Temporally organized reactivation of experiences during awake immobility periods is thought to underlie cognitive processes like planning and evaluation. While replay of trajectories is well established for the hippocampus, it is unclear whether the medial prefrontal cortex (mPFC) can reactivate sequential behavioral experiences in the awake state to support task execution. We simultaneously recorded from hippocampal and mPFC principal neurons in rats performing a mPFC-dependent rule-switching task on a plus maze. We found that mPFC neuronal activity encoded relative positions between the start and goal. During awake immobility periods, the mPFC replayed temporally organized sequences of these generalized positions, resembling entire spatial trajectories. The occurrence of mPFC trajectory replay positively correlated with rule-switching performance. However, hippocampal and mPFC trajectory replay occurred independently, indicating different functions. These results demonstrate that the mPFC can replay ordered activity patterns representing generalized locations and suggest that mPFC replay might have a role in flexible behavior.

The replay of patterns of activity related to past experiences and memories is a striking manifestation of brain spontaneous activity. So is the coherent activation of sets of brain areas during rest, in particular, the default mode network (DMN). We propose that these two phenomena are strongly intertwined: their potential functions overlap, encompassing the reinstatement, reprocessing, and consolidation of memories, and the simulation of potential outcomes of actions. In our cascaded memory systems model, we hypothesize that the DMN forms the backbone for the propagation of replay, mediating interactions between the hippocampus and the whole neocortex for consolidation of new memories. The DMN may independently ignite replay cascades, which support reactivation of older memories, or high-level semantic representations. Transient cortical activations, inducing long-range correlation across the neocortex, are a key mechanism supporting a hierarchy of representations, from simple percepts, to semantic representations of causes, to whole episodes. Recent data show that similar, feedback-driven phenomena are widespread in the cortex [39][40][41] .

Vicarious trial-and-errors (VTEs) are back-and-forth movements of the head exhibited by rodents and other animals when faced with a decision. These behaviors have recently been associated with prospective sweeps of hippocampal place cell firing, and thus may reflect a rodent model of deliberative decision-making. The aim of the current study was to test whether the hippocampus is essential for VTEs in a spatial memory task and in a simple visual discrimination (VD) task. We found that lesions of the hippocampus with ibotenic acid produced a significant impairment in the accuracy of choices in a serial spatial reversal (SR) task. In terms of VTEs, whereas sham-lesioned animals engaged in more VTE behavior prior to identifying the location of the reward as opposed to repeated trials after it had been located, the lesioned animals failed to show this difference. In contrast, damage to the hippocampus had no effect on acquisition of a VD or on the VTEs seen in this task. For both lesion and sham-lesion animals, adding an additional choice to the VD increased the number of VTEs and decreased the accuracy of choices. Together, these results suggest that the hippocampus may be specifically involved in VTE behavior during spatial decision making.

Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single‐unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted‐in‐Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention‐related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed‐modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location‐independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty‐induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.

The mammalian hippocampal formation (HF) plays a key role in several higher brain functions, such as spatial coding, learning and memory. Its simple circuit architecture is often viewed as a trisynaptic loop, processing input originating from the superficial layers of the entorhinal cortex (EC) and sending it back to its deeper layers. Here, we show that excitatory neurons in layer 6b of the mouse EC project to all sub-regions comprising the HF and receive input from the CA1, thalamus and claustrum. Furthermore, their output is characterized by unique slow-decaying excitatory postsynaptic currents capable of driving plateau-like potentials in their postsynaptic targets. Optogenetic inhibition of the EC-6b pathway affects spatial coding in CA1 pyramidal neurons, while cell ablation impairs not only acquisition of new spatial memories, but also degradation of previously acquired ones. Our results provide evidence of a functional role for cortical layer 6b neurons in the adult brain.