Sarah L. Parylak

Nuclear RNA-seq of single neurons reveals molecular signatures of activation

Single-cell sequencing methods have emerged as powerful tools for identification of heterogeneous cell types within defined brain regions. Application of single-cell techniques to study the transcriptome of activated neurons can offer insight into molecular dynamics associated with differential neuronal responses to a given experience. Through evaluation of common whole-cell and single-nuclei RNA-sequencing (snRNA-seq) methods, here we show that snRNA-seq faithfully recapitulates transcriptional patterns associated with experience-driven induction of activity, including immediate early genes (IEGs) such as Fos, Arc and Egr1. SnRNA-seq of mouse dentate granule cells reveals large-scale changes in the activated neuronal transcriptome after brief novel environment exposure, including induction of MAPK pathway genes. In addition, we observe a continuum of activation states, revealing a pseudotemporal pattern of activation from gene expression alone. In summary, snRNA-seq of activated neurons enables the examination of gene expression beyond IEGs, allowing for novel insights into neuronal activation patterns in vivo.

An in vivo model of functional and vascularized human brain organoids

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

In vivo imaging of dendritic pruning in dentate granule cells

We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs.

Increasing the resolution of the adult neurogenesis picture.

The birth of new neurons in the adult mammalian brain—once thought impossible—is now a well-accepted phenomenon that takes place in the subventricular zone of the lateral ventricles and the hippocampus. This review focuses on the recent work that has sharpened our views of how hippocampal newborn neurons are regulated and function. Areas of study include (a) how neurogenesis contributes to behavioral pattern separation, (b) how pattern separation may be influenced by the properties and circuitry of newborn neurons, (c) differences along the dorsal-ventral axis of how neurogenesis is regulated and functions, and (d) adult neurogenesis in primates, including new human data. These current avenues of research reveal new details of adult neurogenesis and foreshadow what we may learn about this exciting phenomenon in the near future.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

Significance Reward boosts forms of learning and memory through dopamine-mediated neuromodulation in the brain. However, the influence of dopamine has been an underappreciated component of episodic information in the hippocampus. Using a cross-disciplinary approach, we demonstrate that dopaminergic input in the dentate gyrus, a hippocampal subregion critical for the formation of high-resolution memories, impairs subsequent learning by suppressing cortical inputs and ensemble neuronal activity in this area. This work reveals a mechanism by which dopamine signal biases memory storage of events leading to rather than subsequent to the reward. Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

The role of adult hippocampal neurogenesis in brain health and disease

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.

Mother's milk programs offspring's cognition

A study finds that immune factors transmitted through breast milk regulate the cognitive function of offspring. Changes in milk composition alter hippocampal development and have effects on memory that last into adulthood.

A novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons

Activity-induced remodeling of neuronal circuits is critical for memory formation. This process relies in part on transcription, but neither the rate of activity nor baseline transcription is equal across neuronal cell types. In this study, we isolated mouse hippocampal populations with different activity levels and used single nucleus RNA-seq to compare their transcriptional responses to activation. One hour after novel environment exposure, sparsely active dentate granule (DG) neurons had a much stronger transcriptional response compared to more highly active CA1 pyramidal cells and vasoactive intestinal polypeptide (VIP) interneurons. Activity continued to impact transcription in DG neurons up to 5 h, with increased heterogeneity. By re-exposing the mice to the same environment, we identified a unique transcriptional signature that selects DG neurons for reactivation upon re-exposure to the same environment. These results link transcriptional heterogeneity to functional heterogeneity and identify a transcriptional correlate of memory encoding in individual DG neurons.Single nuclei RNA-seq has been used to characterize transcriptional signature of environment-related activity in cells of the dentate gyrus. Here the authors use this approach to show that whether a neuron will be reactivated in response to re-exposure to a previous environment can be predicted by its transcriptional signature.

Erratum: An in vivo model of functional and vascularized human brain organoids

Nat. Biotechnol. 36, 432–441 (2018); published online 16 April 2018; corrected after print 18 July 2018 In the version of this article initially published, credit for part of Figure 4a was omitted. The image of a lens and microscope stage was originally published elsewhere. The error has been corrected in the HTML and PDF versions of the article.

Corrigendum: Nuclear RNA-seq of single neurons reveals molecular signatures of activation

Nature Communications 7: Article number:1102210.1038/ncomms11022 (2016); Published April192016; Updated June142016