Unraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model.

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while excessive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

Minimally dependent activity subspaces for working memory and motor preparation in the lateral prefrontal cortex.

The lateral prefrontal cortex is involved in the integration of multiple types of information, including working memory and motor preparation. However, it is not known how downstream regions can extract one type of information without interference from the others present in the network. Here, we show that the lateral prefrontal cortex of non-human primates contains two minimally dependent low-dimensional subspaces: one that encodes working memory information, and another that encodes motor preparation information. These subspaces capture all the information about the target in the delay periods, and the information in both subspaces is reduced in error trials. A single population of neurons with mixed selectivity forms both subspaces, but the information is kept largely independent from each other. A bump attractor model with divisive normalization replicates the properties of the neural data. These results provide new insights into neural processing in prefrontal regions.

Time-invariant working memory representations in the presence of code-morphing in the lateral prefrontal cortex.

Maintenance of working memory is thought to involve the activity of prefrontal neuronal populations with strong recurrent connections. However, it was recently shown that distractors evoke a morphing of the prefrontal population code, even when memories are maintained throughout the delay. How can a morphing code maintain time-invariant memory information? We hypothesized that dynamic prefrontal activity contains time-invariant memory information within a subspace of neural activity. Using an optimization algorithm, we found a low-dimensional subspace that contains time-invariant memory information. This information was reduced in trials where the animals made errors in the task, and was also found in periods of the trial not used to find the subspace. A bump attractor model replicated these properties, and provided predictions that were confirmed in the neural data. Our results suggest that the high-dimensional responses of prefrontal cortex contain subspaces where different types of information can be simultaneously encoded with minimal interference.

Mixed selectivity morphs population codes in prefrontal cortex.

The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. Here we show that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. We found that neurons with mixed-selective responses were necessary and sufficient for the morphing of code and that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. This suggests that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.