Advanced Tool Maps Detailed Brain Neuronal Connections

Scientists at the Salk Institute have developed an innovative new brain-mapping tool named Single Transcriptome Assisted Rabies Tracing (START). This pioneering technology merges monosynaptic rabies virus tracing and single-cell transcriptomics, allowing for unprecedented detail in mapping the connections between specific neuronal subtypes within the cerebral cortex. The development of START marks a significant step forward in understanding how different parts of our brains connect and function together. 
 
The team's revolutionary research was published on September 30, 2024, in Neuron. It is considered the first study to resolve cortical connectivity at such a microscopic level—that of transcriptomic cell types. 
 
Edward Callaway, professor and Vincent J. Coates Chair in Molecular Neurobiology at Salk, explains that current treatments for neurological disorders are akin to trying to fix a machine without fully understanding its components. But START's ability to create a detailed blueprint of the brain’s numerous parts and their interconnections may lead to more accurately targeted therapies for conditions like autism or schizophrenia. 
 
Neurons can be broadly categorized into excitatory neurons that stimulate brain activity or inhibitory ones that suppress it—not unlike an accelerator or brake pedal, respectively, in an automobile analogy. These broad categories can be further divided based on varying characteristics, such as their location within layers of the brain or by marker proteins they express. 
 
Advancements in transcriptomics now allow these subclasses to be broken down even further using single-cell RNA sequencing grouping cells with similar gene expression patterns, defining each cluster as a unique neuronal subtype. 
 
START combines this technique with another method previously developed by Callaway’s lab: monosynaptic rabies virus tracing, which allows modified viruses to jump from one cell type directly connected cells, enabling researchers to map cellular connections. 
   
Applying START allowed scientists to identify distinct connectivity patterns across various subtypes of inhibitory neurons—information previously unattainable through existing methodologies. 
 
Maribel Patiño, first author and former graduate student in Callaway's lab, explains that inhibitory neurons are often treated as a uniform group. However, START reveals their diversity and unique connectivity patterns, which contribute to the formation of sophisticated microcircuits integral to brain functions. 
 
For example, an inhibitory subtype called Sst Chodl cells associated with sleep regulation was found densely connected to layer 6 excitatory neurons known for coordinating sleep rhythms via connections to the thalamus. 
 
The detailed insights provided by START will enable neuroscientists to understand how specific neuronal subtypes shape brain circuitry leading our thoughts, perceptions, emotions, and behaviors. 
 
The team aims to create viral vectors and gene-editing technologies targeting individual cell subtypes, potentially paving the way for future therapeutics selectively modifying neuron populations contributing conditions like autism or schizophrenia. 
 
Callaway concludes, saying while it remains uncertain exactly how this information will be used decades from now, rapid technological advancements suggest treatment methods today may not be the same in the future. He adds that all resources related to START methodology, including viruses, are freely available for entire neuroscience community use.