Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means.

SignificanceChanges in brain state modulate how information is processed in sensory cortical areas. Here we use population imaging and intracellular recording to show that arousal regulates frequency tuning in layer 2/3 of primary auditory cortex. Increased arousal reduces lateral inhibition, broadens frequency tuning and enhances cortical representations of pure tones. Despite the arousal-dependent reduction in stimulus selectivity, frequency discrimination by cell ensembles improves due to a reduction in correlated variability (noise correlations).

Cells regulate gene expression in response to salient external stimuli. In neurons, depolarization leads to the expression of inducible transcription factors (ITFs) that direct subsequent gene regulation. Depolarization encodes both a neuron's action potential (AP) output and synaptic inputs, via excitatory postsynaptic potentials (EPSPs). However, it is unclear if distinct types of electrical activity can be transformed by an ITF into distinct modes of genomic regulation. Here, we show that APs and EPSPs in mouse hippocampal neurons trigger two spatially segregated and molecularly distinct induction mechanisms that lead to the expression of the ITF NPAS4. These two pathways culminate in the formation of stimulus-specific NPAS4 heterodimers that exhibit distinct DNA binding patterns. Thus, NPAS4 differentially communicates increases in a neuron's spiking output and synaptic inputs to the nucleus, enabling gene regulation to be tailored to the type of depolarizing activity along the somato-dendritic axis of a neuron.

Background Prior exposure to stress is a risk factor for developing post-traumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacological manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2c receptor (5-HT2CR) activity during memory consolidation are necessary for stress enhancement of fear memory, but neither process affects fear memory in unstressed mice. Additionally, prior stress increases amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also show that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusion Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals, and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.

transport to the dendrites would result in inverted spatiotemporal dynamics from what we observed (Farris et al., 2014;Okuno et al., 2012).Summation of EPSPs during tetanic stimulation produces large NMDAR-mediated Ca signals and may, in principle, gate L-VGCCs localized to the apical dendrites or soma (Magee and Johnston, 1995;Marrion and Tavalin, 1998). To determine if one or both of these Ca sources are associated with synaptically-induced NPAS4, afferents in SR were stimulated in the presence of NMDAR or L-VGCC antagonists (CPP and Nim, respectively; Figure S1J).Blockade of NMDARs prevented NPAS4 induction in the dendrites and soma, whereas antagonism of L-VGCCs had no effect (Figure 1J). This result indicates that activation of NMDARs, but not L-VGCCs, accounts for both the dendritic and somatic NPAS4 protein induced by synaptic potentials. Thus, APs and EPSPs originating in SR engage distinct Ca sources to induce NPAS4 and result in NPAS4 expression patterns with unique spatiotemporal profiles along the somato-dendritic axis of the PN.NPAS4 protein has not been previously observed in the dendrites of PNs, thus we sought to determine if sensory experiences can induce dendritic NPAS4 in vivo. Mice (P21−28) were transferred from their home cage (HC) into an enriched environment (EE) for 5 minutes, and then returned to their HC (Figure 1K). At various time points after return to the HC (1−90 min), hippocampi were removed, fixed, sectioned and stained for NPAS4 and NeuN. In WT mice, NPAS4 protein was detected in SR 3−5 minutes after exposure to EE, followed by an increase in immunofluorescence in SP (Figure 1L, M), recapitulating our observations in acute slices.Deletion of Npas4 in excitatory neurons (Npas4 f/f :: Emx1 Cre ) eliminated the experiencedependent NPAS4 induction in SR and SP (Figure 1N), whereas Npas4 knockout in inhibitory neurons (Npas4 f/f :: GAD2 Cre ) had no impact (Figure 1O), indicating that dendritic and somatic NPAS4 protein is produced in PNs. Moreover, analysis of other hippocampal subregions revealed dendritically localized NPAS4 in CA3 PNs (Figure S2A−D) suggesting this expression profile may be a general feature of PNs. In dentate granule cells, NPAS4 protein was detected within minutes of return to the HC (Figure S2E−H) but was not clearly localized to dendrites, possibly due to their compact morphologies. Thus, immediately after novel sensory experiences NPAS4 protein is observed in the dendrites of PNs in vivo, reflecting increases in local synaptic transmission.