Journal Club

Our Journal Club highlights high-profile work from our young scientists-in-training and discusses the impact of the Neuroscience Institute's research on the field, our understanding of the brain, and potential breakthroughs that may translate into improved patient care.

A Synaptic and Circuit Switch Enables Context-Dependent Behavior

by Tom Hindmarsh Sten and Eleni Papadoyannis

Sounds do not always have the same meaning. For example, in linguistics the same word often has multiple meanings, requiring humans to integrate previously learned associations, their behavioral context, and sensory information to arrive at a meaningful interpretation. Though this ability is vital to behaving animals, the precise synaptic and circuit elements in the brain that enable such context-dependent processing have remained poorly understood. In our most recent work (Kuchibhotla et al. 2016), we took a multifaceted approach to this question, and revealed how a neural “switch” in the brain modulates the way sounds are encoded in behaving animals.

In our work, we trained mice to switch between two different contexts; in one, mice passively listened to pure tones, while in the other, mice performed a stimulus recognition task to the same stimuli. Two tones were played to each animal: a target tone to which the animal is trained to lick for a small water reward, and a foil tone to which the animal is trained to withhold licking to avoid a short time-out – requiring the animal to actively discriminate between the two tones.  In the passive context the lick tube that is present in the active context is removed, and the two tones are played but the animal does not make a response.

To monitor the activity of hundreds of neurons in the auditory cortex, we performed in vivo cell-type specific two-photon calcium imaging during behavior. In the passive context, while mice were simply listening to sounds, we found a large number of tone-responsive neurons. Interestingly, however, as soon as the mice switched to a task-engaged state a new, smaller set of neurons became tone responsive, while most others were significantly less responsive. To understand these changes, we recorded both inhibitory and excitatory currents using whole-cell voltage-clamp, and found that while excitation was stable, inhibition changed rapidly with behavioral context. These changes appeared to largely be gated by three different subtypes of inhibitory interneurons in the auditory cortex (SOM+, VIP+, and PV+), each with their own distinct contextual modulations and response properties. To fully understand the interactions between these four circuit elements, we used optogenetics to suppress the activity of each during behavior. We found that PV+ and SOM+ interneurons appear to provide direct inhibition to excitatory neurons, while VIP+ interneurons had a disinhibitory role.

This circuit reveals how the brain modulates the activity of sensory neurons in response to behavioral context. Yet, it does not answer the question of how behavioral context is communicated to this region of the brain. The Nucleus Basalis (NB) is a region in the basal forebrain which has long been implicated in modulating attention and learning by providing cholinergic input. We hypothesized that the brain may utilize some of this neural machinery to convey context in a rapid and reversible manner. To test this, we used calcium imaging to monitor the activity of axons projecting from the NB to the auditory cortex during the context-switching paradigm. We found that the calcium activity of these projections strongly increased during task engagement, while pharmacological blocking of muscarinic receptors severely reduced the animal’s performance. Remarkably, by optically stimulating these NB axons during passive context, causing the release of endogenous acetylcholine, we were able to partially induce a “fictive” active state where the animal licked to target tones without presentation of the water reward. Thus, we found that cholinergic signals from the NB were necessary and partially sufficient to convey behavioral context. A network model captured these dynamics across neuronal subtypes only when cholinergic signals coincidently drove inhibitory and disinhibitory circuit elements, ruling out either as sole computational responses to cholinergic modulation.  

A major challenge for neural systems is to provide logic to complex neural dynamics. We present a cohesive model, based on experiments and theory, that shows how parallel processing of cholinergic modulation by diverse cortical interneurons enables the same sensory stimuli to trigger different behaviors depending on context. Furthermore, we hope this project will provide insight into how diseases, such as post-traumatic stress disorder (PTSD), may hijack the flexible perception mechanisms during pathological states in humans.

Kishore V Kuchibhotla, Jonathan V Gill, Grace W Lindsay, Eleni S Papadoyannis, Rachel E Field, Tom A Hindmarsh Sten, Kenneth D Miller & Robert C Froemke Parallel processing by cortical inhibition enables context-dependent behavior. Nature Neuroscience, published online October 31, 2016


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