Cingulate-motor circuits update rule representations for sequential choice decisions.

Anterior cingulate cortex mediates the flexible updating of an animal's choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the terminal projections of cingulate cortical neurons in secondary motor cortex in the rat disrupts choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreases rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that is temporally targeted to error trials immediately after rule switches exacerbates errors in the following trials. These results suggest that cingulate cortex monitors behavioral errors and updates rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.

Engram Cell Excitability State Determines the Efficacy of Memory Retrieval.

Animals need to optimize the efficacy of memory retrieval to adapt to environmental circumstances for survival. The recent development of memory engram labeling technology allows a precise investigation of the processes associated with the recall of a specific memory. Here, we show that engram cell excitability is transiently increased following memory reactivation. This short-term increase of engram excitability enhances the subsequent retrieval of specific memory content in response to cues and is manifest in the animal's ability to recognize contexts more precisely and more effectively. These results reveal a hitherto unknown transient enhancement of context recognition based on the plasticity of engram cell excitability. They also suggest that recall of a contextual memory is influenced by previous but recent activation of the same engram. The state of excitability of engram cells mediates differential behavioral outcomes upon memory retrieval and may be crucial for survival by promoting adaptive behavior.

Cre/loxP recombination-activated neuronal markers in mouse neocortex and hippocampus.

A new strategy for visualizing neuronal cell morphology of mouse brain based on Cre/loxP recombination-activated gene expression is described. A "reporter" transgenic line was generated which expressed a fusion gene encoding a dendrite-targeted green fluorescent protein (MAP2-GFP) upon deletion of a transcription/translation STOP (transcription and translation stop signal) cassette. Cre transgenic "deleter" lines were established that activated reporter gene expression at various frequencies in pyramidal neurons in the forebrain. A deleter line was identified which activated a MAP2-GFP reporter gene at very low frequency (less than 0.1% of pyramidal neurons) and allowed the visualization of dendritic structures of individual neocortical and hippocampal pyramidal neurons. In addition, vertical "columns" of pyramidal neurons in the neocortex were labeled in these mice. In a second deleter line, a MAP2-GFP reporter gene was selectively activated in pyramidal neurons of the CA-1 subregion of the hippocampus in young mice. With its combinatorial property, this binary recombination-activated neuronal marker system should facilitate the study of detailed morphology, connectivity, and plasticity of defined classes of live neurons in vitro and in vivo.

Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice.

Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system, and the N-methyl-D-aspartate-selective glutamate receptor (NR) consisting of the NR1 subunit and an NR2 or NR3 subunit plays crucial roles in synaptic transmission, plasticity, and learning and memory. By using a knockout mouse strain, in which the NR1 gene deletion is primarily targeted to the CA1 pyramidal cells of the hippocampus, we investigated the in vivo effect of the loss of the NR1 subunit on the cellular expression and intracellular distribution of the NR2 subunits. The NR1 gene deletion had no apparent effect on the levels of NR2A or NR2B mRNA but led to severe reductions of NR2A and NR2B protein in dendrites of CA1 pyramidal cells. This reduced dendritic distribution of the NR2 subunits accompanied their robust accumulation in perikarya, where they were condensed in the lumen of the endoplasmic reticulum as electron-dense granules. These granules were also observed in CA1 pyramidal cells of the control mice but they were much fewer and contained no detectable levels of the NR2 subunit. The effect of the NR1 knockout on intracellular localization of the NR2 subunits was specific in that no such effect was observed for the GluR1 and PSD-95, two other major postsynaptic proteins. These results suggest that the NR1 subunit plays a crucial role in the release of the NR2 subunit from the endoplasmic reticulum in hippocampal pyramidal cells in vivo, and when the NR1 subunit is unavailable, the NR2 subunits are retained and aggregate into intracisternal granules.