July 29, 2003 Boston, MA -- Scientists at Harvard Medical School have cleared up some of the mystery surrounding a key structure in the developing brain that helps form the visual circuits. Their findings, which appear in the July 25 issue of Science, could provide new insight into early brain defects that are linked to conditions like cerebral palsy and learning disabilities.
During development, nerve cells in the eye send messages to the thalamus, a region located deep within the brain. The thalamus then passes these messages on to the area of the outer cerebral cortex that deals with vision. The connection between the thalamus and cortex initially passes through a transient and seldom studied structure called the subplate. By removing parts of the subplate in cats, the HMS researchers have shown that this structure is a key component in strengthening the thalamus to cortex connection and in mapping out further cortical wiring patterns important for vision.
The subplate neurons are acting "kind of like teachers," says senior author Carla Shatz, the Nathan Marsh Pusey professor of neurobiology and head of the HMS Department of Neurobiology. "They're needed for the thalamic connections to strengthen and grow so that they can become strong enough to talk to the cortical neurons."
Shatz, who is also co-chair of the Harvard Center for Neurodegeneration and Repair (hcnr.med.harvard.edu), says that an intact subplate normally acts like a form of building scaffolding for the neural circuits, directing and strengthening important nerve signals, before disappearing. "You make sure all the connections in the building are really strong so the thing doesn't fall down, and then you remove the scaffolding." Once the brain is fully developed and the subplate neurons start to die, a hand-off of sorts occurs in which the thalamus starts sending its signals directly to the developing visual cortex, bypassing the dismantling subplate.
In humans, the subplate scaffolding disappears by two years of age. But it is highly susceptible to damage even in the womb. During this developmental stage, the subplate neurons are the first to mature and thus require lots of oxygen for their many metabolic processes. Oxygen deprivation early on, as occurs in hypoxic injury in the womb or at birth, could harm the subplate and lead to defects like cerebral palsy or other disabilities later in life. If it turns out that the subplate is linked to such defects, understanding more about its function could eventually lead to new therapies.
Research looking at the subplate neurons has proven difficult in the past because of problems accessing the cells, which are located deep below the cerebral cortical plate, and because the structure disappears by adulthood. This did not deter Kanold and colleagues, who used toxins that targeted specific molecules on the subplate neurons to selectively remove parts of the structure.
The study looks closely at the neural connections that start at the lateral geniculate nucleus (LGN), a thalamic region that receives inputs from the retinal cells, and end in a late-developing area of the visual cortex labeled layer 4. From there, highly specialized columns of cells form, which are involved in analyzing visual stimuli. Nobel prize-winning work by David Hubel and Torsten Wiesel at Harvard Medical School demonstrated that the thalamic connections to the nerve cells in the cortex help form these columns. One type of column, for determining ocular dominance, forms based on visual signals it receives from either the left or right eye. Another kind of column forms in response to bars of light presented to the eyes at different orientations--for example, neurons in one such column may respond to vertical lines like telephone poles, while cells of another column may recognize horizontal lines like the wires crossing between the poles.
By examining the brains of cats with their subplate neurons removed, the researchers have shown that not only is the structure involved in strengthening the signal from the LGN to the layer 4 neurons, but without it, the distinctive ocular dominance and orientation columns do not form. "Basically, taking out the subplate arrests cortical development," says Patrick Kanold, a research fellow in neurobiology at HMS and lead author of the study. Kanold showed that neurons in the visual cortex with a disrupted subplate could not distinguish light bars of different orientations--whether the lines were vertical, horizontal, or at an angle. This was a clear indication that their orientation columns had not formed properly. By measuring neural activity, he also showed that the signals between the LGN and the layer 4 neurons were much weaker in brains with missing subplate neurons.
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