Rick Robinson

Jan 17th 2022

Brain Function: One Underlying Mechanism Could Change the Way Doctors Approach Neurodevelopmental Disorders


Autism spectrum disorders and schizophrenia have some things in common: According to the National Institutes of Health (NIH), both conditions are disorders of brain function associated with complex behavioral traits, notably “problems with social interaction and emotion, verbal and nonverbal communication, and odd or inflexible behavior.”

Per the NIH, autism and schizophrenia were not distinguished as separate conditions until the 1970s. Previously, autism was regarded simply as an earlier stage in the development of schizophrenia, though according to Spectrum News, modern clinical experience with the two conditions “feels like a very different interaction.”

As Spectrum News explains, “Although autism and schizophrenia are characterized differently in popular books and film, scientists have long suspected that the two conditions are somehow linked.” Now, a new study reported by Neuroscience News and concurrently by MIT suggests that both may result from similar underlying dysfunctions in neural circuitry, ultimately linked to a basic process known as gene expression.

Exploring the Complex World of the Thalamus

The new research examines a section of the brain known as the thalamus. According to News Medical, the thalamus is located near the center of the brain and acts as a switching system for nervous-system signals from the rest of the body. It registers the signal as a sensation, which “is then passed onto the cerebral cortex for interpretation as touch, pain or temperature.” The thalamus is also believed to play a gate-keeping role in brain function, deciding which signals should be passed along to the cortex.

Earlier studies have shown that the thalamus displays strong expression of gene variants that are associated with autism and schizophrenia. As Brown University explains, gene expression is the process by which genes trigger specific biochemical reactions that ultimately “express” themselves in outward physical or behavioral results.

In particular, a 2016 study by the same MIT research team behind the new study — headed by Guoping Feng, Dheeraj Roy and Ying Zhang — showed that when laboratory mice had a specific gene called Ptchd1 “knocked down” (effectively disabled) in one section of their thalamus, the mice showed attention deficits and hyperactivity. But that section, called the thalamic reticular nucleus (TRN), did not seem to relate to the learning disorders also seen in human patients with Ptchd1 mutations.

So, the researchers started exploring other sections of the thalamus with high levels of Ptchd1 expression. One such area is the anterodorsal (AD) thalamus — a small region involved in spatial learning.

Genes and Memories

The researchers found that, at least in mice, the AD thalamus is closely connected to another region within the brain, the retrosplenial cortex (RSC).

Moreover, the research team was able to establish that the neural circuit between them plays a key role in two distinct kinds of memory. One is fear-related memory — in this case, of a chamber that gives the mice a mild electrical shock — and the other is “working memory” used to build a mental map of the mouse’s surroundings. What the researchers found was that “knocking down” Ptchd1 in the AD thalamus caused a dramatic reduction in the mouse’s ability to absorb and learn fear-related and working memories.

Along the way, the team also discovered another new brain complexity. The anteroventral (or AV) thalamus, near the AD thalamus, helps the brain distinguish between similar memories. As Dheeraj Roy explains, “These experiments showed that two neighboring subdivisions in the thalamus contribute differentially to memory formation, which is not what we expected.”

Blocking Hyperexcitability

The researchers went on to perform a similar set of experiments with four other genes — one associated with autism and the other three with schizophrenia. All the “knockdowns” resulted in the same deficiency in learning memories. And they all produced hyperexcitability of the AD thalamus neurons.

This effect was not a surprise; it confirms the existing theory that what we call “learning” results from the strengthening of synapses when they are used more frequently. As Ying Zhang explains, “When an animal is learning, these neurons have to fire more, and that increase correlates with how well you learn.” Zhang adds, “Our simple idea was if a neuron fires too high at baseline, you may lack a learning-induced increase.”

The team also discovered that cognitive function could be restored to mice with mutations in these genes by artificially suppressing their hyperactivity. This was achieved using a cutting-edge technology called chemogenetics.

According to Addgene, “Chemogenetics refers to the engineering of protein receptors to respond to previously unrecognized small molecules.” The downside, as Neuroscience News and MIT notes, is that chemogenetics is not yet approved for use on humans. But the researchers explain that other tools may be able to produce the same results.

According to senior author Guoping Feng, “The findings lend support to the idea that grouping diseases by the circuit malfunctions that underlie them may help to identify potential drug targets that could help many patients.”

Understanding the Human Mind

If further research bears out these findings, they have broad implications not only for treatment but also for our understanding of autism spectrum disorders and schizophrenia.

These were identified as separate disorders because of their differing symptoms — which, per Spectrum News, “lent such a qualitatively different feel” to clinicians’ experience of dealing with patients on the autism spectrum of those with schizophrenia. And since it is the symptoms in the form of behavioral traits that can affect the lives of patients, a focus on treating those symptoms has been the natural course of action.

But the new findings may lead scientists back toward their long-held suspicion that important links tie together these neurodivergent traits, despite their outward differences. And for those seeking a way to manage such behavioral traits, this research could hold promise. Certainly, as scientists and researchers further explore this connection deep in the genetic structures of the human brain and nervous system, we at least stand to gain a better understanding of the human mind at large.

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