Alzheimer’s disease (AD) is a typical neurodegenerative disease featuring deficits in spatial memory, which relies on spatial representations by hippocampal place cells. Place cells exhibit task-responsive representation to support memory encoding and retrieval processes. Yet, it remains unclear how this task-responsive spatial representation was interrupted under AD pathologies. Here, we employed a delayed match-to-place spatial memory task with associative and predictive memory processes, during which we electrophysiologically recorded hippocampal place cells with multi-tetrode hyperdrives in rats with i.c.v. amyloid/saline injection. We found that the directional selectivity of place cells coding was maintained in the Amyloid group. The firing stability was higher during predictive memory than during associative memory in both groups. However, the spatial specificity was decreased in the Amyloid group during both associative and predictive memory. Importantly, the place cells in the Amyloid group exhibited attenuated task-responsive representations, i.e. lack of spatial over-representations towards the goal zone and a higher representation of the rest zone, especially during the predictive memory stage. These results raise a hypothesis that the disrupted task-responsive representations of place cells could be an underlying mechanism of spatial memory deficits induced by amyloid proteins.

The experience-dependent spatial cognitive process requires sequential organization of hippocampal neural activities by theta rhythm, which develops to represent highly compressed information for rapid learning. However, how the theta sequences were developed in a finer timescale within theta cycles remains unclear. In this study, we found in rats that sweep-ahead structure of theta sequences developing with exploration was predominantly dependent on a relatively large proportion of FG-cells, that is a subset of place cells dominantly phase-locked to fast gamma rhythms. These ensembles integrated compressed spatial information by cells consistently firing at precessing slow gamma phases within the theta cycle. Accordingly, the sweep-ahead structure of FG-cell sequences was positively correlated with the intensity of slow gamma phase precession, in particular during early development of theta sequences. These findings highlight the dynamic network modulation by fast and slow gamma in the development of theta sequences which may further facilitate memory encoding and retrieval.

Prefrontal (PFC) and hippocampal (HPC) sequences of neuronal firing modulated by theta rhythms could represent upcoming choices during spatial memory-guided decision-making. How the PFC-HPC network dynamically coordinates theta sequences to predict specific goal locations and how it is interrupted in memory impairments induced by amyloid beta (Aβ) remain unclear. Here, we detected theta sequences of firing activities of PFC neurons and HPC place cells during goal-directed spatial memory tasks. We found that PFC ensembles exhibited predictive representation of the specific goal location since the starting phase of memory retrieval, earlier than the hippocampus. High predictive accuracy of PFC theta sequences existed during successful memory retrieval and positively correlated with memory performance. Coordinated PFC-HPC sequences showed PFC-dominant prediction of goal locations during successful memory retrieval. Furthermore, we found that theta sequences of both regions still existed under Aβ accumulation, whereas their predictive representation of goal locations was weakened with disrupted spatial representation of HPC place cells and PFC neurons. These findings highlight the essential role of coordinated PFC-HPC sequences in successful memory retrieval of a precise goal location.

Studies have shown that spaceflight, featured by the microgravity environment, could affect astronauts' spatial learning and memory ability. The astronauts' hippocarnpal structure and function changed. A previous study indicated that hippocampal place cells' representations could respond to a microgravity environment, but exhibited ambiguous firing patterns when rats first entered the environment. However, the time -dependent changes of place cells' spatial representations in the adaptation of the microgravity environment remain unclear. To address this question, we designed a crotch-tail linkage device that suspended rats from the ground at a 30 degrees Angle to simulate a microgravity (SM) environment and simultaneously recorded the activities of place cells while rats explored the open field. Our results showed that place cells in SM rats exhibited time -dependent adaption spatial representations during 4 -week simulating microgravity. The spatial specificity of place cells showed a significant decrease in the first two weeks of exposure to SM and then significantly increased in the third week. These results indicate that hippocampal place cells adaptively recovered the spatial representations of the environment during long-time SM exposure. Our findings provide the basis for the intrinsic neural mechanism of spatial 'information representation of hippocampal place cells under long-term spaceflight and suggest that long-term spaceflight may have multiple effects on the construction of spatial cognitive maps. Our findings provide insights into the brain's functional changes during spaceflight and might contribute to improving astronautic medicine.

The hippocampus plays a key role in goal-directed navigation, as most excitatory neurons are called place cells whose firing patterns are strongly correlated to specific spatial locations. In addition, locations associated with other salient features in the context, such as rewards, are also represented by a subset of hippocampal neurons. However, the cellular coding mechanism underlying this representation remains elusive. To address this question, we designed a delayed match-to-sample spatial memory task which requires rats to learn two goal locations individually. The results showed that the neurons that overexpressed the reward location could be classified as two types: the reward cells, and the place cells representing the reward location (stable cells). We further found that these two types of neurons exhibited different firing patterns in spatial memory. The reward cells, but not stable cells, encoded the goal location by high spatial specificity and accurate coding mode in correct trials compared to that in error trials. These findings suggest that the precise representation of goal locations by reward cells prominently contributes to successful memory retrieval. Our study may provide a new direction for further understanding the internal mechanisms of reward encoding in the brain.

Hippocampal CA2 supports social memory and encodes information about social experiences. Our previous study showed that CA2 place cells responded specifically to social stimuli (Nat Commun, (Alexander et al. 2016)). In addition, a prior study showed that activation of CA2 induces slow gamma rhythms ( 25–55 Hz) in the hippocampus (Elife, (Alexander 2018)). Together, these results raise the question of whether slow gamma rhythms coordinate CA2 activity during social information processing. We hypothesized that slow gamma would be associated with transmission of social memories from CA2 to CA1, perhaps to integrate information across regions or promote social memory retrieval. We recorded local field potentials from hippocampal subfields CA1, CA2, and CA3 of 4 rats performing a social exploration task. We analyzed the activity of theta, slow gamma, and fast gamma rhythms, as well as sharp wave-ripples (SWRs), within each subfield. We assessed interactions between subfields during social exploration sessions and during presumed social memory retrieval in post-social exploration sessions. We found that CA2 slow gamma rhythms increased during social interactions but not during non-social exploration. CA2–CA1 theta-show gamma coupling was enhanced during social exploration. Furthermore, CA1 slow gamma rhythms and SWRs were associated with presumed social memory retrieval. In conclusion, these results suggest that CA2–CA1 interactions via slow gamma rhythms occur during social memory encoding, and CA1 slow gamma is associated with retrieval of social experience.

Hippocampal place cells replay spatial pathways in time-compressed sequences during sharp-wave ripples (SWRs), which supports the consolidation of spatial memory in rats. Our previous study found that the replay sequences developed a bias to represent the correct reward location. However, little is known about whether these replay sequences represent trajectories of past experience or future prediction in memory retrieval of the precise location. We detected replay events within SWRs and separated them into two types according to their preferred representing trajectories, clockwise (CW) event for the past trajectory and counterclockwise (CCW) event for the future trajectory. We found that the occurrence of replay event in the CCW direction increased as rats learned the task with improving performance. Furthermore, replay events of both trajectories exhibited more occurrence in correct trials than in error trials, with higher occurrence of CCW events than CW events. These results suggest that in the process of learning a precise reward location, the successful memory retrieval would be strongly correlated with the hippocampal replay sequences including information for future planning.

The excitatory neurons of the medial prefrontal cortex (mPFC) respond to social stimuli. However, little is known about how the neural activity is altered during social avoidance, and whether it could act as a target of low-intensity focused ultrasound stimulation (LIFUS) to rescue social deficits. The present study aimed to investigate the mechanisms of neuronal activities and inflammatory responses underlying the effect of LIFUS on social avoidance. We found that chronic LIFUS stimulation can effectively improve social avoidance in the defeated mice. Calcium imaging recordings by fiber photometry in the defeated mice showed inhibited ensemble activity during social behaviors. LIFUS instantaneously triggered the mPFC neuronal activities, and chronic LIFUS significantly enhanced their neuronal excitation related to social interactions. We further found that the excessive activation of microglial cells and the overexpression of the inflammation signaling, i.e. Toll-like receptors(TLR4)/nuclear factor-kappaB(NF-КB), in mPFC were significantly inhibited by LIFUS. These results suggest that the LIFUS may inhibit social avoidance behavior by reducing activation of the inflammatory response, increasing neuronal excitation, and protecting the integrity of the neuronal structure in the mPFC. Our findings raised the possibility of LIFUS being applied as novel neuromodulation for social avoidance treatment in neuropsychiatric diseases.

Alzheimer's disease (AD) is a neurodegenerative disease in which Aβ accumulation occurs early in the disease. It is characterized by memory loss and progressive neurocognitive dysfunction. Theta rhythm, slow gamma rhythm and fast gamma rhythm of the hippocampus exhibit important contributions to the encoding and retrieval of memory. Previous studies have shown that gamma rhythms were impaired in AD model animals under free exploration behaviors. However, little is known about how the neural dynamics is changed under spatial memory state as AD rats performed a mnemonic task. We recorded the local field potential of hippocampal CA1 in rats during the free exploration task and a delayed match-to-sample spatial memory task, and the effects of Aβ on neural rhythm in two behavioral phase were analyzed. Our study found that injection of Ab reduced the power of slow gamma and fast gamma during the free exploration phase, while the decrement of fast gamma power was further exacerbated during the memory phase. In addition, Aβ also reduces the theta-fast gamma coupling strength in the free exploration phase. These findings provide new evidence for impairment of high frequency neural rhythm during memory phase of AD model rats, which could be a potential target of neural modulation for AD.

Medial prefrontal cortex (mPFC) plays an essential role in social behaviors, with both the excitatory pyramidal neurons and inhibitory interneurons specifically activated during social activities. However, the firing patterns of these two types of neurons under the social condition are still unclear. In this study, we found that the putative pyramidal neurons exhibited a strongly stable firing pattern and high spatial information during the social behaviors rather than during object exploration, whereas this was not found in putative interneurons. These results provide additional evidence for neural mechanisms of social behaviors with distinct firing patterns of excitatory and inhibitory neurons in the mPFC.

The synergy of hippocampus (HPC) and prefrontal cortex (PFC) plays key roles in memory processing. A large amount of evidence shows that PFC and HPC support the formation, consolidation and retrieval of episodic memory through the synchronous action of characteristic neural rhythms (theta, gamma, sharp wave ripples(SWRs) rhythms). Based on the study of the neural rhythms in the HPC-PFC network, this review summarizes the role of synchronous interaction of theta, gamma and SWRs rhythms between two brain regions in episodic memory. With the development of animal learning and memory, the HPC-PFC coherence of theta rhythm, as well as gamma rhythms, were significantly increased. These data indicated that HPC and PFC communicate closely through oscillatory information flow in this network when animals have strong memory capabilities. HPC SWRs during either sleep or awake rest were coordinated with cortical SWRs and some other low-frequency rhythms to promote memory consolidation, while awake SWRs can further promote memory retrieval. On the other hand, mental illness is often accompanied by learning and memory dysfunction. EEG studies based on humans and animals have found that the coupling of neural rhythms between HPC and PFC was disordered, which could be treated as an important indicator of pathological cognitive impairment. This review also summarizes the abnormal performance of neural rhythms in HPC-PFC network in schizophrenia and depression and their underlying mechanisms, providing objective evidence for the rapid diagnosis of psychiatric diseases in the future.