level research is when one synthesizes enough observations to move from one level to a higher one. Emergence is a term used to describe what occurs when simpler rules interact to form complex behavior. It’s when a particular combination of properties or (typically nonlinear) processes gives rise to something surprising and/or non-obvious. To give a basic example, hydrogen and oxygen both support fire. Surprisingly, their combination — water — puts fires out and expands when frozen.
An Example of Emergence: The Neural Basis of Memory
A recent article by Raymond and Redman (Journal of Neurophysiology, 2002) takes a close look at three separate subcellular mechanisms that appear to support LTP (reminder: LTP is long-term potentiation, which is one of the best candidates to-date for the neural basis of memory.
Raymond and Redman replicate the earlier finding that longer bouts of electrical stimulation can cause LTP to be more powerful (resulting in larger postsynaptic responses), and last longer. They demonstrated three different levels of LTP in their experiment by using three different length trains of electrical stimulation. This stimulation-dependent property of LTP has been taken as the basis for synaptic modification rules used in neural network models; (Neural Network “Learning Rules”)
Interestingly, the researchers then demonstrated that by blocking three different cellular mechanisms – ryanodine receptors, IP3 receptors and L-type VDCCs respectively – they were able to selectively block LTP from the shortest, intermediate or longest stimulation trains.
Taken together, these results suggest that the high-level phenomenon of LTP is actually composed of (at least) three separate underlying processes. These separate processes appear to cover different timespans, contributing to an exponential curve relating LTP to the time and strength of neuronal activity.
The study mentioned in this post contributes to the field by helping to lending additional evidence to our current theoretical understanding of a mechanism which is likely to underpin memory. From a theoretical perspective LTP appears to be a meaningful construct which emerges from mutliple, dissociable subcellular processes.
More generally, the study is an excellent demonstration of emergence: three separate processes from a particular level (subcellular receptor proteins) appear to jointly support a more abstract, single processes at a higher level (LTP in cellular electrophysiology). As a result, computational modelers can feel more comfortable with assumptions of an LTP-like assumption in their simulations.
A final thought is that this type of research also clearly highlights the importance of interdisciplinary research in the neurosciences.
This image illustrates the dissociation between primary and secondary rewards in the orbitofrontal cortex, a frontal region of the brain that is known to play a role in the evaluation of gratification. The more primitive region (in the back, shown in yellow) represents the value of erotic images shown to the participants, while the most recent region (in the front, in blue) represents the value of monetary prizes won by the volunteers in the experiment. Credit: © Sescousse / Dreher
A team of French researchers headed by Jean-Claude Dreher of the Centre de Neuroscience Cognitive in Lyon, France, has provided the first evidence that the orbitofrontal cortex (located in the anterior ventral part of the brain) contains distinct regions that respond to secondary rewards like money as well as more primary gratifications like erotic images. These findings, published in The Journal of Neuroscience, open new perspectives in the understanding of certain pathologies, such as gambling addiction, and the study of the neural networks involved in motivation and learning.
In our everyday lives, we often encounter various types of “rewards”: a 20-euro bill, a chocolate bar, a glass of good wine… Moreover, we must often choose between them, or trade one for another. To do this, we must be able to compare their relative value on a single consistent scale, which suggests that all types of rewards are assessed in the same brain areas. At the same time it is possible that, due to their individual characteristics, different rewards may activate distinct cerebral regions. In particular, there could be a dissociation between so-called “primary” gratifications such as food or sex, which satisfy basic vital needs and have an innate value, and more “secondary” rewards such as money or power, which are not essential for survival and whose value is assessed by association with primary gratifications.
To verify these hypotheses, Jean-Claude Dreher and Guillaume Sescousse conducted an original experiment in the form of a game that rewarded 18 volunteers with money or erotic images, while their cerebral activity was monitored using an FMRI (functional magnetic resonance imaging) scanner.
The experiment showed that the rewards are indeed evaluated in partially shared cerebral regions, namely the ventral striatum, insula, mesencephalon and anterior cingulate cortex. The researchers have also confirmed that there is a dissociation between primary and secondary rewards in the orbitofrontal cortex. Its posterior region (more primitive) is specifically stimulated by erotic images (a primary reward), while its anterior region (which is more recent in man) is activated by monetary gain (a secondary reward). The more abstract and complex the reward, the more its representation stimulates the anterior regions of the orbitofrontal cortex.
The volunteers in the experiment played a game in which they could win money or view erotic images, while their cerebral activity was recorded using an FMRI scanner. Credit: © CERMEP – Imagerie du Vivant
These results provide the first evidence of a dissociation in the brain between two types of reward, suggesting the existence of distinct regions corresponding to various gratifications. Dreher and Sescousse’s research could lead to a better understanding of certain psychiatric disorders, including gambling addiction.
More information: G. Sescousse, J. Redouté, J-C Dreher (2010) The architecture of reward value coding in the orbitofrontal cortex. J Neurosci, 30 (39)
Provided by CNRS
G. Sescousse, J. Redoute, J.-C. Dreher. The Architecture of Reward Value Coding in the Human Orbitofrontal Cortex. Journal of Neuroscience, 2010; 30 (39): 13095 DOI: 10.1523/JNEUROSCI.3501-10.2010
The Monkey Business Illusion
“Imagine you are asked to watch a short video (above) in which six people-three in white shirts and three in black shirts-pass basketballs around. While you watch, you must keep a silent count of the number of passes made by the people in white shirts. At some point, a gorilla strolls into the middle of the action, faces the camera and thumps its chest, and then leaves, spending nine seconds on screen. Would you see the gorilla?
Almost everyone has the intuition that the answer is “yes, of course I would.” How could something so obvious go completely unnoticed? But when we did this experiment at Harvard University several years ago, we found that half of the people who watched the video and counted the passes missed the gorilla. It was as though the gorilla was invisible.
This experiment reveals two things: that we are missing a lot of what goes on around us, and that we have no idea that we are missing so much. To our surprise, it has become one of the best-known experiments in psychology. It is described in most introductory textbooks and is featured in more than a dozen science museums. It has been used by everyone from preachers and teachers to corporate trainers and terrorist hunters, not to mention characters on the TV show C.S.I., to help explain what we see and what we don’t see. And it got us thinking that many other intuitive beliefs that we have about our own minds might be just as wrong. We wrote The Invisible Gorilla to explore the limits of human intuition and what they mean for ourselves and our world. We hope you read it, and if you do, we would love to hear what you think.”