The anterior cingulate cortex directs exploration of alternative strategies.

The ability to adjust one's behavioral strategy in complex environments is at the core of cognition. Doing so efficiently requires monitoring the reliability of the ongoing strategy and, when appropriate, switching away from it to evaluate alternatives. Studies in humans and non-human primates have uncovered signals in the anterior cingulate cortex (ACC) that reflect the pressure to switch away from the ongoing strategy, whereas other ACC signals relate to the pursuit of alternatives. However, whether these signals underlie computations that actually underpin strategy switching or merely reflect tracking of related variables remains unclear. Here we provide causal evidence that the rodent ACC actively arbitrates between persisting with the ongoing behavioral strategy and temporarily switching away to re-evaluate alternatives. Furthermore, by individually perturbing distinct output pathways, we establish that the two associated computations-determining whether to switch strategy and committing to the pursuit of a specific alternative-are segregated in the ACC microcircuitry.

Expanding the Optogenetics Toolkit by Topological Inversion of Rhodopsins.

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.

A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons.

Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations. VIDEO ABSTRACT.

Expression of the type 1 metalloproteinase in the rat hippocampus after the intracerebroventricular injection of ß-amyloid peptide (25-35).

The expression of matrix metalloproteinase of the first type was studied in frontal sections of the adult rat brain one month after a single intracerebroventricular injection of beta-amyloid peptide (25-35), which is known to be a well-known model of the development of Alzheimer's disease. Brain sections were stained immunocytochemically to detect MMP-1 expression, and histologically to reveal the state of hippocampal neurons. Administration of beta-amyloid peptide induced a significant degeneration of cells in the dorsal hippocampus. This was demonstrated by a significant decrease in the total number of cells and by the appearance of acidophilic neurons of altered (often triangular) shape. Altered cells were most often found in the hippocampal field CA3, and in a smaller quantity in the CA1 field. MMP-1-like immunoreactivity was found in the same hippocampal areas, the staining being restricted to the cells of altered shape (staining of somata and primary neurites). The data suggest possible involvement of the type 1 metalloproteinase in the development of Alzheimer's disease.