SUMMARY Spatiotemporal trajectories are coded by “theta sequences”, ordered series of hippocampal place cell spikes that reflect the order of behavioral experiences. Theta sequences are thought to be organized by co-occurring gamma rhythms (~25–100 Hz). Yet, the question of how sequences of locations are represented during distinct slow (~25–55 Hz) and fast (~60–100 Hz) gamma subtypes remains poorly understood. We found that slow gamma-associated theta sequences activated on a compressed time scale and represented relatively long paths extending ahead of the current location. Fast gamma-associated theta sequences more closely followed an animal’s actual location in real time. When slow gamma occurred, sequences of locations were represented across successive slow gamma phases. Conversely, fast gamma phase coding of spatial sequences was not observed. These findings suggest that slow gamma promotes activation of temporally compressed representations of upcoming trajectories, whereas fast gamma supports coding of ongoing trajectories in real time.

The hippocampus supports a cognitive map of space and is critical for encoding declarative memory (who, what, when and where). Recent studies have implicated hippocampal subfield CA2 in social and contextual memory but how it does so remains unknown. Here we find that in adult male rats, presentation of a social stimulus (novel or familiar rat) or a novel object induces global remapping of place fields in CA2 with no effect on neuronal firing rate or immediate early gene expression. This remapping did not occur in CA1, suggesting this effect is specific for CA2. Thus, modification of existing spatial representations might be a potential mechanism by which CA2 encodes social and novel contextual information.

In hippocampal area CA1 of rats, the frequency of gamma activity has been shown to increase with running speed (Ahmed and Mehta, 2012). This finding suggests that different gamma frequencies simply allow for different timings of transitions across cell assemblies at varying running speeds, rather than serving unique functions. However, accumulating evidence supports the conclusion that slow (~25–55 Hz) and fast (~60–100 Hz) gamma are distinct network states with different functions. If slow and fast gamma constitute distinct network states, then it is possible that slow and fast gamma frequencies are differentially affected by running speed. In this study, we tested this hypothesis and found that slow and fast gamma frequencies change differently as a function of running speed in hippocampal areas CA1 and CA3, and in the superficial layers of the medial entorhinal cortex (MEC). Fast gamma frequencies increased with increasing running speed in all three areas. Slow gamma frequencies changed significantly less across different speeds. Furthermore, at high running speeds, CA3 firing rates were low, and MEC firing rates were high, suggesting that CA1 transitions from CA3 inputs to MEC inputs as running speed increases. These results support the hypothesis that slow and fast gamma reflect functionally distinct states in the hippocampal network, with fast gamma driven by MEC at high running speeds and slow gamma driven by CA3 at low running speeds.

CRISPR/dCas9 systems can precisely control endogenous gene expression without interrupting host genomic sequence and have provided a novel and feasible strategy for the treatment of cancers at the transcriptional level. However, development of CRISPR/dCas9‐based anti‐cancer therapeutics remains challenging due to the conflicting requirements for the design of the delivery system: a cationic and membrane‐binding surface facilitates the tumor accumulation and cellular uptake of the CRISPR/dCas9 system, but hinders the circulating stability in vivo. Here, a multistage delivery nanoparticle (MDNP) that can achieve tumor‐targeted delivery of CRISPR/dCas9 systems and restore endogenous microRNA (miRNA) expression in vivo is described. MDNP is designed as a core‐shell structure in which the shell is made of a responsive polymer that endows MDNP with the capability to present different surface properties in response to its surrounding microenvironment, allowing the MNDP overcoming multiple physiological barriers and delivering the payload to tumor tissues with an optimal efficiency. Systemic administration of MDNP/dCas9‐miR‐524 to tumor‐bearing mice achieved effective upregulation of miR‐524 in tumors, leading to the simultaneous interferences of multiple signal pathways related to cancer cell proliferation and presenting remarkable tumor growth retardation, suggesting the feasibility of utilizing MDNP to achieve tumor‐targeting delivery of CRISPR/dCas9 with sufficient levels to realize its therapeutic effects.

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated (Cas) enzyme, Cas13a, holds great promise in cancer treatment due to its potential for selective destruction of tumor cells via collateral effects after target recognition. However, these collateral effects do not specifically target tumor cells and may cause safety issues when administered systemically. Herein, a dual‐locking nanoparticle (DLNP) that can restrict CRISPR/Cas13a activation to tumor tissues is described. DLNP has a core–shell structure, in which the CRISPR/Cas13a system (plasmid DNA, pDNA) is encapsulated inside the core with a dual‐responsive polymer layer. This polymer layer endows the DLNP with enhanced stability during blood circulation or in normal tissues and facilitates cellular internalization of the CRISPR/Cas13a system and activation of gene editing upon entry into tumor tissue. After carefully screening and optimizing the CRISPR RNA (crRNA) sequence that targets programmed death‐ligand 1 (PD‐L1), DLNP demonstrates the effective activation of T‐cell‐mediated antitumor immunity and the reshaping of immunosuppressive tumor microenvironment (TME) in B16F10‐bearing mice, resulting in significantly enhanced antitumor effect and improved survival rate. Further development by replacing the specific crRNA of target genes can potentially make DLNP a universal platform for the rapid development of safe and efficient cancer immunotherapies.

Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of β-amyloid (Aβ) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of Aβ-induced neurotoxicity and the elimination of Aβ aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic Aβ aggregates and mitigate Aβ-induced neurotoxicity in AD mice. This nanocomposite was designed to be a small-sized particle (14 ± 4 nm) with Aβ-binding peptides (KLVFF) integrated on the surface. The nanocomposite was prepared by wrapping a protein molecule with a cross-linked KLVFF-containing polymer layer synthesized by in situ polymerization. The presence of the nanocomposite remarkably changed the morphology of Aβ aggregates, which led to the formation of Aβ/ nanocomposite coassembled nanoclusters instead of Aβ oligomers. With the reduction of the pathological Aβ oligomers, the nanocomposites attenuated the Aβ-induced neuron damages, regained endocranial microglia's capability to phagocytose Aβ, and eventually protected hippocampal neurons against apoptosis. Thus, we anticipate that the small-sized nanocomposite will potentially offer a feasible strategy in the development of novel AD treatments.

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Hippocampal gamma rhythms increase during mnemonic operations (Johnson and Redish, 2007;Montgomery and Buzsáki, 2007; Sederberg et al., 2007;Jutras et al., 2009; Trimper et al., 2014) and may affect memory encoding by coordinating activity of neurons that code related information (Jensen and Lisman, 2005). Here, a hippocampal-dependent, object-place association task (Clark et al., 2000; Broadbent et al., 2004;Eacott and Norman, 2004; Lee et al., 2005; Winters et al., 2008;Barker and Warburton, 2011) was used in rats to investigate how slow and fast gamma rhythms in the hippocampus relate to encoding of memories for novel object-place associations. In novel object tasks, the degree of hippocampal dependence has been reported to vary depending on the type of novelty (Eichenbaum et al., 2007; Winters et al., 2008). Therefore, gamma activity was examined during three novelty conditions: a novel object presented in a location where a familiar object had been (NO), a familiar object presented in a location where no object had been (NL), and a novel object presented in a location where no object had been (NOϩNL). The strongest and most consistent effects were observed for fast gamma rhythms during the NOϩNL condition. Fast gamma power, CA3-CA1 phase synchrony, and phase-locking of place cell spikes increased during exploration of novel, compared to familiar, object-place associations. Additionally, place cell spiking during exploration of novel object-place pairings was increased when fast gamma rhythms were present. These results suggest that fast gamma rhythms promote encoding of memories for novel object-place associations.Key words: CA1; gamma oscillations; gamma rhythms; hippocampus; memory; place cells Significance StatementThis study provides the first evidence that links fast gamma rhythms in the hippocampus to encoding of novel object-place associations in a behavioral task. The results also relate these effects to firing patterns in place cells that resemble stimulation patterns that are routinely used to induce long-term potentiation, the presumed synaptic substrate of memory formation.