Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles

Abstract Previous gain-of-function studies using an optogenetic technique showed that manipulation of the hippocampal dentate gyrus or CA1 cell ensembles is important for memory reactivation and to generate synthetic or false memory. However, gain-of-function study manipulating CA3 cell ensembles has not been reported. The CA3 area of the hippocampus comprises a recurrent excitatory circuit, which is thought to be important for the generation of associations among the stored information within one brain region. We investigated whether the coincident firing of cell ensembles in one brain region, hippocampal CA3, associates distinct events. CA3 cell ensembles responding to context exploration and during contextual fear conditioning were labeled with channelrhodopsin-2 (ChR2)-mCherry. The synchronous activation of these ensembles induced freezing behavior in mice in a neutral context, in which a foot shock had never been delivered. The recall of this artificial associative fear memory was context specific. In vivo electrophysiological recordings showed that 20-Hz optical stimulation of ChR2-mCherry-expressing CA3 neurons, which is the same stimulation protocol used in behavioral experiment, induced long-term potentiation at CA3-CA3 synapses. Altogether, these results demonstrate that the synchronous activation of ensembles in one brain region, CA3 of the hippocampus, is sufficient for the association of distinct events. The results of our electrophysiology potentially suggest that this artificial association of memory events might be induced by the strengthening of synaptic efficacy between CA3 ensembles via recurrent circuit

Artificial Association of Pre-stored Information to Generate a Qualitatively New Memory

Memory is thought to be stored in the brain as an ensemble of cells activated during learning. Although optical stimulation of a cell ensemble triggers the retrieval of the corresponding memory, it is unclear how the association of information occurs at the cell ensemble level. Using optogenetic stimulation without any sensory input in mice, we found that an artificial association between stored, non-related contextual, and fear information was generated through the synchronous activation of distinct cell ensembles corresponding to the stored information. This artificial association shared characteristics with physiologically associated memories, such as N-methyl-D-aspartate receptor activity and protein synthesis dependence. These findings suggest that the association of information is achieved through the synchronous activity of distinct cell ensembles. This mechanism may underlie memory updating by incorporating novel information into pre-existing networks to form qualitatively new memories

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage