Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation remain unknown. We found that neocortical prefrontal memory engram cells, critical for remote contextual fear memory, were rapidly generated during initial learning via inputs from both hippocampal-entorhinal cortex and basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, are maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.Memories are thought to be initially stored within the hippocampal-entorhinal cortex (HPC-EC) (recent memory) and over-time are slowly consolidated within the neocortex for permanent storage (remote memory) (1-7). Systems memory consolidation models suggest that the interaction between the HPC-EC and the neocortex during and after an experience is crucial (8)(9)(10)(11)(12). Experimentally, prolonged inhibition of hippocampal or neocortical networks during the consolidation period produces deficits in remote memory formation (13-15). However, little is known regarding specific neural circuit mechanisms underlying the formation and maturation of neocortical memories through interactions with the HPC-EC network. By employing activity-dependent cell labeling technology (16-18) combined with viral vector-based transgenic, anatomical (19, 20), and optogenetic strategies (19, 21) for We first traced entorhinal projections to frontal cortical structures (the medial prefrontal cortex (PFC), caudal anterior cingulate cortex (cACC), retrosplenial cortex (RSC)) involved in contextual fear memory, and the basolateral amygdala (BLA), with injections of the retrograde tracer cholera toxin subunit B (CTB)-Alexa555 into these regions ( fig. S1). CTB injections resulted in labeling in the medial entorhinal cortex (MEC) specifically in cells in layer Va (Fig. 1A-D, H and fig. S1A-D (Fig. 1F). Terminal inhibition during memory recall tests did not affect memory retrieval (Fig. 1G). Finally, terminal inhibition in the cACC or RSC during CFC or recall had no effect on memory throughout these periods (Fig. 1J-L and fig. S2G-I).The above results suggest that MEC-Va input into the PFC during CFC is crucial for the eventual formation of remote memory. This hypothesis was supported by several findings. First, CFC increased the number of c-Fos + cells in the PFC compared to that of homecage mice ( Fig. 1M-O), whereas context only exposure did not increase c-Fos activity in the PFC (Fig. 1O). Second, optogenetic terminal inhibition of MEC-Va projections within the PFC during CFC inhibited the observed incr...

What happens to memories as days, weeks and years go by has long been a fundamental question in neuroscience and psychology. For decades, researchers have attempted to identify the brain regions in which memory is formed and to follow its changes across time. The theory of systems consolidation of memory (SCM) suggests that changes in circuitry and brain networks are required for the maintenance of a memory with time. Various mechanisms by which such changes may take place have been hypothesized. Recently, several studies have provided insight into the brain networks driving SCM through the characterization of memory engram cells, their biochemical and physiological changes and the circuits in which they operate. In this Review, we place these findings in the context of the field and describe how they have led to a revamped understanding of SCM in the brain.

The facial width-to-height ratio, a size-independent sexually dimorphic property of the human face, is correlated with aggressive behaviour in men. Furthermore, observers' estimates of aggression from emotionally neutral faces are accurate and are highly correlated with the facial width-to-height ratio. We investigated whether observers use the facial width-to-height ratio to estimate propensity for aggression. In experiments 1a-1c, estimates of aggression remained accurate when faces were blurred or cropped, manipulations that reduce featural cues but maintain the facial width-to-height ratio. Accuracy decreased when faces were scrambled, a manipulation that retains featural information but disrupts the facial width-to-height ratio. In experiment 2, computer-modeling software identified eight facial metrics that correlated with estimates of aggression; regression analyses revealed that the facial width-to-height ratio was the only metric that uniquely predicted these estimates. In experiment 3, we used a computer-generated set of faces varying in perceived threat (Oosterhof and Todorov, 2008 Proceedings of the National Academy of Sciences of the USA 105 11087-11092) and found that as emotionally neutral faces became more 'threatening', the facial width-to-height ratio increased. Together, these experiments suggest that the facial width-to-height ratio is an honest signal of propensity for aggressive behaviour.

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ϳ80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ϳ40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes.

Anatomical connectivity and single neuron coding suggest a segregation of information representation within lateral (LEC) and medial (MEC) portions of the entorhinal cortex, a brain region serving as the primary input/output of the hippocampus and maintaining widespread connections to many association cortices. The present study aimed to expand this idea by examining whether these two subregions differentially contribute to memory retrieval for an association between temporally discontiguous stimuli. We found that reversible inactivation of the LEC, but not the MEC, severely impaired the retrieval of the recently and remotely acquired memory in rat trace eyeblink conditioning, in which a stimulus-free interval was interposed between the conditioned and unconditioned stimulus. Conversely, inactivation of the LEC had no effect on retrieval in delay eyeblink conditioning, where two stimuli were presented without an interval. Therefore, the LEC, but not the MEC, plays a long-lasting role in the retrieval of a memory for an association between temporally discontiguous stimuli.