Journal Article

Asymmetric effects of activating and inactivating cortical interneurons

Hasenstaub, Andrea R, Phillips, Elizabeth AK

2016

Overview

Bidirectional manipulations – activation and inactivation – are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons’ computational functions. The brain processes information through the activity of many different types of neurons. A common assumption is that we can work out the role of each type of neuron by increasing or decreasing its activity experimentally and observing the consequences. Imagine, for example, that increasing the activity of a group of neurons boosts the formation of memories, whereas decreasing their activity has the opposite effect. Can we conclude that the natural role of those neurons is to support memory formation? This question has become increasingly pertinent in recent years, as advances in molecular genetic techniques such as optogenetics have made it easier to experimentally manipulate the activity of neurons. However, the ease with which these experiments can be done masks how difficult it can be to interpret the results. To test the assumption that dialing a neuron’s activity up or down provides a straightforward readout of its role in the brain, Phillips and Hasenstaub used optogenetics to inactivate two types of neurons in an area of the mouse brain responsible for processing sound. Inactivating each cell type produced different outcomes. The standard way of interpreting these results is to conclude that the neurons must therefore have different, separable roles. However, using optogenetics to increase the activity of the neurons revealed no such differences in the neurons’ roles. Using a computer model, Phillips and Hasenstaub showed that relatively small changes in factors such as the spontaneous activity of the neurons can affect the outcome of the experiments. Under certain circumstances, the two types of neurons respond in the same way to activation and inactivation; under other circumstances, they respond differently. The results presented by Phillips and Hasenstaub remind us that the conclusions we draw about a neuron’s role can be sensitive to how the cell was manipulated. Future studies should address how other aspects of experimental manipulations, such as their timing or pattern, affect the apparent behavior of neurons.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Action Potentials / Animals / Auditory Cortex - physiology / cortex / Cortex (auditory) / Gene expression / Interneurons / Interneurons - chemistry / Interneurons - physiology / Mice / Models, Neurological / Neocortex / Neural circuitry / Neurons / Neuroscience / Neurosciences / Optogenetics / Parvalbumin / Parvalbumins - analysis / Physiological aspects / Population / Somatostatin / Somatostatin - analysis / Standard deviation