Methodological Caveats in the Detection of Coordinated Replay between Place Cells and Grid Cells

At rest, hippocampal “place cells,” neurons with receptive fields corresponding to specific spatial locations, reactivate in a manner that reflects recently traveled trajectories. These “replay” events have been proposed as a mechanism underlying memory consolidation, or the transfer of a memory representation from the hippocampus to neocortical regions associated with the original sensory experience. Accordingly, it has been hypothesized that hippocampal replay of a particular experience should be accompanied by simultaneous reactivation of corresponding representations in the neocortex and in the entorhinal cortex, the primary interface between the hippocampus and the neocortex. Recent studies have reported that coordinated replay may occur between hippocampal place cells and medial entorhinal cortex grid cells, cells with multiple spatial receptive fields. Assessing replay in grid cells is problematic, however, as the cells exhibit regularly spaced spatial receptive fields in all environments and, therefore, coordinated replay between place cells and grid cells may be detected by chance. In the present report, we adapted analytical approaches utilized in recent studies of grid cell and place cell replay to determine the extent to which coordinated replay is spuriously detected between grid cells and place cells recorded from separate rats. For a subset of the employed analytical methods, coordinated replay was detected spuriously in a significant proportion of cases in which place cell replay events were randomly matched with grid cell firing epochs of equal duration. More rigorous replay evaluation procedures and minimum spike count requirements greatly reduced the amount of spurious findings. These results provide insights into aspects of place cell and grid cell activity during rest that contribute to false detection of coordinated replay. The results further emphasize the need for careful controls and rigorous methods when testing the hypothesis that place cells and grid cells exhibit coordinated replay

Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior.

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits

Memory processing of novel experiences in the hippocampus

The hippocampus is a brain structure critical for learning and memory. With limited resources, memory processing in the hippocampus must involve extraction of useful information from daily experiences. A potential factor in this selection may be novelty of incoming information. To avoid redundancy in memory storage, the hippocampus may prefer to process novel stimuli. In this dissertation, I used extracellular tetrode recording techniques in freely behaving rats to demonstrate selective reactivation of novel experiences in the hippocampus. The principle neurons of the hippocampus, known as ‘place cells’, exhibit place-selective activity that is thought to reflect spatial aspects of a memory. In addition, during sleep and rest, ensembles of hippocampal neurons periodically engage in coordinated firing that results in signature patterns in local field potential recordings, called ‘sharp wave-ripples’. I show that during sharp wave-ripples, which are believed to reflect a retrieval mode of the hippocampal network, the place cells that were active in a novel environment fired more often than other place cells that were active in a familiar environment. In addition, firing sequences during sharp wave-ripples primarily reflected trajectories in the novel environment. To investigate how hippocampal representations of a familiar experience incorporate novel information, rats were trained to learn a new goal location within a familiar environment. I found selective modification of spatial representations near a newly-learnt goal in the familiar environment. Moreover, firing sequences during sharp wave-ripples preferentially terminated near the goal location after learning, suggesting preferential memory retrieval of the goal. Together, these results support the hypothesis that novel experiences are preferentially processed in the hippocampus.Neuroscienc

Local dentate circuits support spatial working memory regardless of position along the longitudinal hippocampal axis /

The dentate gyrus (DG) is the initial site of information processing in the hippocampus. Previous studies have shown that the rostral-dorsal DG (rdDG) is essential in the rat's ability to discriminate similar spatial locations. In addition, the DG has been shown to support spatial working memory(WM). However, the question of how the DG supports spatial WM remains unclear. We demonstrated that spatial WM performance in rats is not selectively supported by a specific region along the longitudinal axis of the DG. Rats with 20 -40% volume reduction specific to the rdDG or the caudal-ventral DG (cvDG) did not impair spatial WM, suggesting a mechanism independent of the anatomical location of the DG could support WM. To further elucidate the mechanism responsible for WM in the DG, we investigated whether a compensatory activity of neurons existed in the remaining DG of the rdDG or cvDG lesion rats. Using immediate early gene c-fos to label active neurons in the DG granule cell layer, we quantified the number of active neurons for each group (control, rdDG lesion, and cvDG lesion) through stereological methods. The fraction of c-fos labeled granule neurons in the lesion groups did not change compared to control. Thus, WM is supported in rats with cvDG or rdDG lesions without compensatory activity of granule neurons.The result implies that local dentate circuits with a network in which sparsity is retained can support dentate-dependent memor

Local dentate circuits support spatial working memory regardless of position along the longitudinal hippocampal axis /

The dentate gyrus (DG) is the initial site of information processing in the hippocampus. Previous studies have shown that the rostral-dorsal DG (rdDG) is essential in the rat's ability to discriminate similar spatial locations. In addition, the DG has been shown to support spatial working memory(WM). However, the question of how the DG supports spatial WM remains unclear. We demonstrated that spatial WM performance in rats is not selectively supported by a specific region along the longitudinal axis of the DG. Rats with 20 -40% volume reduction specific to the rdDG or the caudal-ventral DG (cvDG) did not impair spatial WM, suggesting a mechanism independent of the anatomical location of the DG could support WM. To further elucidate the mechanism responsible for WM in the DG, we investigated whether a compensatory activity of neurons existed in the remaining DG of the rdDG or cvDG lesion rats. Using immediate early gene c-fos to label active neurons in the DG granule cell layer, we quantified the number of active neurons for each group (control, rdDG lesion, and cvDG lesion) through stereological methods. The fraction of c-fos labeled granule neurons in the lesion groups did not change compared to control. Thus, WM is supported in rats with cvDG or rdDG lesions without compensatory activity of granule neurons.The result implies that local dentate circuits with a network in which sparsity is retained can support dentate-dependent memor

Hippocampal place cell sequences differ during correct and error trials in a spatial memory task

Here the authors compare place cell sequence coding during correct and error trials in a spatial memory task. Sequences coded paths that were longer and more temporally compressed during correct trials and developed a bias to replay paths to a goal location during rest periods of correct but not error trials

Creation of an albino squid line by CRISPR-Cas9 and its application for in vivo functional imaging of neural activity

Cephalopods are remarkable among invertebrates for their cognitive abilities, adaptive camouflage, novel structures, and propensity for recoding proteins through RNA editing. Due to the lack of genetically tractable cephalopod models, however, the mechanisms underlying these innovations are poorly understood. Genome editing tools such as CRISPR-Cas9 allow targeted mutations in diverse species to better link genes and function. One emerging cephalopod model, Euprymna berryi, produces large numbers of embryos that can be easily cultured throughout their life cycle and has a sequenced genome. As proof of principle, we used CRISPR-Cas9 in E. berryi to target the gene for tryptophan 2,3 dioxygenase (TDO), an enzyme required for the formation of ommochromes, the pigments present in the eyes and chromatophores of cephalopods. CRISPR-Cas9 ribonucleoproteins targeting tdo were injected into early embryos and then cultured to adulthood. Unexpectedly, the injected specimens were pigmented, despite verification of indels at the targeted sites by sequencing in injected animals (G0s). A homozygote knockout line for TDO, bred through multiple generations, was also pigmented. Surprisingly, a gene encoding indoleamine 2,3, dioxygenase (IDO), an enzyme that catalyzes the same reaction as TDO in vertebrates, was also present in E. berryi. Double knockouts of both tdo and ido with CRISPR-Cas9 produced an albino phenotype. We demonstrate the utility of these albinos for in vivo imaging of Ca2+ signaling in the brain using two-photon microscopy. These data show the feasibility of making gene knockout cephalopod lines that can be used for live imaging of neural activity in these behaviorally sophisticated organisms

Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons

Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.Fil: Sasaki, Takuya. University of California at San Diego; Estados Unidos. The University of Tokyo; Japón. Japan Science and Technology Agency; JapónFil: Piatti, Veronica del Carmen. University of California at San Diego; Estados UnidosFil: Hwaun, Ernie. University of California at San Diego; Estados UnidosFil: Ahmadi, Siavash. University of California at San Diego; Estados UnidosFil: Lisman, John E.. Brandeis University; Estados UnidosFil: Leutgeb, Stefan. University of California at San Diego; Estados UnidosFil: Leutgeb, Jill K.. University of California at San Diego; Estados Unido