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.

Knowledge of thalamocortical (TC) processing comes mainly from studying core thalamic systems that project to middle layers of primary sensory cortices. However, most thalamic relay neurons comprise a matrix of cells that are densest in the “nonspecific” thalamic nuclei and usually target layer 1 of multiple cortical areas. A longstanding hypothesis is that matrix TC systems are crucial for regulating neocortical excitability during changing behavioral states, yet we know almost nothing about the mechanisms of such regulation. It is also unclear whether synaptic and circuit mechanisms that are well established for core sensory TC systems apply to matrix TC systems. Here we describe studies of thalamic matrix influences on mouse prefrontal cortex using optogenetic and in vitro electrophysiology techniques. Channelrhodopsin-2 was expressed in midline and paralaminar (matrix) thalamic neurons, and their layer 1-projecting TC axons were activated optically. Contrary to conventional views, we found that matrix TC projections to layer 1 could transmit relatively strong, fast, high-fidelity synaptic signals. Layer 1 TC projections preferentially drove inhibitory interneurons of layer 1, especially those of the late-spiking subtype, and often triggered feedforward inhibition in both layer 1 interneurons and pyramidal cells of layers 2/3. Responses during repetitive stimulation were far more sustained for matrix than for core sensory TC pathways. Thus, matrix TC circuits appear to be specialized for robust transmission over relatively extended periods, consistent with the sort of persistent activation observed during working memory and potentially applicable to state-dependent regulation of excitability.

Nicotinic acetylcholine receptors (nAChRs) affect a wide array of biological processes, including learning and memory, attention, and addiction. lynx1, the founding member of a family of mammalian prototoxins, modulates nAChR function in vitro by altering agonist sensitivity and desensitization kinetics. Here we demonstrate, through the generation of lynx1 null mutant mice, that lynx1 modulates nAChR signaling in vivo. Its loss decreases the EC(50) for nicotine by approximately 10-fold, decreases receptor desensitization, elevates intracellular calcium levels in response to nicotine, and enhances synaptic efficacy. lynx1 null mutant mice exhibit enhanced performance in specific tests of learning and memory. Consistent with reports that mutations resulting in hyperactivation of nAChRs can lead to neurodegeneration, aging lynx1 null mutant mice exhibit a vacuolating degeneration that is exacerbated by nicotine and ameliorated by null mutations in nAChRs. We conclude that lynx1 functions as an allosteric modulator of nAChR function in vivo, balancing neuronal activity and survival in the CNS.

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Regulation of intracellular calcium influences neuronal excitability, synaptic plasticity, gene expression, and neurotoxicity. In this study, we investigated the role of calcium in mechanisms underlying nicotine-mediated neuroprotection from glutamate excitotoxicity. Neuroprotection by nicotine in primary cortical cultures was not seen in knock-out mice lacking the beta2 subunit of the nicotinic acetylcholine receptor (nAChR). Neuroprotection was partially blocked in wild-type cultures by alpha-bungarotoxin, an antagonist of the alpha7 nAChR subtype, suggesting a potential cooperative role for these subtypes. Pretreatment with nicotine decreased glutamate-mediated calcium influx in primary cortical cultures by 41%, an effect that was absent in cultures from knock-out mice lacking the beta2 subunit of the nAChR. This effect was dependent on calcium entry through L-type channels during nicotine pretreatment in wild-type cultures. The ability of nicotine to decrease glutamate-mediated calcium influx was occluded by cotreatment with nifedipine during glutamate application, suggesting that nicotine pretreatment decreased subsequent activity of L-type calcium channels. Treatment with the calcineurin antagonists FK506 and cyclosporine during pretreatment eliminated both nicotine-mediated neuroprotection and the effects of nicotine on L-type channels. We conclude that neuroprotective effects of nicotine in cortical neurons involve both beta2- and alpha7-containing nAChRs, activation of calcineurin, and decreased intracellular calcium via L-type channels.

Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs 1 , 2 . One powerful means of transformation involves interactions between excitatory thalamocortical neurons that carry data to cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate flow of those data 3 – 6 . Despite enduring recognition of its importance 7 – 9 , understanding of TRN cell types, their organization, and their functional properties has lagged that of the thalamocortical systems they control. Here we address this, investigating somatosensory and visual circuits of the TRN. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated, physiologically distinct, and connect reciprocally with independent thalamocortical nuclei via dynamically divergent synapses. Calbindin-expressing cells, located in the central core, connect with the ventral posterior nucleus (VP), the primary somatosensory thalamocortical relay. In contrast, somatostatin-expressing cells, residing along the surrounding edges of TRN, synapse with the posterior medial thalamic nucleus (POM), a higher-order structure that carries both top-down and bottom-up information 10 – 12 . The two TRN cell groups process their inputs in pathway-specific ways. Synapses from VP to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from POM to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. Thus, processing specializations of two somatosensory TRN subcircuits appear to be tuned to the signals they carry—a primary central subcircuit to discrete sensory events, and a higher-order edge subcircuit to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide fundamental insights about how subnetworks of TRN neurons may differentially process distinct classes of thalamic information.

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