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Untangling the brain
The brain's astonishing complexity has been appreciated and confounding for over 100 years. It began when pioneer scientists first trained microscopes on a profusion of branching twists and turns that connect each neuron. Even in the tiniest areas of brain tissue, neural pathways are tangled. Neuroscientists today are still trying to determine what these cells and the networks they form are communicating to each other. It is the ultimate grand-challenge problem.
In Nature Neuroscience, a team from Cold Spring Harbor Laboratory (CSHL) reports on their use of advanced technologies to illuminate the connectivity patterns in chandelier cells, a distinct type of inhibitory cell in the mammalian brain. They reveal for the first time how this candelabra-shaped cell interacts with hundreds of excitatory cells in its neighborhood, receiving information from some, imparting information to others.
In experiments just reported, these highly specific interactions between chandelier cells and other neurons are part of a larger global network sometimes regulating the fear response in mice.
Chandelier cells play similar roles in other networks, they inhibit "excitement producing" neurons in a variety of situations. The research suggests more broadly how communication hierarchies may be shaped in the brain, in that diverse and often intermingled sets of neurons in "local" brain areas both receive input from and send output out, to distinct brain areas near and far.
The team, led by Cold Spring Harbor Laboratory (CSHL) Professor Z. Josh Huang along with researcher Joshua Gordon MD, PhD, director of the National Institute of Mental Health, focused on dense crowds of excitatory cells called "pyramidal neurons." Several hundred pyramidal neurons can connect with a single chandelier cell. So each chandelier cell may therefore control the firing of hundreds of pyramidal neurons. It has been suggested that they exert a kind of "veto" power over local excitatory messages. But there is more to the story. The research shows, each chandelier cell also can receive inputs from hundreds of excitatory cells, input that influences whether or not it inhibits a circuit.
The new research reveals how intermixed pyramidal neurons are with single chandelier cells in the mouse prelimbic cortex. And, how neurons segregate into two groups distinguished according to (1) where in the brain their projections extend and (2) their likely function.
One group of pyramidal cells was shown to transmit information to the amygdala, resulting in a fear response in the mouse. This ensemble of pyramid cells was inhibited by the chandelier cell. A second ensemble projected into cortical areas conveying information from the thalamus, a relay station that Huang speculates is sending higher-order information to the chandelier cell. The information being sent might reflect, for example, whether the individual (mouse, person, or other mammal) should be afraid of something that it has sensed in its environment, based on past experience.
Huang sumarizes: "This circuit highlights the exquisite selectivity of neuronal wiring with respect to inhibition in the most complex and heterogeneous part of the brain. It also illustrates the directionality of information flow in local and global brain networks. The messages move in a specific direction - the chandelier cell's overall inhibitory and information-routing role being the result of signals to it and from it by specific sets of neurons to which it is connected."
The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala (BLAPC) compared to those projecting to contralateral cortex (CCPC). These ChCs in turn receive preferential input from local and contralateral CCPCs as opposed to BLAPCs and BLA neurons (the prelimbic cortex–BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLAPCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks.
All authors: Jiangteng Lu, Jason Tucciarone, Nancy Padilla-Coreano, Miao He, Joshua A Gordon and Z. Josh Huang.
This research was supported by the National Institutes of Health; the CSHL Robertson Neuroscience Fund; the Hope for Depression Research Foundation; NRSA F30 Medical Scientist Predoctoral Fellowships; Brain & Behavior Research Foundation/NARSAD Postdoctoral Fellowship; the National Science Foundation.
About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program hosts more than 12,000 scientists from around the world each year on its campuses in Long Island and in Suzhou, China. The Laboratory's education arm also includes an academic publishing house, a graduate school and programs for middle and high school students and teachers. For more information, visit http://www.cshl.edu
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The chandelier cell, discovered only 45 years ago, is one of the most distinctive cells in a mammalian brain. Each cell can synapse with hundreds of neighboring excitatory cells, which accounts for its candelabra-like shape. Research is just beginning to reveal how each cell works..
Image Credit: Huang Lab, Cold Spring Harbor Laboratory