Initially, scientists learned about disorders when disaster happened – Paul Broca made his mark when he linked posterior left frontal lobe damage to speech production; losing his hippocampus made Henry Molaison, better known as H.M., the world’s most famous amnesiac; and being run through with a railroad spike turned Phineas Gage into a psychological phenomenon.
Later, neuroscientists relied on in vitro cell cultures or animal models to see what was happening. Although less devastating for the subjects, this route still has many limitations. A rat’s brain is significantly different to a human brain, particularly regarding the cortex, and a single type of cell in a dish can in no way represent the magnitude or the complexity of the human brain as a whole.
“Can we capture in a dish more of these elaborate processes that are underlying brain development and brain function?“
The limitations shown in the traditional methods of neurological research raised an important question, as summarized by Sergiu Pasca of Stanford University (CA, USA): “Can we capture in a dish more of these elaborate processes that are underlying brain development and brain function?”
The answer? Yes; scientists have developed ways to take stem cells and grow cerebral organoids (Figure 1), or ‘mini-brains’, which, as they grow, model the development of the human brain.
Starting as induced pluripotent stem cells (iPSCs), organoids are lab-grown (Figure 2), miniature versions of the body’s organs. The 3D anatomy and variety of tissue and cell types make them the most realistic models of human anatomy to date. Researchers have developed organoids for all major organs, from the heart to the pancreas, but one of those gaining serious attention is that of the brain.
First developed by Lancaster et al. in 2013 , these cerebral organoids were shown to be realistic models of the human brain, modeling distinct regions and cellular organization patterns. They can grow to 3–4 mm and can survive up to 10 months. Staining experiments demonstrated the presence of a distinct forebrain at 16 days of development and further sub-regionalization to a ventral and dorsal cortex at later stages of growth. Hippocampal cells can be observed, although they lack the localization seen in vivo and are found throughout the organoid.
“I think that these brain organoids hold incredible potential for modeling human neurological disease in completely new ways,” commented Paola Arlotta of Harvard’s Department of Stem Cell and Regenerative Biology (MA, USA), who has been described as a pioneer in brain organoids .
“Human brain organoids generated from cells of patients carry extraordinary potential to serve as transformative models to understand and develop treatments for prominent human neuropathologies, like neuropsychiatric disease.”
Back to the start; rewinding neural development
The development of psychiatric diseases is poorly understood. Often starting in the womb, it is difficult to capture the nature of abnormal brain development and watch as these changes occur.
“What if we could somehow go back, so to speak?” questions Arlotta. “What if we could take a sample of blood from a child with autism, make his or her own stem cells and turn those into a model of their brain? Could we then begin to watch in some small part how the brain had formed?” .
A recent study from the SALK institute (CA, USA) did just that, and demonstrated that neurons derived from skin cells of individuals with autism spectrum disorder (ASD) show different patterns of development and growth when compared with cells of neurotypical individuals .
“Neuropsychologist Donald Hebb first coined the phrase ‘cells that fire together wire together’ in respect to synaptic plasticity and the associative learning process.”
When re-differentiating skin cell-derived iPSCs into neurons, researchers noticed that the neurons derived from people with ASD grew at a faster rate and had longer, more complex branches. The team then used a subset of the neurons to develop cerebral organoids and found that those from ASD cells were larger and had an increased thickness of the cortical plate.
“The current diagnostic methods are mostly subjective and occur after the emergence of behavioral abnormalities in young children,” commented lead author Simon Schafer. “We hope these studies will serve as a framework for developing novel approaches for diagnosis during an early period of child development – long before behavioral symptoms manifest – to have the maximum impact on treatment and intervention.”
These results supported those of a smaller 2015 study where the organoids grown from ASD patient’s stem cells showed increased expression of genes that control neuronal growth and development . Overexpression of the transcription factor FOXG1 in particular was found to lead to the overproduction of inhibitory GABAergic neurons, creating an imbalance in the excitatory/inhibitory neuron ratio. ASD-derived organoids were also found to have an accelerated cell cycle.
Growing your connections: do neurons that fire together really wire together?
Neuropsychologist Donald Hebb first coined the phrase ‘cells that fire together wire together’ in respect to synaptic plasticity and the associative learning process. Though not to be taken literally – neurons firing together results in seizures – the abstract concept is valid; firing of cell A is needed to initiate the firing of cell B and with repeated or persistent activity, the efficiency of cell A in causing the firing of cell B is increased.
This form of synaptic strengthening is believed to be the underlying cause of neural plasticity, that being the alteration of neural networks throughout life, as well as the learning process and beginning of structuring the brain.
Read the full article in BioTechniques here.