Effects of Stimulus Timing on the Acquisition of an Olfactory Working Memory Task in Head-Fixed Mice.

Acquisition of a behavioral task is influenced by many factors. The relative timing of stimuli is such a factor and is especially relevant for tasks relying on short-term memory, like working memory paradigms, because of the constant evolution and decay of neuronal activity evoked by stimuli. Here, we assess two aspects of stimulus timing on the acquisition of an olfactory delayed nonmatch-to-sample (DNMS) task. We demonstrate that head-fixed male mice learn to perform the task more quickly when the initial training uses a shorter sample-test odor delay without detectable loss of generalizability. Unexpectedly, we observed a slower task acquisition when the odor-reward interval was shorter. The effect of early reward timing was accompanied by a shortening of reaction times and more frequent sporadic licking. Analysis of this result using a drift-diffusion model indicated that a primary consequence of early reward delivery is a lowered threshold to act, or a lower decision bound. Because an accurate performance with a lower decision bound requires greater discriminability in the sensory representations, this may underlie the slower learning rate with early reward arrival. Together, our results reflect the possible effects of stimulus timing on stimulus encoding and its consequence on the acquisition of a complex task.SIGNIFICANCE STATEMENT This study describes how head-fixed mice acquire a working memory task (olfactory delayed nonmatch-to-sample task). We simplified and optimized the stimulus timing, allowing robust and efficient training of head-fixed mice. Unexpectedly, we found that early reward timing leads to slower learning. Analysis of this data using a computational model (drift-diffusion model) revealed that the reward timing affects the behavioral threshold, or how quickly animals respond to a stimulus. But, to still be accurate with early reaction times, the sensory representation needs to become even more refined. This may explain the slower learning rate with early reward timing.

What does engram encode?: Heterogeneous memory engrams for different aspects of experience.

Long-lasting synaptic changes within the neuronal network mediate memory. Neurons bearing such physical traces of memory (memory engram cells) are often equated with neurons expressing immediate early genes (IEGs) during a specific experience. However, past studies observed the expression of different IEGs in non-overlapping neurons or synaptic plasticity in neurons that do not express a particular IEG. Importantly, recent studies revealed that distinct subsets of neurons expressing different IEGs or even IEG negative-(yet active) neurons support different aspects of memory or computation, suggesting a more complex nature of memory engram cells than previously thought. In this short review, we introduce studies revealing such heterogeneous composition of the memory engram and discuss how the memory system benefits from it.

Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice.

Human myelin disorders are commonly studied in mouse models. Since both clades evolutionarily diverged approximately 85 million years ago, it is critical to know to what extent the myelin protein composition has remained similar. Here, we use quantitative proteomics to analyze myelin purified from human white matter and find that the relative abundance of the structural myelin proteins PLP, MBP, CNP, and SEPTIN8 correlates well with that in C57Bl/6N mice. Conversely, multiple other proteins were identified exclusively or predominantly in human or mouse myelin. This is exemplified by peripheral myelin protein 2 (PMP2), which was specific to human central nervous system myelin, while tetraspanin-2 (TSPAN2) and connexin-29 (CX29/GJC3) were confined to mouse myelin. Assessing published scRNA-seq-datasets, human and mouse oligodendrocytes display well-correlating transcriptome profiles but divergent expression of distinct genes, including Pmp2, Tspan2, and Gjc3. A searchable web interface is accessible via www.mpinat.mpg.de/myelin. Species-dependent diversity of oligodendroglial mRNA expression and myelin protein composition can be informative when translating from mouse models to humans.

Like the electrical wires in our homes, the processes of nerve cells ­ the axons, thin extensions that project from the cell bodies ­ need to be insulated to work effectively. This insulation takes the form of layers of a membrane called myelin, which is made of proteins and fats and produced by specialized cells called oligodendrocytes in the brain and the spinal cord. If this layer of insulation becomes damaged, the electrical impulses travelling along the nerves slow down, affecting the ability to walk, speak, see or think. This is the cause of several illnesses, including multiple sclerosis and a group of rare genetic diseases known as leukodystrophies. A lot of the research into myelin, oligodendrocytes and the diseases caused by myelin damage uses mice as an experimental model for humans. Using mice for this type of research is appropriate because of the ethical and technical limitations of experiments on humans. This approach can be highly effective because mice and humans share a large proportion of their genes. However, there are many obvious physical differences between the two species, making it important to determine whether the results of experiments performed in mice are applicable to humans. To do this, it is necessary to understand how myelin differs between these two species at the molecular level. Gargareta, Reuschenbach, Siems, Sun et al. approached this problem by studying the proteins found in myelin isolated from the brains of people who had passed away and donated their organs for scientific research. They used a technique called mass spectrometry, which identifies molecules based on their weight, to produce a list of proteins in human myelin that could then be compared to existing data from mouse myelin. This analysis showed that myelin is very similar in both species, but some proteins only appear in humans or in mice. Gargareta, Reuschenbach, Siems, Sun et al. then compared which genes are turned on in the oligodendrocytes making the myelin. The results of this comparison reflected most of the differences and similarities seen in the myelin proteins. Despite the similarities identified by Gargareta, Reuschenbach, Siems, Sun et al., it became evident that there are unexpected differences between the myelin of humans and mice that will need to be considered when applying results from mice research to humans. To enable this endeavor, Gargareta, Reuschenbach, Siems, Sun et al. have created a searchable web interface of the proteins in myelin and the genes expressed in oligodendrocytes in the two species.