Hierarchical gradients of encoded spatial and sensory information in the neocortex are attenuated by dorsal hippocampal lesions.

During navigation, the neocortex must actively integrate learned spatial context with current sensory experience to guide behaviours. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties in familiar environments, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behaviour on a familiar cued treadmill, the locations of two added obstacles were interchanged to decouple place-tuning from cue-tuning among the position correlated cells with fields at those locations. The subpopulations of place- and cue-tuned cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position correlated cells in motor cortex also formed translaminar gradients; cells closer to the cortical surface were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted but retrosplenial cortex exhibited significantly increased cue-tuning and, in motor cortices, both position correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of top-down feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of bottom-up sensory inputs.Significance statement During learning, the hippocampus imparts spatial context to memory representations throughout the superficial neocortex. However, the post-learning role of the hippocampus has not been well defined. The results of this study suggest that, during navigation of a familiar environment, the hippocampus continues to link unreliable sensory attributes to a stable contextual framework, effectively updating the learned model of the environment. The results are also consistent with top-down suppression of sensory-evoked activity during behaviour, which varied in strength according to hierarchical proximity to the hippocampus. This effect was abolished by bilateral lesions of the dorsal hippocampus, supporting that the hippocampus plays an ongoing role in propagating context-dependent predictions throughout the cortical hierarchy, a core hypothesis of the predictive coding theoretical framework.

Place navigation in the Morris water task results in greater nuclear Arc mRNA expression in dorsal compared to ventral CA1.

Previous work has shown that the dorsal hippocampus has greater activity than ventral regions during place navigation. Exposure to a novel context has also been found to increase hippocampal activation, possibly due to increased spatial demands. However, activation patterns in dorsal and ventral regions have not been investigated in the Morris water task (MWT), which remains the most popular assay of place memory in rodents. We measured activity in a large population of neurons across the CA1 dorsal-ventral axis by estimating nuclear Arc mRNA with stereologic systematic-random sampling procedures following changes to goal location or spatial context in the MWT in rats. Following changes to goal location or spatial context in the MWT, we did not find an effect on Arc mRNA expression in CA1. However, Arc expression was greater in the dorsal compared to the ventral aspect of CA1 during task performance. Several views might account for these observed differences in dorsal-ventral Arc mRNA expression, including task parameters or the granularity of representation that differs along the dorsal-ventral hippocampal axis. Future work should determine the effects of task differences and required memory precision in relation to dorsal-ventral hippocampal neuronal activity.

Postnatal development of Homer1a in the rat hippocampus.

Homer1a (H1a) is an immediate early gene involved in multiple forms of synaptic plasticity. It exhibits a postnatal increase in the rat forebrain (Brakeman et al. (1997) Nature 386:284-288) and reduces the density and size of dendritic spines in hippocampal neurons (Sala et al. (2003) J Neurosci 23:6327-6337). We evaluated hippocampal H1a expression at different postnatal ages (P3, P5, P7, P9, P15, P19, P23, P35, and adult) using Fluorescence In Situ Hybridization (FISH) and qRT-PCR. Maximal electroconvulsive shock (MECS) was used to induce maximal expression relative to home cage (HC) controls. Large scale images and confocal z-stacks from dorsal subiculum (DS), CA1, CA3, and dentate gyrus (DG) were analyzed by both manual and automated methods. In DS, CA1, and CA3 a significant proportion of cells (40%) expressed small but detectable levels of H1a from P3; however, MECS did not up-regulate H1a during the first postnatal week. MECS induced H1a positive cells during the second postnatal week and induction reached adult levels at P9. H1a-Intra Nuclear Foci (INF) size and intensity varied with age, increasing at P19-23 in CA1 and CA3 and from P9 to P23 in DS. In DG, H1a expression exhibited a lamination pattern and an H1a-INF size and intensity gradient across the granule cell layer, consistent with the outside-in maturation of DG granule cells. The developmental progression of H1a corresponds to the synaptic refinement period supporting the conclusion that H1a could play an important role in this process.

The biomedical and bioengineering potential of protein nanocompartments.

Protein nanocompartments (PNCs) are self-assembling biological nanocages that can be harnessed as platforms for a wide range of nanobiotechnology applications. The most widely studied examples of PNCs include virus-like particles, bacterial microcompartments, encapsulin nanocompartments, enzyme-derived nanocages (such as lumazine synthase and the E2 component of the pyruvate dehydrogenase complex), ferritins and ferritin homologues, small heat shock proteins, and vault ribonucleoproteins. Structural PNC shell proteins are stable, biocompatible, and tolerant of both interior and exterior chemical or genetic functionalization for use as vaccines, therapeutic delivery vehicles, medical imaging aids, bioreactors, biological control agents, emulsion stabilizers, or scaffolds for biomimetic materials synthesis. This review provides an overview of the recent biomedical and bioengineering advances achieved with PNCs with a particular focus on recombinant PNC derivatives.

Limitations of the GENSAT Egr1-EGFP transgenic mouse strain for neural circuit activity mapping.

Transgenic immediate-early gene reporter mouse strains are valuable tools for studying activity-dependent neural cell populations in vivo. However, routine characterization of the Gene Expression Nervous System Atlas (GENSAT) "Egr1-EGFP" reporter mouse strain produced results that were highly inconsistent with endogenous Egr1 expression. Activity-dependent EGFP expression was not observed, and EGFP protein did not co-localize with native Egr1 protein. This precautionary study outlines the limitations of the Egr1-EGFP transgenic line as a tool to study the activity-dependent expression of Egr1 and emphasizes the necessity of taking into account the potential loss of regulatory elements, stability determinants, or translational modulation in transgenic reporter strains.