Sleep-dependent decorrelation of hippocampal spatial representations.

Neuronal ensembles are crucial for episodic memory and spatial mapping. Sleep, particularly non-REM (NREM), is vital for memory consolidation, as it triggers plasticity mechanisms through brain oscillations that reactivate neuronal ensembles. Here, we assessed their role in consolidating hippocampal spatial representations during sleep. We recorded hippocampus activity in rats performing a spatial object-place recognition (OPR) memory task, during encoding and retrieval periods, separated by intervening sleep. Successful OPR retrieval correlated with NREM duration, during which cortical oscillations decreased in power and density as well as neuronal spiking, suggesting global downregulation of network excitability. However, neurons encoding specific spatial locations (i.e., place cells) or objects during OPR showed stronger synchrony with brain oscillations compared to non-encoding neurons, and the stability of spatial representations decreased proportionally with NREM duration. Our findings suggest that NREM sleep may promote flexible remapping in hippocampal ensembles, potentially aiding memory consolidation and adaptation to novel spatial contexts.

Interspecies effectors of a transgenerational memory of bacterial infection in Caenorhabditis elegans.

The inheritance of memory is an adaptive trait. Microbes challenge the immunity of organisms and trigger behavioral adaptations that can be inherited, but how bacteria produce inheritance of a trait is unknown. We use Caenorhabditis elegans and its bacteria to study the transgenerational RNA dynamics of interspecies crosstalk leading to a heritable behavior. A heritable response of C. elegans to microbes is the pathogen-induced diapause (PIDF), a state of suspended animation to evade infection. We identify RsmY, a small RNA involved in quorum sensing in Pseudomonas aeruginosa as a trigger of PIDF. The histone methyltransferase (HMT) SET-18/SMYD3 and the argonaute HRDE-1, which promotes multi-generational silencing in the germline, are also needed for PIDF initiation. The HMT SET-25/EHMT2 is necessary for memory maintenance in the transgenerational lineage. Our work is a starting point to understanding microbiome-induced inheritance of acquired traits, and the transgenerational influence of microbes in health and disease.

Optogenetic Suppression of Lateral Septum Somatostatin Neurons Enhances Hippocampus Cholinergic Theta Oscillations and Local Synchrony.

The septal complex regulates both motivated and innate behaviors, chiefly by the action of its diverse population of long-range projection neurons. A small population of somatostatin-expressing GABAergic cells in the lateral septum projects deep into subcortical regions, yet on its way it also targets neighboring medial septum neurons that profusely innervate cortical targets by ascending synaptic pathways. Here, we used optogenetic stimulation and extracellular recordings in acutely anesthetized transgenic mice to show that lateral septum somatostatin neurons can disinhibit the cholinergic septo-hippocampal pathway, thus enhancing the amplitude and synchrony of theta oscillations while depressing sharp-wave ripple episodes in the dorsal hippocampus. These results suggest that septal somatostatin cells can recruit ascending cholinergic pathways to promote hippocampal theta oscillations.

Bacterially produced metabolites protect C. elegans neurons from degeneration.

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.

Diapause induces functional axonal regeneration after necrotic insult in C. elegans.

Many neurons are unable to regenerate after damage. The ability to regenerate after an insult depends on life stage, neuronal subtype, intrinsic and extrinsic factors. C. elegans is a powerful model to test the genetic and environmental factors that affect axonal regeneration after damage, since its axons can regenerate after neuronal insult. Here we demonstrate that diapause promotes the complete morphological regeneration of truncated touch receptor neuron (TRN) axons expressing a neurotoxic MEC-4(d) DEG/ENaC channel. Truncated axons of different lengths were repaired during diapause and we observed potent axonal regrowth from somas alone. Complete morphological regeneration depends on DLK-1 but neuronal sprouting and outgrowth is DLK-1 independent. We show that TRN regeneration is fully functional since animals regain their ability to respond to mechanical stimulation. Thus, diapause induced regeneration provides a simple model of complete axonal regeneration which will greatly facilitate the study of environmental and genetic factors affecting the rate at which neurons die.