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The miracle of brain development

Cold Spring Harbor Lab
All images credit Huang Lab, CSHL

Genetic “fate-mapping” technologies developed by (Cold Spring Harbor Laboratory) Professor Josh Huang and colleagues show in exquisite detail how an important part of the mammalian brain—here, a mouse brain—self-assembles over a few short weeks during the embryonic period. In the sequence featured below, follow the emergence of the striatum, a brain area that enables information processed by the cortex to be translated into precise physical movements and actions, as mediated through the basal ganglia.

Although in anatomical terms individuals do differ in small ways, the miracle of brain development is consistency from individual to individual. The brain’s basic scaffold is the work of a genetic program that directs its assembly. The result is a brain at the species level—whether in a mouse or a human—that is highly stereotypical.

By far the most complex entity that science has so far attempted to understand, the brain in a person can sense, process, evaluate, select, even think, plan and imagine, as a consequence of structures, connections and networks that we all possess. These give rise to the extraordinary functional capacities whose secrets we are only just beginning to learn. Tiny perturbations in brain development, sometimes influenced by environmental circumstances and/or small variations in an individual’s genetic code, are almost certainly among the root causes of serious disorders and illnesses including autism, Parkinson’s disease and schizophrenia.

The embryonic brain begins to take shape

precursor neuron cells
Areas that glow red in this image, made on the mouse embryo’s 10th day, register precursor cells that will seed the emerging brain with neurons. They’re arrayed within the crescent-shaped neural tube, the forerunner of the central nervous system that matures to become the brain and spinal cord. The building of the striatum begins with activity in the boxed area, the LGE, or lateral ganglionic eminence.

Neuronal nursery

aIP cells
Neurons that will populate the striatum are born in the LGE and begin to migrate. Neuronal progenitors called aIP cells (white arrows) are located near the base membrane of the LGE. They give rise to ‘threads’ of maturing neurons, which extend across the LGE en route to the developing striatum, where they will form island-like striosomes.

Common ancestors

ancestor RG cells
The same ‘ancestor’ RG cells spawn two kinds of intermediate precursors, which split to form baby neurons that will populate the two functional ‘compartments’ of the striatum, striosomes and matrix.
Left: aIPs intermediate precursors generate neurons that assemble to form island-like striosomes in the maturing striatum. Right: bIPs intermediaries generate neurons that form the matrix ‘compartment’ of the striatum.

Striosome ‘islands’ take shape

striatal sea
Neurons born in the LGE of aIP intermediate precursors are first to migrate into the bulb-shaped area that will become the mature striatum. In this view, they look like islands in the striatal sea. Inset: close-up shows the striosome neurons, called spiny projection neurons.

The matrix materializes

matrix compartment
Images on the 14th, 15th and 17th embryonic days show how the matrix ‘compartment’ of the striatum self-assembles. Left: bIP precursors give birth to neurons (red) which migrate (center) to form the matrix compartment of the striatum (right).

A mysterious finishing touch

striosome islands
Striosome “islands” (black) in the striatum (green) are enclosed by ring-shaped structures (orange). Their function is not yet known.

The striatum matures

maturing striatum compartments
Striosomes (green) and Matrix (red).

Different connections, different functions

cross section of mouse brain
Cross sections of the mature mouse brain, as seen from the front looking backward. The two colors, red and green, show projection patterns of neurons that populate the striosome (top) and matrix (bottom). These different projection patterns reflect the different functions of the striatum’s two main ‘compartments.’

Born of the same cellular “parents,” neurons that form the striosomes and matrix portions of the striatum have different but complementary functions. The two “compartments” develop in parallel, the striosomal “islands” getting a slight head start. Neurons that form them know where to go and how to connect thanks to instructions encoded in genes.

The Huang team’s experiments confirm that the striatum has a second layer of organization that is superimposed over the striosome/matrix organizational plan. Circuits within both striosomes and matrix form two distinct pathways that connect the striatum to other parts of the basal ganglia. In both the striosomes and matrix, one network of neurons forms what neuroscientists call the direct pathway. Signaling within this pathway promotes action. Another network in each compartment, called the indirect pathway, conveys signals that inhibit action. We depend deeply on the proper development and functioning of these interrelated networks. When they are disrupted, for instance in Parkinson’s disease, precision in movements is lost (e.g., difficulty initiating action; shuffling gait) and unwanted movements (e.g., tremor) appear.

Written By: Peter Tarr, Senior Science Writer | publicaffairs@cshl.edu | 516-367-8455