Hope for a Grand Explanatory Theory of Cognitive Disease?


A just-published series of mouse studies by MIT researchers suggests that a missing or defective Ptchd1 gene may underlie a number of common cognitive impairments.

The researchers, Dheeraj Roy, Ying Zhang, Guoping Feng, et al, using CRISPR-cas9 gene editing, disabled the Ptchd1 gene in mice and found that it caused behaviors akin to those seen in individuals afflicted with autism and/or schizophrenia. The researchers even hypothesize that that gene may be involved with ADHD and impulse disorders. Importantly, the researchers were able, using chemogenomic treatment, to restore normal memory function. (Use of chemogenomics to clinically treat humans is currently prohibited.)

For years now, both the brain’s thalamus and the Ptchd1 gene have been considered central to memory and to cognitive impairment, but this series of studies takes it a step further: The studies identified a linkage between that gene and two previously under-considered parts of the thalamus. When the researchers disabled expression of Ptchd1, they found a major deficit in memory encoding for both fearful memories and working memory.

This research also bolstered the field’s dominant contention that memory defects can occur when synapses’ baseline level of excitation is too high: When new input enters synapses in that area of the thalamus, there’s not enough ceiling left in the synapses’ excitation level to store that input. In addition to the aforementioned Ptchd1 gene, the Ywhag and Herc1 genes also appear to affect excitation.

This gives the MIT researchers hope for therapeutics for humans that would decrease the baseline excitation in those synapses. The researchers find additional hope in that the chemogenomic approach is only one of a number of ways to fix that thalamic circuitry.

That line of research provides even broader hope: Rather than classifying people’s cognitive impairments by their symptoms, doctors will hopefully more accurately diagnose them based on the person’s neural circuitry, as measured by brain imaging. That should make more effective treatments possible.

In many fields, from cosmology to cancer, the holy grail is a grand explanatory theory. This series of studies seems to clear away at least a bit of the fog that is clouding our understanding of that intricate process between our brain first receiving an input and it being able to make full and focused use of it.

That, in turn, offers what every sufferer of a disease, mental or corporeal, desperately craves: hope.

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