How do scientists determine information flow in the brain?

Today I want to summarize the tools used in the article Active dendritic currents gate descending cortical outputs in perception. These tools were key in determining how apical dendrites modulate activity in neurons. This particular study tried to understand how dendritic currents are integral in performing information gating. Specifically information gating refers to how the brain determines what stimuli to focus to pay attention to, and what stimuli to ignore. For example, the brain attends to stimuli necessary for a given task, and ignores stimuli that are irrelevant to the task at hand. This can be accomplished with apical dendritic activation that can generate calcium spikes. This in turn lowers the threshold for neurons to fire.

With that in mind, the authors set out to determine if neurons in the barrel cortex of rats are modulated by dendritic calcium currents. They set up an experiment where they could control the vibrations of specific whiskers with a small magnetic field. These whiskers have very stereotypical receptive fields in the barrel cortex. With this, they were able to derive a psychometric curve where whisker vibration versus task performance correlated strongly with neural activation. Moreover, they showed that these thresholds could be manipulated with optogenetic activation, dreadd receptors inhibition, and task dependency.

They used three different tools in this study. The first tool they used was optogenetics. Optogenetics relies on using 2-photon fluorescence. Specifically, they design a GCAMP6f protein which is a modified calmodulin protein with a fluorescent protein attached to it. When calcium is bound to the calmodulin domain, the fluorescent protein is excited by the light, and will emit photons. This allows the scientists to quantify calcium concentrations using the intensity of this light. Moreover they can visualize the calcium currents in the apical dendrite of the neuron.

The second technique they used is called optogenetics. Here they make use of a genetically modified version of channelrhodopsin (its one word for some reason). This ion channel is from a photosensitive algae. When blue light touches channelrhodopsin the channel opens and lets sodium and calcium in. Furthermore, there is a specific genetic marker for apical dendrites pyramidal cells in the barrel cortex specifically. Thus they can edit for that marker and insert the channel into a very specific part of the membrane. This way they can activate only the apical dendrite. Moreover they show using this technique that the apical dendrite lowers the threshold and thus gating the information.

The third technique they used is DREADD receptors. These are designed receptors exclusively activated by designer drugs. Here they use a inhibitory receptor for chlorine. The receptor only responds to the drug Clozapine N-oxide which is biologically inert. They again can insert this into the dendritic membrane, and inhibit them. They show this makes it harder for the signal to propagate through the barrel cortex. All of this information together shows that the apical dendrites are key in modulating attention of stimuli.

Author: Alexander White

Original Paper: Takahashi, Naoya, et al. "Active dendritic currents gate descending cortical outputs in perception." Nature Neuroscience 23.10 (2020): 1277-1285.