The neural representation of absolute direction during mental navigation in conceptual spaces

When humans mentally “navigate” bidimensional uniform conceptual spaces, they recruit the same grid-like and distance codes typically evoked when exploring the physical environment. Here, using fMRI, we show evidence that conceptual navigation also elicits another kind of spatial code: that of absolute direction. This code is mostly localized in the medial parietal cortex, where its strength predicts participants’ comparative semantic judgments. It may provide a complementary mechanism for conceptual navigation outside the hippocampal formation.

Representational content determines the long-term dynamics of the CA1 spatial code

Hippocampal subregion CA1 is thought to support episodic memory by reinstating a stable spatial code. Yet recent experiments have demonstrated that this code is largely unstable on a timescale of days, challenging its presumed function. While these dynamics may indeed reflect homogenous drift within the population, they may alternatively reflect distinct time-varying representational component(s) which coexists alongside other stable components. Here we adjudicate between these possibilities. To this end, we characterized the mouse CA1 spatial code over more than a month of daily experience in an extended geometric morph paradigm. We find that this code is governed by distinct representational components with different long-term dynamics, including stable components representing spatial geometry and prior experience. These components are mediated by separate neural ensembles with similar short-term spatial reliability and precision. Together, these results demonstrate that the long-term dynamics of the CA1 spatial code are defined by representational content, not homogenous drift.

Extended experience reveals distinct representational dynamics governing the CA1 spatial code

SummaryHippocampal subregion CA1 is thought to support episodic memory by reinstating a stable spatial code. However, recent calcium imaging experiments have challenged this presumed function by demonstrated that this code is largely unstable on a timescale of days. This turnover may reflect homogenous drift within the population; alternatively, it may reflect distinct time-varying representational component(s) which coexists alongside other stable components. Here we characterized the mouse CA1 spatial code over more than a month of daily free exploration experience in an extended geometric morph paradigm. We find that this code is governed by distinct representational components with different long-term dynamics, including stable components representing the shape of space and prior experience. These components are mediated by separate neural ensembles with similar short-term spatial reliability and precision. Together, these results demonstrate that the long-term dynamics of the CA1 spatial code are defined by representational content, not homogenous drift.

Distinct role of 5′UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code

The neurotrophin Brain-derived neurotrophic factor (BDNF) is encoded by multiple bipartite transcripts. Each BDNF transcript is composed by one out of 11 alternatively spliced exons containing the 5′untranslated region (UTR), and one common exon encompassing the coding sequence (CDS) and the 3′UTR with two variants (short and long). In neurons, BDNF mRNA variants have a distinct subcellular distribution, constituting a “spatial code”, with exon 1, 3, 5, 7 and 8 located in neuronal somata, exon 4 extending into proximal dendrites, and exon 2 and 6 reaching distal dendrites. We previously showed that the CDS encodes constitutive dendritic targeting signals (DTS) and that both the 3′UTR-short and the 3′UTR-long contain activity-dependent DTS. However, the role of individual 5′UTR exons in mRNA sorting remains unclear. Here, we tested the ability of each different BDNF 5′UTRs to affect the subcellular localization of the green fluorescent protein (GFP) reporter mRNA. We found that exon 2 splicing isoforms (2a, 2b, and 2c) induced a constitutive dendritic targeting of the GFP reporter mRNA towards distal dendritic segments. The other isoforms did not affect GFP-mRNA dendritic trafficking. Through a bioinformatic analysis, we identified five unique cis-elements in exon 2a, 2b, and 2c which might contribute to building a DTS. This study provides additional information on the mechanism regulating the cellular sorting of BDNF mRNA variants.

Inferring the spatial code of cell-cell interactions and communication across a whole animal body

Cell-cell interactions are crucial for multicellular organisms as they shape cellular function and ultimately organismal phenotype. However, the spatial code embedded in the molecular interactions that drive and sustain spatial organization, and in the organization that in turns drives intercellular interactions across a living animal remains to be elucidated. Here we use the expression of ligand-receptor pairs obtained from a whole-body single-cell transcriptome of Caenorhabditis elegans larvae to compute the potential for intercellular interactions through a Bray-Curtis-like metric. Leveraging a 3D atlas of C. elegans’ cells, we implement a genetic algorithm to select the ligand-receptor pairs most informative of the spatial organization of cells. Validating the strategy, the selected ligand-receptor pairs are involved in known cell-migration and morphogenesis processes and we confirm a negative correlation between cell-cell distances and interactions. Thus, our computational framework helps identify cell-cell interactions and their relationship with intercellular distances, and decipher molecular bases encoding spatial information in a whole animal. Furthermore, it can also be used to elucidate associations with any other intercellular phenotype and applied to other multicellular organisms.Graphical abstract

Distinct role of 5’UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code.

The neurotrophin Brain-derived neurotrophic factor (BDNF) is encoded by multiple bipartite transcripts. Each BDNF transcript is composed by one out of eleven alternatively spliced exons containing the 5’untranslated region (UTR), and one common exon encompassing the coding sequence (CDS) and the 3’UTR with two variants (short and long). In neurons, BDNF mRNA variants have a distinct subcellular distribution, constituting a “spatial code”, with exon 1, 3, 5, 7 and 8 located in neuronal somata, exon 4 extending into proximal dendrites, and exon 2 and 6 reaching distal dendrites. We previously showed that the CDS encodes constitutive dendritic targeting signals (DTS) and that both the 3’UTR-short and the 3’UTR-long contain activity-dependent DTS. However, the role of individual 5’UTR exons in mRNA sorting remains unclear. Here, we tested the ability of each different BDNF 5'UTRs to affect the subcellular localization of the green fluorescent protein (GFP) reporter mRNA. We found that exon 2 splicing isoforms (2a, 2b, and 2c) induced a constitutive dendritic targeting of the GFP reporter mRNA towards distal dendritic segments. The other isoforms did not affect GFP-mRNA dendritic trafficking. Through a bioinformatic analysis, we identified five unique cis-elements in exon 2a, 2b, and 2c which might contribute to building a DTS. This study provides additional information on the mechanism regulating the cellular sorting of BDNF mRNA variants.

Distinct role of 5’UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code.

The neurotrophin Brain-derived neurotrophic factor (BDNF) is encoded by multiple bipartite transcripts. Each BDNF transcript is composed by one out of eleven alternatively spliced exons containing the 5’untranslated region (UTR), and one common exon encompassing the coding sequence (CDS) and the 3’UTR with two variants (short and long). In neurons, BDNF mRNA variants have a distinct subcellular distribution, constituting a “spatial code”, with exon 1, 3, 5, 7 and 8 located in neuronal somata, exon 4 extending into proximal dendrites, and exon 2 and 6 reaching distal dendrites. We previously showed that the CDS encodes constitutive dendritic targeting signals (DTS) and that both the 3’UTR-short and the 3’UTR-long contain activity-dependent DTS. However, the role of individual 5’UTR exons in mRNA sorting remains unclear. Here, we tested the ability of each different BDNF 5'UTRs to affect the subcellular localization of the green fluorescent protein (GFP) reporter mRNA. We found that exon 2 splicing isoforms (2a, 2b, and 2c) induced a constitutive dendritic targeting of the GFP reporter mRNA towards distal dendritic segments. The other isoforms did not affect GFP-mRNA dendritic trafficking. Though a bioinformatic analysis, we identified five unique cis-elements in exon 2a, 2b, and 2c which might contribute to building a DTS. This study provides additional information on the mechanism regulating the cellular sorting of BDNF mRNA variants.