REVIEW: Principles of Neural Science, 6th edition.

In 2024 I set a goal to read Principles of Neural Science so that I could get a broad overview of my chosen field. This is a massive, 1,600-page tome that serves as a comprehensive overview of basically every mature subfield of neuroscience.

After reading it all the way through, it’s clear to me that there are some areas of neuroscience that we understand very well, but there are also lots of gaps. In my review, I’ll summarize some of the successes, then move on to some areas for improvement.

Neuroanatomy

We have very detailed maps of the peripheral and central nervous systems based on histology, cell type-specific labeling, and MRI. Lesion studies have also been useful for determining which parts of the nervous system may be necessary for specific functions.

Molecular biology

Neuroscientists have a good understanding of the structure and function of single proteins in the nervous system, such as ion channels and synaptic proteins. Understanding the structure and function of these proteins is foundational for higher-order phenomena like action potential generation and synaptic plasticity.

Sensory systems

Probably the greatest triumph for neuroscience in the 20th (and early 21st) century is that we now know how light, sound, touch, temperature, taste, smell, and acceleration are transduced from physical and chemical phenomena into action potentials. As evidence of this triumph, seven Nobel prizes in Physiology or Medicine have been awarded for discoveries related to mammalian sensory systems¹.

These sensory systems are as beautiful and elegant as biology can be, and they should evoke wonder in each of us. For example, if you want to be amazed at what we creatures of mere flesh and blood can do, learn about how the primate retina can detect single photons.

Disease

Neuroscience has much more progress to make in addressing neurological disease, especially in some of the most common diseases (e.g. depression, Parkinson’s Disease, autism spectrum disorder). We have made significant gains in understanding and treating monogenic/monocausal diseases (e.g. spinal muscular atrophy, stroke) but there is a huge gap between those relatively ‘simple’ diseases and more complex ones.

One of the original hopes of the Human Genome Project (as I have heard it described to me by people “who were there”) was that every human disease and phenotype would have a matching gene that could be targeted for treatment. While there are a large number of rare, monogenic diseases, the majority of the disease that we care about is complex, polygenic, and often has interactions with development and the environment. I predict that a necessary precondition for improved treatments of complex diseases will be better tools for working with complex, dynamical systems, like the interactions between genes, proteins, and metabolism that happen in every human cell.

Perception, action, cognition, and consciousness

No Nobel prizes have been awarded for discoveries in any of these areas. Will a Nobel ever be awarded for work on the generation of action in motor cortex? Or the mechanisms of cognition in prefrontal cortex? Lots of data have been gathered over the past fifty years, and the rate of data collection is accelerating. Large-scale recordings of hundreds to thousands of neurons are becoming more and more common, using a variety of optical and electrophysiological tools. While the new data have been transformational in developing some new theories, some people think the field is ready for a Kuhnian scientific revolution.

For my part, during my reading of Principles of Neural Science, I was struck that some chapters had so little to offer in terms of comprehensive theories. As one example, the chapter on motor cortex was full of very interesting experiments but never seemed to articulate how motor cortex might work, in contrast to the chapter on intermediate-level visual processing in lower visual cortex which had clear explanations of retinotopic receptive fields and orientation tuning.

I’m not an expert in any of these areas, but it seems to me like the past 50 years of work on perception, action, cognition, and consciousness have not yielded the same clarity that we now have in sensory systems or molecular neuroscience. To me, that indicates the need for a change. It may be a change of methods, a change of definitions, or a full-blown scientific revolution, but my hope is that a few decades from now I will be able to enjoy understanding these ‘higher-level’ brain functions in the same way that I enjoy understanding the mechanisms of hearing or synaptic release.

And there will probably be a Nobel along the way for the scientists who manage to pull it off.