Introduction
Neuroscientists have traditionally taken a reductionist approach to understanding the immense complexity of nervous systems. As is the case in other fields of biology, the method of reducing nervous systems into their constitutive parts has proven useful for understanding neural circuits and how they function. As a result, modern neuroscience has thrived on cataloging and scrutinizing individual components of complicated neural systems. However, substantial gaps persist in understanding how these disparate components connect and interact to generate higher-order functions. Bridging these gaps requires a concerted effort to integrate knowledge across sub-fields in neuroscience and, more broadly, across biology. Systems biology is a scientific approach used to examine complex biological processes at the level of systems, rather than focusing on individual discrete parts (Kitano, 2002; Mesarovic, 1968). A “system” is a group of mutually dependent components that work together to form a unified whole. The goal of a systems approach is to understand a holistic big picture in the context of integrated systems that are dynamic and interrelated. By taking a systems biology approach to understanding the nervous system, we can attempt to integrate and understand interactions between the different neural components that give rise to higher-order emergent phenomena (Geschwind and Konopka, 2009; Grillner et al., 2005).
The struggle between understanding individual parts and the larger whole has been a part of neuroscience since its origin as a scientific discipline. Over a century ago, the field was shaped by the opposing theories of two leading neuroanatomists, Santiago Ramón y Cajal and Camillo Golgi. On the one hand, Golgi’s reticular doctrine posited that the nervous system was an interconnected nerve network (“a large syncytium”) that was seamless and continuous (Glickstein, 2012). In contrast, Cajal proposed the neuron doctrine which stated that individual nerve cells were the basic structural and functional units of the nervous system (Cajal, 1888; Cajal, 1899). The structural evidence from the microscopes and stains available to scientists at the time supported Cajal’s neuron doctrine. In fact, it was actually Golgi’s la reazione nera or “black reaction” (now known as the Golgi stain) that produced the most convincing structural evidence that neurons were structurally separated elements. The introduction of the electron microscope in the 1940s definitively demonstrated that neurons were not continuous but were instead distinct entities separated by synapses with extracellular space in between them (Palay, 1956; Porter et al., 1945). While both Ramón y Cajal and Golgi were awarded the Nobel Prize in 1906 for their work on the structure of the nervous system, it was Ramón y Cajal who would widely be considered as the founder of modern neuroscience, and his neuron doctrine has long served as a foundation for the field.
Perhaps because of this foundation on the neuron doctrine, many of the workhorse techniques and methods in modern neuroscience have been catered to investigating individual components that make up neural circuits. For example, Golgi stains and patch-clamp electrophysiology highlight individual neurons. This conceptual focus on individual neurons has led to a compartmentalization of knowledge that has obscured, to some extent, our ability to integrate data on how individual functions enable higher-order processes (Yuste, 2015). Moreover, the reductionist bias and a reliance on big data or methods-driven approaches in neuroscience has left us with many descriptions, but few explanations (Krakauer et al., 2017). As a result, what is generally lacking in the field are accepted theories of nervous system function that explain how individual neurons or groups of neurons (e.g., circuits) contribute to neural systems that then give rise to behavior, cognition, or other emergent properties of nervous systems.