Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. We investigated this selectivity using cell type–specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning.
SUMMARY Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information.
Summary CA1 pyramidal cells (PCs) are not homogeneous, but rather can be grouped by molecular, morphological, and functional properties. However, less is known about synaptic sources differentiating PCs. Using paired recordings in vitro, 2-photon Ca2+ imaging in vivo and computational modeling, we found that parvalbumin-expressing basket cells (PVBCs) evoked greater inhibition in CA1 PCs located in the deep compared to superficial layer of stratum pyramidale. In turn, analysis of reciprocal connectivity revealed more frequent excitatory inputs to PVBCs by superficial PCs, demonstrating bias in target selection by both the excitatory and inhibitory local connections in CA1. Additionally, PVBCs further segregated among deep PCs, preferentially innervating the amygdala-projecting PCs but receiving preferential excitation from the prefrontal cortex-projecting PCs, thus revealing distinct perisomatic inhibitory interactions between separate output channels. These results demonstrate the presence of heterogeneous PVBC-PC microcircuits, potentially contributing to the sparse and distributed structure of hippocampal network activity.
Summary The mammalian hippocampus is critical for spatial information processing and episodic memory. Its primary output cells, CA1 pyramidal cells (CA1 PCs), vary in genetics, morphology, connectivity, and electrophysiological properties. It is therefore possible that distinct CA1 PC subpopulations encode different features of the environment and differentially contribute to learning. To test this hypothesis, we optically monitored activity in deep and superficial CA1 PCs segregated along the radial axis of the mouse hippocampus and assessed the relationship between sublayer dynamics and learning. Superficial place maps were more stable than deep during head-fixed exploration. Deep maps, however, were preferentially stabilized during goal-oriented learning, and representation of the reward zone by deep cells predicted task performance. These findings demonstrate that superficial CA1 PCs provide a more stable map of an environment while their counterparts in deeper layers provide a more flexible representation that is shaped by learning about salient features in the environment.
Summary Mossy cells in the hilus of the dentate gyrus constitute a major excitatory principal cell type in the mammalian hippocampus, however, it remains unknown how these cells behave in vivo. Here, we have used two-photon Ca2+ imaging to monitor the activity of mossy cells in awake, behaving mice. We find that mossy cells are significantly more active than dentate granule cells in vivo, exhibit spatial tuning during head-fixed spatial navigation, and undergo robust remapping of their spatial representations in response to contextual manipulation. Our results provide the first characterization of mossy cells in the behaving animal and demonstrate their active participation in spatial coding and contextual representation.
Fluorescence imaging is a powerful method for monitoring dynamic signals in the nervous system. However, analysis of dynamic fluorescence imaging data remains burdensome, in part due to the shortage of available software tools. To address this need, we have developed SIMA, an open source Python package that facilitates common analysis tasks related to fluorescence imaging. Functionality of this package includes correction of motion artifacts occurring during in vivo imaging with laser-scanning microscopy, segmentation of imaged fields into regions of interest (ROIs), and extraction of signals from the segmented ROIs. We have also developed a graphical user interface (GUI) for manual editing of the automatically segmented ROIs and automated registration of ROIs across multiple imaging datasets. This software has been designed with flexibility in mind to allow for future extension with different analysis methods and potential integration with other packages. Software, documentation, and source code for the SIMA package and ROI Buddy GUI are freely available at http://www.losonczylab.org/sima/.
Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a 'network inhibition hypothesis' in which temporal lobe seizures disrupt brainstem-diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1-2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.
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