A team of researchers at Baylor College of Medicine, the Texas Heart Institute and Texas Children's Hospital have developed a powerful new approach to understanding the formation of new neurons in the mammalian adult brain. Published in the journal Cell Reports , this work opens exciting new pathways that can be further developed to repair malfunctioning brain circuits.
"The mammalian brain is a composite of diverse cell types." However, despite rapid advances in the field of neuroscience, "a lead author, Dr. Benjamin Arenkiel, is a limited number of cell types in the brain are known and well-characterized. . "Identifying all cellular subtypes is crucial to unraveling how brain circuits function and will yield insights into brain activity under designed and injured conditions."
In this study, Arenkiel and his colleagues described an innovative approach that identified novel cellular targets and genetic pathways involved in the wiring of adult-born neurons into existing brain circuits.
Researchers now know that the brain is not just composed of four or five cell types performing generic roles . Most circuits consist of unique subtypes of cells, many of which are currently uncharacterized, explained Arenkiel. For instance there are possibly thousands of functional subtypes within a particular class of neurons.
" Therefore, the first task to begin understanding brain circuits is to identify all the cellular players," said Arenkiel, who is also a McNair scholar at Baylor College of Medicine. "This would allow you to genetically probe them to reveal their biological functions , a necessary knowledge to fix these circuits when something goes wrong."
In most adult mammals, only two regions of the brain, the hippocampus and the olfactory bulb (OB), have been shown to integrate new neurons into existing brain circuits. Arenkiel joined forces with co-corresponding author Dr. James Martin. The team applied to a relatively new technology, single cell RNA sequencing , to identify novel cellular subtypes in the OB.
To perform single cell RNA sequencing , Burak Tepe, to graduate student in the Arenkiel lab and one of the primary authors of this paper, and colleagues prepared to single-cell suspension by disassociating brain tissue using enzymes. This mixture was sorted into a microfluidic chamber in which every cell was co-encapsulated in microparticles (beads) with unique barcodes that kept track of the cellular origin of each mRNA transcript.
Additionally, the team uncovered genes and / or pathways that are chronologically turned "on" or "off" in these lines during brain development. This study leverages the combined power of single-cell RNA sequencing analysis of adult-born neurons with bioinformatics to compare how gene expression profiles from different neuronal lines progress over time.
Putative developmental trajectory
This powerful method has allowed the authors to recreate a putative developmental trajectory ("pseudo-timeline") of the neuronal lineages in the OB-from migrating neural progenitors to fully functioning mature neurons-along with information of when and where specific genes genetic networks are turned 'on' or 'off.' Consistent with this, the authors found specific subtypes of neurons were differentially enriched or depleted in response to distinct sensory cues.
"In addition to identifying key players and providing crucial mechanistic insights into adult neurogenesis in OB, we think this study has a broader impact because other researchers can now use this approach to identify and tease out the function of new neuronal circuits in other parts of the adult mammalian brain, "Arenkiel said.