Low rate hippocampal delay period activity encodes behavioral experience.

Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.

The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.

Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress.

Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, we demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PaVN) in the adult rat is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in PaVN dopaminergic neurons that coexpress vesicular glutamate transporter 2 (VGLUT2), is accompanied by a loss of dopamine type 2 receptors (D2Rs) on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF. Suppressing activity of all PaVN glutamatergic neurons decreases the number of inhibitory PaVN dopaminergic neurons, indicating homeostatic regulation of transmitter expression in the PaVN.

Stability of medial entorhinal cortex representations over time.

Distinct functional cell types in the medial entorhinal cortex (mEC) have been shown to represent different aspects of experiences. To further characterize mEC cell populations, we examined whether spatial representations of neurons in mEC superficial layers depended on the scale of the environment and changed over extended time periods. Accordingly, mEC cells were recorded while rats repeatedly foraged in a small or a large environment in sessions that were separated by time intervals from minutes to hours. Comparing between large and small environments, we found that the overall precision of grid and non-grid cell spatial maps was higher in smaller environments. When examining the stability of spatial firing patterns over time, differences and similarities were observed across cell types. Within-session stability was higher for grid cells than for non-grid cell populations. Despite differences in baseline stability between cell types, stability levels remained consistent over time between sessions, up to 1 hr. Even for sessions separated by 6 hrs, activity patterns of grid cells and of most non-grid cells lacked any systematic decrease in spatial similarity over time. However, a subset of ~15% of mEC non-grid cells recorded preferentially from layer III exhibited dramatic, time dependent changes in firing patterns across 6 hrs, reminiscent of previous characterizations of the hippocampal CA2 subregion. Collectively, our data suggest that mEC grid cell input to hippocampus in conjunction with many time invariant non-grid cells may aid in stabilizing hippocampal spatial maps, while a subset of time varying non-grid cells could provide complementary temporal information.

The hippocampal code for space in Mongolian gerbils.

Large parts of our knowledge about the physiology of the hippocampus in the intact brain are derived from studies in rats and mice. While many of those findings fit well to the limited data available from humans and primates, there are also marked differences, for example, in hippocampal oscillation frequencies and in the persistence of theta oscillations. To test whether the distinct sensory specializations of the visual and auditory system of primates play a key role in explaining these differences, we recorded basic hippocampal physiological properties in Mongolian gerbils, a rodent species with high visual acuity, and good low-frequency hearing, similar to humans. We found that gerbils show only minor differences to rats regarding hippocampal place field activity, theta properties (frequency, persistence, phase precession, theta compression), and sharp wave ripple events. The only major difference between rats and gerbils was a considerably higher degree of head direction selectivity of gerbil place fields, which may be explained by their visual system being able to better resolve distant cues. Thus, differences in sensory specializations between rodent species only affect hippocampal circuit dynamics to a minor extent, which implies that differences to other mammalian lineages, such as bats and primates, cannot be solely explained by specialization in the auditory or visual system.

Recent and remote retrograde memory deficit in rats with medial entorhinal cortex lesions.

The hippocampus is critically involved in the acquisition and retrieval of spatial memories. Even though some memories become independent of the hippocampus over time, expression of spatial memories have consistently been found to permanently depend on the hippocampus. Recent studies have focused on the adjacent medial entorhinal cortex (MEC), as it provides major projections to the hippocampus. These studies have shown that lesions of the MEC disrupt spatial processing in the hippocampus and impair spatial memory acquisition on the watermaze task. MEC lesions acquired after learning the watermaze task also disrupt recently acquired spatial memories. However, the effect of MEC lesions on remotely acquired memories is unknown. The current study examined the effect of MEC lesions on recent and remote memory retrieval using three hippocampus-dependent tasks: the watermaze, trace fear conditioning, and novel object recognition. MEC lesions caused impaired retrieval of recently and remotely acquired memory for the watermaze. Rats with MEC lesions also showed impaired fear memory when exposed to the previously conditioned context or the associated tone, and this reduction was seen both when the lesion occurred soon after trace fear condition and when it occurred a month after conditioning. In contrast, MEC lesions did not disrupt novel object recognition. These findings indicate that even with an intact hippocampus, rats with MEC lesions cannot retrieve recent or remote spatial memories. In addition, the involvement of the MEC in memory extends beyond is role in navigation and place memory.

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.

Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention. SIGNIFICANCE STATEMENT: Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.

Memory and Space: Towards an Understanding of the Cognitive Map.

More than 50 years of research have led to the general agreement that the hippocampus contributes to memory, but there has been a major schism among theories of hippocampal function over this time. Some researchers argue that the hippocampus plays a broad role in episodic and declarative memory, whereas others argue for a specific role in the creation of spatial cognitive maps and navigation. Although both views have merit, neither provides a complete account of hippocampal function. Guided by recent reviews that attempt to bridge between these views, here we suggest that reconciliation can be accomplished by exploring hippocampal function from the perspective of Tolman's (1948) original conception of a cognitive map as organizing experience and guiding behavior across all domains of cognition. We emphasize recent studies in animals and humans showing that hippocampal networks support a broad range of domains of cognitive maps, that these networks organize specific experiences within the contextually relevant map, and that network activity patterns reflect behavior guided through cognitive maps. These results are consistent with a framework that bridges theories of hippocampal function by conceptualizing the hippocampus as organizing incoming information within the context of a multidimensional cognitive map of spatial, temporal, and associational context. SIGNIFICANCE STATEMENT: Research of hippocampal function is dominated by two major views. The spatial view argues that the hippocampus tracks routes through space, whereas the memory view suggests a broad role in declarative memory. Both views rely on considerable evidence, but neither provides a complete account of hippocampal function. Here we review evidence that, in addition to spatial context, the hippocampus encodes a wide variety of information about temporal and situational context, about the systematic organization of events in abstract space, and about routes through maps of cognition and space. We argue that these findings cross the boundaries of the memory and spatial views and offer new insights into hippocampal function as a system supporting a broad range of cognitive maps.

Neuronal code for extended time in the hippocampus.

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.

Localized APP expression results in progressive network dysfunction by disorganizing spike timing.

Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.

Hippocampal activation during the recall of remote spatial memories in radial maze tasks.

Temporally graded retrograde amnesia is observed in human patients with medial temporal lobe lesions as well as in animal models of medial temporal lobe lesions. A time-limited role for these structures in memory recall has also been suggested by the observation that the rodent hippocampus and entorhinal cortex are activated during the retrieval of recent but not of remote memories. One notable exception is the recall of remote memories for platform locations in the water maze, which requires an intact hippocampus and results in hippocampal activation irrespective of the age of the memory. These findings raise the question whether the hippocampus is always involved in the recall of spatial memories or, alternatively, whether it might be required for procedural computations in the water maze task, such as for calculating a path to a hidden platform. We performed spatial memory testing in radial maze tasks to distinguish between these possibilities. Radial maze tasks require a choice between spatial locations on a center platform and thus have a lesser requirement for navigation than the water maze. However, we used a behavioral design in the radial maze that retained other aspects of the standard water maze task, such as the use of multiple start locations and retention testing in a single trial. Using the immediate early gene c-fos as a marker for neuronal activation, we found that all hippocampal subregions were more activated during the recall of remote compared to recent spatial memories. In areas CA3 and CA1, activation during remote memory testing was higher than in rats that were merely reexposed to the testing environment after the same time interval. Conversely, Fos levels in the dentate gyrus were increased after retention testing to the extent that was also observed in the corresponding exposure control group. This pattern of hippocampal activation was also obtained in a second version of the task that only used a single start arm instead of multiple start arms. The CA3 and CA1 activation during remote memory recall is consistent with the interpretation that an older memory might require increased pattern completion and/or relearning after longer time intervals. Irrespective of whether the hippocampus is required for remote memory recall, the hippocampus might engage in computations that either support recall of remote memories or that update remote memories.

Low Rate Hippocampal Delay Period Activity Encodes Behavioral Experience.

Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex.

Place-specific firing in the hippocampus is determined by path integration-based spatial representations in the grid-cell network of the medial entorhinal cortex. Output from this network is conveyed directly to CA1 of the hippocampus by projections from principal neurons in layer III, but also indirectly by axons from layer II to the dentate gyrus and CA3. The direct pathway is sufficient for spatial firing in CA1, but it is not known whether similar firing can also be supported by the input from CA3. To test this possibility, we made selective lesions in layer III of medial entorhinal cortex by local infusion of the neurotoxin gamma-acetylenic GABA. Firing fields in CA1 became larger and more dispersed after cell loss in layer III, whereas CA3 cells, which receive layer II input, still had sharp firing fields. Thus, the direct projection is necessary for precise spatial firing in the CA1 place cell population.

A role for medial entorhinal cortex in spatial and nonspatial forms of memory in rats.

Many studies have focused on the role of the medial entorhinal cortex (MEC) in spatial memory and spatial processing. However, more recently, studies have suggested that the functions of the MEC may extend beyond the spatial domain and into the temporal aspects of memory processing. The current study examined the effect of MEC lesions on spatial and nonspatial tasks that require rats to learn and remember information about location or stimulus-stimulus associations across short temporal gaps. MEC- and sham-lesioned male rats were tested on a watermaze delayed match to position (DMP) task and trace fear conditioning (TFC). Rats with MEC lesions were impaired at remembering the platform location after both the shortest (1 min) and the longest (6 h) delays on the DMP task, never performing as precisely as sham rats under the easiest condition and performing poorly at the longest delay. On the TFC task, although MEC-lesioned rats were not impaired at remembering the conditioning context, they showed reduced freezing in response to the previously associated tone. These findings suggest that the MEC plays a role in bridging temporal delays during learning and memory that extend beyond its established role in spatial memory processing.

Multimodal neural recordings with Neuro-FITM uncover diverse patterns of cortical-hippocampal interactions.

Many cognitive processes require communication between the neocortex and the hippocampus. However, coordination between large-scale cortical dynamics and hippocampal activity is not well understood, partially due to the difficulty in simultaneously recording from those regions. In the present study, we developed a flexible, insertable and transparent microelectrode array (Neuro-FITM) that enables investigation of cortical-hippocampal coordinations during hippocampal sharp-wave ripples (SWRs). Flexibility and transparency of Neuro-FITM allow simultaneous recordings of local field potentials and neural spiking from the hippocampus during wide-field calcium imaging. These experiments revealed that diverse cortical activity patterns accompanied SWRs and, in most cases, cortical activation preceded hippocampal SWRs. We demonstrated that, during SWRs, different hippocampal neural population activity was associated with distinct cortical activity patterns. These results suggest that hippocampus and large-scale cortical activity interact in a selective and diverse manner during SWRs underlying various cognitive functions. Our technology can be broadly applied to comprehensive investigations of interactions between the cortex and other subcortical structures.

Precisely timed theta oscillations are selectively required during the encoding phase of memory.

Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

Concordant neurophysiological signatures of cognitive control in humans and rats.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.

Attractor-map versus autoassociation based attractor dynamics in the hippocampal network.

The autoassociative memory model of hippocampal field CA3 postulates that Hebbian associations among external input features produce attractor states embedded in a recurrent synaptic matrix. In contrast, the attractor-map model postulates that a two-dimensional continuum of attractor states is preconfigured in the network during development and that transitions among these states are governed primarily by self-motion information ("path-integration"), giving rise to the strong spatial characteristic of hippocampal activity. In this model, learned associations between "coordinates" on the attractor map and external cues can result in abrupt jumps between states, in the case of mismatches between the current input and previous associations between internal coordinates and external landmarks. Both models predict attractor dynamics, but for fundamentally different reasons; however, the two models are not a priori mutually exclusive. We contrasted these two models by comparing the dynamics of state transitions when two previously learned environmental shapes were morphed between their endpoints, in animals that had first experienced the environments either at the same location, or at two different locations, connected by a passageway through which they walked. As predicted from attractor-map theory, the latter animals expressed abrupt transitions between representations at the midpoint of the morph series. Contrary to the predictions of autoassociation theory, the former group expressed no evidence of attractor dynamics during the morph series; there was only a gradual transition between endpoints. The results of this critical test thus cast the autoassociator theory for CA3 into doubt and indicate the need for a new theory for this structure.

Hippocampal firing rates count.

STANDFIRST: Sun et al. discover that neuronal firing rates of hippocampal place cells code for periodically repeating events and that the rate code can flexibly transfer to new situations. These findings suggest that abstract neural representations of regularly occurring events may be foundational for performing complex cognitive tasks.

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes.

The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity. In particular, neuronal activity regulates BBB efflux transporter expression and function, which is critical for excluding many small lipophilic molecules from the brain parenchyma. Furthermore, we found that neuronal activity regulates the expression of circadian clock genes within brain endothelial cells, which in turn mediate the activity-dependent control of BBB efflux transport. These results have important clinical implications for CNS drug delivery and clearance of CNS waste products, including Aß, and for understanding how neuronal activity can modulate diurnal processes.