Action Potential

Methods for drug screening efforts during drug discovery are mostly inadequate to address the complexity of interactions within the intact body. These limits become even more apparent when the drugs are meant to target behavior and psychology. A paper published earlier this year (“Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation” January 15, 2010 in Science) presents a promising technique to address these limits.

The team developed a whole organism, high-throughput screen for drugs. They placed individual zebrafish larva into wells with the drug that they wanted to test. Each plate had 80 zebrafish larva moving around in their own wells. Behavior was automatically measured using video recording techniques and automated tracking software. The results went through cluster analysis.

Behavioral profiling results showed:

• relationships between the drugs tested and their targets
• a conserved vertebrate neuropharmacology
• identified regulators of the target behavior

Individual drugs with unknown targets were clustered with drugs with known neuropharmacological properties. The well-known drugs could predict the targets for the drugs without characterized targets that were clustered with them. In addition, behavioral profiling identified previously unidentified pathways involved in the target behavior. I recommend this article to anyone wondering how to get a handle on the huge number of variables that need to be addressed in drug discovery, systems biology, and neuroscience.

Information acquired through touch seems to exert broad influence over thought. Shoppers more readily understand and are confident about products they touch. Impressions formed by touching one thing can influence perceptions about another thing. For example, water seems to taste better from a firm bottle than from a flimsy bottle. The recent paper “Incidental Haptic Sensations Influence Social Judgments and Decisions” published June 25, 2010 in Science presents these examples to emphasize the under appreciated importance of touch.

The research team tested how the experience of weight, texture, and hardness through active touch influenced judgments and decisions about unrelated events, situations, and objects.

The researchers point out the weight is metaphorically associated with concepts of seriousness and importance. “That’s heavy!” In one study individuals were asked to evaluate a job candidate by reviewing resumes on either light or heavy clipboards. Evaluations using heavy clipboards rated the job candidates as better overall and as displaying more serious interest in the position. The individuals evaluating the candidates using heavy clipboards also evaluated their own accuracy on the task as more important than did those using the light clipboards.

In another study, individuals were asked whether particular public issues should receive more or less government funding. Men allocated more money to social issues when the clipboard was heavy than when it was light. Women chose to fund social issues at close to the maximum amount irrespective of clipboard weight.

Next, the research addressed texture’s effects on an individual’s perceptions of social interactions. They point out that metaphorically roughness and smoothness are associated with concepts of difficulty and harshness. “I’m having a rough day.” Participants who interacted with rough textures rated observed social interactions as more difficult and harsh than did participants who interacted with smooth surfaces.

Finally, the experience of hardness in active touch and its effect on thought was investigated. Hardness is metaphorically associated with the concepts of stability, rigidity, and strictness. Individuals who felt a hard block judged employees to be more rigid or strict than participants who felt a soft blanket.

The research then went a step further and tested passive touch’s influences on thought. Participants were primed by the seat of their pants. They either sat on a hard wooden chair or a soft cushioned chair. Participants sitting on hard chairs judged employees to be more stable and less emotional than did participants in soft chairs.

It’s become clear that adult brain anatomy is far from static and inflexible. New neurons are born from stem cells. Old connections break and new connections are made. Within this context a research team asked what the detailed circuit dynamics might be in rodent whisker related cerebral cortex. They published their results in the recent paper “Axonal Dynamics of Excitatory and Inhibitory Neurons in Somatosensory Cortex” ( June 2010 in PLoS Biology).

Not familiar with the whisker system? See my blog post Wiggling Whiskers for a Living? or some of the other posts listed below under “Other related blog posts.”

The paper takes a look at the horizontal connections of layer 2/3 pyramidal cells and inhibitory interneurons in whisker related cerebral cortex of mice during normal and modified experience using genetically engineered viruses and two-photon microscopy.

Connections (synapses) between nerve cells (neurons) in the brain are dynamic during normal experience. Old connections are broken and new connections are made. The research team observed that excitatory axons in adult brains with normal experience have a constant rate of connection turnover of 6% per week (6% are broken and 6% are new providing a no net gain of connections). Inhibitory axons broke connections at 10% per week and made new connections at 8% per week (with a net loss of 2% per week!).

To (dramatically) modify whisker sensory experience in their mice the research team plucked two full rows of whiskers (D and E rows) every day (whiskers grow back). They observed massive and rapid reorganization of the axons of both excitatory and inhibitory neurons along with a transient increase in the number of connections between neurons.

Within hours of whisker plucking, inhibitory neurons in sensory deprived cortex began extending new axons into sensory non-deprived cortex. This was followed by the extension of excitatory neuron axons from sensory non-deprived cortex into sensory deprived cortex.

After whisker plucking the turnover in connections between neurons increased dramatically. In non-deprived cortex excitatory synaptic boutons were added at rates of 43% and eliminated at 29% per month with a net gain of connections. Inhibitory interneurons in non-deprived cortex added new connections at rates of 31% every 2 days and eliminated 23% every 2 days with a net gain of connections.

In sum, this research demonstrated dramatic reciprocal affects of sensory deprivation on excitatory and inhibitory neuron connections within layer 2/3 somatosensory cortex. Some of the circuit connectivity data remain a puzzle to me. In particular, what should we make of the normative inhibitory connection data that show a constant loss of about 2% of the connections every week?

Other related blog posts:

Wiggling Whiskers for a Living?

Wiggling Whiskers: Directional Tuning

Whisker Related Brain Anatomy Data for Building Simulations

Wiggling Whiskers: Neurons in the Barrel Cortex and Object Localization