Summary Comparative analysis of BACarray data can provide important insights into complex biological systems. As demonstrated in the accompanying paper, BACarray translational profiling permits comprehensive studies of translated mRNAs in genetically defined cell populations following physiological perturbations. To establish the generality of this approach, we present BACarray translational profiles for twenty four CNS cell populations, and identify known cell-specific and enriched transcripts for each population. We report thousands of cell-specific mRNAs that were not detected in whole tissue microarray studies, and provide examples that demonstrate the benefits deriving from comparative analysis. To provide a foundation for further biological and in silico studies, we provide a resource of sixteen transgenic mouse lines, their corresponding anatomic characterization, and BACarray translational profiles for cell types from a variety of CNS structures. This resource will enable a wide spectrum of molecular and mechanistic studies of both well known and previously uncharacterized neural cell populations.

In the above article, Figure 2A is stated to summarize data from Figures 1A and 1B; however, we inadvertently displayed a plot of a different data set that was collected with a similar but slightly different experimental design. The data in Figures 1A and 1B are from an experiment in which one group of flies underwent mock conditioning and an independent group was conditioned with electric shock, whereas the data in Figure 2A were from an experiment in which the same population of flies sequentially underwent mock conditioning and actual conditioning.We provide here a corrected graph for Figure 2A plotting the data from Figure 1. The new plot does not affect the description of the results in the paper or the conclusions drawn. We apologize for any inconvenience caused by this error.

Major depressive disorder (MDD) is a prevalent illness that can be precipitated by acute or chronic stress. Studies of patients with Wolfram syndrome and carriers have identified Wfs1 mutations as causative for MDD. The medial prefrontal cortex (mPFC) is known to be involved in depression and behavioral resilience, although the cell types and circuits in the mPFC that moderate depressive behaviors in response to stress have not been determined. Here, we report that deletion of Wfs1 from layer 2/3 pyramidal cells impairs the ability of the mPFC to suppress stress-induced depressive behaviors, and results in hyperactivation of the hypothalamic–pituitary–adrenal axis and altered accumulation of important growth and neurotrophic factors. Our data identify superficial layer 2/3 pyramidal cells as critical for moderation of stress in the context of depressive behaviors and suggest that dysfunction in these cells may contribute to the clinical relationship between stress and depression.DOI: http://dx.doi.org/10.7554/eLife.08752.001

New protein synthesis is known to be required for the consolidation of memories, yet existing methods to block translation lack spatiotemporal precision and cell-type specificity, preventing investigation of cell-specific contributions of protein synthesis. Here, we developed a combined knock-in mouse and chemogenetic approach for cell type-specific and drug-inducible protein synthesis inhibition (ciPSI) that enables rapid and reversible phosphorylation of eIF2α, leading to inhibition of general translation by 50% in vivo. We use ciPSI to show that targeted protein synthesis inhibition pan-neuronally and in excitatory neurons in lateral amygdala (LA) impaired long-term memory. This could be recovered with artificial chemogenetic activation of LA neurons, though at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eIF2α in excitatory neurons in LA enhanced memory strength, but reduced memory fidelity and behavioral flexibility. Our findings provide evidence for a cell-specific translation program during consolidation of threat memories. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger 1 . Survival also depends on suppressing the threat-response during a stimulus that predicts absence of threat, i.e. safety 2 – 5 . Understanding the biological substrates of emotional memories in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as PTSD 5 . A key brain area for processing and storing threat memories is the centrolateral amygdala (CeL), which is an important node in the neuronal circuit mediating defensive responses 6 – 9 . Here, we applied intersectional chemogenetic strategies in CeL inhibitory neurons (INs) to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α), respectively. We show that de novo translation in CeL Somatostatin-expressing (SOM) INs is necessary for long-term storage of conditioned-threat response whereas de novo translation in CeL protein kinase Cδ (PKCδ)-expressing INs is necessary for conditioned-response inhibition to a safety cue. Our results provide new insight into the role of de novo protein synthesis in distinct CeL inhibitory neuron populations during consolidation of long-term memories.

Critical bacterial processes, including motility, are influenced by c-di-GMP, which is controlled by environment-responsive synthetic and degradative enzymes. Because bacteria such as Vibrio fischeri use motility to colonize their hosts, understanding the roles of c-di-GMP-modulating enzymes in controlling motility has the potential to inform on microbe-host interactions.

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46Translational control of memory processes is a tightly regulated process where the coordinated interaction and 47 modulation of translation factors provides a permissive environment for protein synthesis during memory 48 formation. Existing methods used to block translation lack the spatiotemporal precision to investigate cell-49 specific contributions to consolidation of long-term memories. Here, we have developed a novel chemogenetic 50 mouse resource for cell type-specific and drug-inducible protein synthesis inhibition (ciPSI) that utilizes an 51 engineered version of the catalytic kinase domain of dsRNA-activated protein (PKR). ciPSI allows rapid and 52 reversible phosphorylation of eIF2α causing a block on general translation by 50% in vivo. Using this resource, 53 we discovered that temporally structured pan-neuronal protein synthesis is required for consolidation of long-54 term auditory threat memory. Targeted protein synthesis inhibition in CamK2α expressing glutamatergic 55 neurons in lateral amygdala (LA) impaired long-term memory, which was recovered with artificial chemogenetic 56 reactivation at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eIF2α in 57 CamK2α positive neurons in LA enhanced memory strength, but was accompanied with reduced memory 58 fidelity and behavior inflexibility. Our findings provide evidence for a finely tuned translation program during 59 consolidation of long-term threat memories. Introduction 82Memory is the capacity of an organism to encode, store, and retrieve information, and often guides the 83 action of the organism towards a better survival outcome. Aversive life-threatening events often lead to long-84 term associative memories between the environment in which those events were experienced in and the 85 threat, such that a salient cue from the event when presented again can elicit species-specific defensive 86 behaviors. Pavlovian cued threat conditioning is a useful experimental paradigm for understanding the 87 biological substrates of an associative threat memory, in which a neutral cue (e.g. light or tone) co-presented 88 with an innately aversive stimulus (e.g. air puff or footshock) elicits a defensive response such as freezing by a 89 repeat presentation by itself 1 . Cued threat conditioning is particularly amenable to studying memory 90 consolidation process because one-trial training is sufficient to form a persistent long-term memory and a 91 unimodal cue can be used for memory retrieval. Long-term aversive memories are thought to recruit a 92 distributed network of neurons across the brain, including subnuclei within amygdala, hippocampus, thalamus, 93 as well as the neocortex, depending on the brain state, cue complexity, and the sensory pathways engaged 2, 3 . 94Lateral amygdala is the central sensory gateway for the amygdaloid complex and is crucially engaged both in 95 the processing and storage of the associative aversive memories 4, 5, 6 . 97Decades of studies have reported that consolidation of long-te...