In this chapter we have introduced the remarkable properties of the nerve cells and some of the mechanisms that allow organisms to perceive their world and to learn from experience. The human body contains multiple types of neurons, each with its own shape, neurotransmitter, number of dendrites, length of axon, and numbers of connections with other neurons. How each of these types of cells develops in precisely the right place and makes appropriate synaptic connections with other neurons and appropriate contacts with surrounding glia remains largely a mystery. What, for instance, are the extracellular signals, transcriptional regulatory circuits, and induced or repressed proteins that tell a neuron to become myelinated or to generate a specific number of dendrites of a specific length? How does a neuron achieve its very long, polarized, branching structure? Why does one part of a neuron become a dendrite and another an axon? Why are certain key membrane proteins clustered at particular points—neurotransmitter receptors in postsynaptic densities in dendrites, Ca²⁺ channels in axon termini, and Na⁺ channels in myelinated neurons at the nodes of Ranvier? Given the enormous number of potential synaptic targets in the brain, how does an individual neuron know what neuron it should synapse with? How does activity change the connections between neurons so that neural circuits change dynamically with experience? Such questions of cell shape, protein targeting, and intercellular communication also apply to other types of cells, but the morphological diversity of different types of neurons and the vast complexity of cell circuits make these particularly intriguing questions in the nervous system.

Advances in the human genetics of neuropsychiatric diseases promise to provide insights into the function of cells and circuits in the brain. By identifying gene mutations that increase risk for human psychiatric diseases, and then determining how these gene products function in individual neurons (or glia) and in neural circuits in model organisms, we may begin to understand how genes and circuits contribute to healthy and unhealthy brain function. An especially exciting approach involves the generation of neurons from induced pluripotent cells (described in Chapter 21) from patients with neuropsychiatric disorders. This provides a means of testing the function of mutations in human neurons without having to harvest neurons from the brain (which is not possible to do from living humans).

Single-cell RNA-sequencing techniques have revealed that the diversity of neurons and glia in the brain is much greater than previously appreciated. For example, we now know that there are a multitude of distinct classes of interneurons that express distinct proteins and have distinct functions: interneurons that express the protein parvalbumin fire action potentials at high rates, and form synapses on the cell bodies and proximal dendrites of target neurons, while interneurons that express the protein somatostatin have low thresholds for action potential firing and form synapses on distal dendrites of target neurons. Even parvalbumin and somatostatin expressing neurons can be subdivided into many different types of interneuron. In a similar manner, single-cell profiling suggests that glial cells exhibit great diversity. These types of experiments promise to generate a new and refined catalog of cell types in the brain. New imaging modalities, involving the clearing of lipids in tissue to permit visualization of individual cells, combined with light sheet microscopy, promise to generate architectural maps of the locations of these various types of neurons and glia within the intact brain.

The advances in the cell biology of the nervous system have been paralleled by extraordinary advances in the development of tools to explore how neural circuitry carries out the interpretation of sensory information, analytical thought, feedback mechanisms for motor control, establishment and retrieval of memories, inheritance of instincts, regulated hormonal control, and emotional responses. Some experiments are done with noninvasive imaging technologies, observing thousands to millions of neurons and detecting global electrical activity in awake, behaving animals. Others are done by observing in vivo a few cells at a time using inserted electrodes. This is being accomplished by improvements in imaging methods (invasive and noninvasive) combined with the development of better ways to manipulate the activities of single neurons, or of large numbers of neurons simultaneously. The use of optogenetics, in which light can be used to manipulate subsets of neurons expressing light-activated channelrhodopsins, permits direct links to be forged between specific neural circuits and behavior. Optogenetics is complemented by an analogous pharmacosynthetic approach called designer receptors exclusively activated by designer drugs (DREADDs), in which cells express a mutated channel that it activated by a pharmacologically delivered ligand. There is every reason to expect these advances to continue, an exciting prospect for understanding the brain and for guiding physicians to do a better job of treating diseases that affect the nervous system.