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Coordinated peri-ripple activity in the hippocampal-neocortical network is essential for mnemonic information processing in the brain. Hippocampal ripples likely serve different functions in sleep and awake states. Thus, the corresponding neocortical activity patterns may differ in important ways. We addressed this possibility by conducting voltage and glutamate wide-field imaging of the neocortex with concurrent hippocampal electrophysiology in awake mice. Contrary to our previously published sleep results, deactivation and activation were dominant in post-ripple neocortical voltage and glutamate activity, respectively, especially in the agranular retrosplenial cortex (aRSC). Additionally, the spiking activity of aRSC neurons, estimated by two-photon calcium imaging, revealed the existence of two subpopulations of excitatory neurons with opposite peri-ripple modulation patterns: one increases and the other decreases firing rate. These differences in peri-ripple spatiotemporal patterns of neocortical activity in sleep versus awake states might underlie the reported differences in the function of sleep versus awake ripples.

There has been considerable research showing populations of neurons encoding for different aspects of space in the brain. Recently, several studies using two-photon calcium imaging and virtual navigation have identified "spatially" modulated neurons in the posterior cortex. We enquire here whether the presence of such spatial representations may be a cortex-wide phenomenon and, if so, whether these representations can be organized in the absence of the hippocampus. To this end, we imaged the dorsal cortex of mice running on a treadmill populated with tactile cues. A high percentage (40-80%) of the detected neurons exhibited sparse, spatially localized activity, with activity fields uniformly localized over the track. The development of this location specificity was impaired by hippocampal damage. Thus, there is a substantial population of neurons distributed widely over the cortex that collectively form a continuous representation of the explored environment, and hippocampal outflow is necessary to organize this phenomenon.SIGNIFICANCE STATEMENT Increasing evidence points to the role of the neocortex in encoding spatial information. Whether this feature is linked to hippocampal functions is largely unknown. Here, we systematically surveyed multiple regions in the dorsal cortex of the same animal for the presence of signals encoding for spatial position. We described populations of cortical neurons expressing sequential patterns of activity localized in space in primary, secondary, and associational areas. Furthermore, we showed that the formation of these spatial representations was impacted by hippocampal lesion. Our results indicate that hippocampal inputs are necessary to maintain a precise cortical representation of space.

The synaptic homeostasis theory of sleep proposes that low neurotransmitter activity in sleep optimizes memory consolidation. We tested this theory by asking whether increasing acetylcholine levels during early sleep would weaken motor memory consolidation. We trained separate groups of adult mice on the rotarod walking task and the single pellet reaching task, and after training, administered physostigmine, an acetylcholinesterase inhibitor, to increase cholinergic tone in subsequent sleep. Post-sleep testing showed that physostigmine impaired motor skill acquisition of both tasks. Home-cage video monitoring and electrophysiology revealed that physostigmine disrupted sleep structure, delayed non-rapid-eye-movement sleep onset, and reduced slow-wave power in the hippocampus and cortex. Additional experiments showed that: (1) the impaired performance associated with physostigmine was not due to its effects on sleep structure, as 1 h of sleep deprivation after training did not impair rotarod performance, (2) a reduction in cholinergic tone by inactivation of cholinergic neurons during early sleep did not affect rotarod performance, and (3) stimulating or blocking muscarinic and nicotinic acetylcholine receptors did not impair rotarod performance. Taken together, the experiments suggest that the increased slow wave activity and inactivation of both muscarinic and nicotinic receptors during early sleep due to reduced acetylcholine contribute to motor memory consolidation.

The brain likely uses offline periods to consolidate recent memories. One hypothesis holds that the hippocampal output provides a unique, global linking or 'index' code for each memory, and that this code is stored in the cortex in association with locally encoded attributes of each memory. Activation of the index code is hypothesized to evoke coordinated memory trace reactivation thus facilitating consolidation. Retrosplenial cortex (RSC) is a major recipient of hippocampal outflow and we have described populations of neurons there with sparse and orthogonal coding characteristics that resemble hippocampal 'place' cells, and whose expression depends on an intact hippocampus. Using two-photon Ca2+ imaging, we recorded ensembles of neurons in the RSC during periods of immobility before and after active running on a familiar linear treadmill track. Synchronous bursting of distinct groups of neurons occurred during rest both prior to and after running. In the second rest epoch, these patterns were associated with the locations of tactile landmarks and reward. Complementing established views on the functions of the RSC, our findings indicate that the structure is involved with processing landmark information during rest. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

A prevalent model is that sharp-wave ripples (SWR) arise 'spontaneously' in CA3 and propagate recent memory traces outward to the neocortex to facilitate memory consolidation there. Using voltage and extracellular glutamate transient recording over widespread regions of mice dorsal neocortex in relation to CA1 multiunit activity (MUA) and SWR, we find that the largest SWR-related modulation occurs in retrosplenial cortex; however, contrary to the unidirectional hypothesis, neocortical activation exhibited a continuum of activation timings relative to SWRs, varying from leading to lagging. Thus, contrary to the model in which SWRs arise 'spontaneously' in the hippocampus, neocortical activation often precedes SWRs and may thus constitute a trigger event in which neocortical information seeds associative reactivation of hippocampal 'indices'. This timing continuum is consistent with a dynamics in which older, more consolidated memories may in fact initiate the hippocampal-neocortical dialog, whereas reactivation of newer memories may be initiated predominantly in the hippocampus.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex.

Simultaneous recording of optical and electrophysiological signals from multiple cortical areas may provide crucial information to expand our understanding of cortical function. However, the insertion of multiple electrodes into the brain may compromise optical imaging by both restricting the field of view and interfering with the approaches used to stabilize the specimen. Existing methods that combine electrophysiological recording and optical imaging in vivo implement either multiple surface electrodes, silicon probes, or a single electrode for deeper recordings. To address such limitation, we built a microelectrode array (hyperdrive, patent US5928143 A) compatible with wide-field imaging that allows insertion of up to 12 probes into a large brain area (8 mm diameter). The hyperdrive is comprised of a circle of individual microdrives where probes are positioned at an angle leaving a large brain area unobstructed for wide-field imaging. Multiple tetrodes and voltage-sensitive dye imaging were used for acute simultaneous registration of spontaneous and evoked cortical activity in anesthetized mice. The electrophysiological signals were used to extract local field potential (LFP) traces, multiunit, and single-unit spiking activity. To demonstrate our approach, we compared LFP and VSD signals over multiple regions of the cortex and analyzed the relationship between single-unit and global cortical population activities. The study of the interactions between cortical activity at local and global scales, such as the one presented in this work, can help to expand our knowledge of brain function.