Real neuroscience in virtual worlds
Highlights
► We review VR methods used to study neural circuitry in genetic model organisms. ► We discuss advantages of VR and experimental paradigms and technologies enabling it. ► We cover recent results from VR research in genetic model organisms. ► We cover important considerations concerning VR experiments. ► We provide an outlook for the future of this exciting experimental toolkit.
Introduction
The behaviors of animals have long fascinated naturalists, who observed animals in their native environments. A more mechanistic understanding of behavior was taken up by the ethologists who combined fieldwork with experiments conducted under more controlled situations where behavioral strategies could be isolated and tested [1]. The spirit of these early investigators is alive and well today and inspires at least two popular approaches to the study of neuronal mechanisms of behavioral control: attaching miniaturized recording devices onto freely maneuvering animals as they interact with a controlled environment and adapting larger recording systems to restrained animals that are stimulated by animal movement controlled dynamic sensory environments. This latter approach — a form of virtual reality (VR) for animals — becomes all the more powerful when it is applied to the small number of organisms, such as flies, mice, zebrafish, and worms that have become genetic model systems in the neuroscience community. While VR has been used for decades in primates to study the neural basis of behavior [2, 3, 4, 5], it is currently only in these model systems that wide-ranging investigations that combine methods in molecular biology, genetics, neural recording, and behavior are possible. We therefore restrict our focus to recent research that has used or made possible VR as a means to dissect the neural circuitry underlying behavior in genetic model organisms.
Section snippets
What is virtual reality and why should one use it?
In general, a VR experiment consists of a simulated environment that is sensed by the animal and is updated based on the animal's actions (Figure 1a). The interaction between the animal and the environment must be parametric; that is, movements of the animal must map to trajectories in parameter space, which in turn correspond to updates of the virtual world. While the simulation is often imperfect, the goal of these methods is to reproduce a sufficiently convincing subset of the stimuli that
The ‘nuts and bolts’: experimental paradigms and technologies enabling VR
The realization of a VR system enabling the two main advantages listed above requires three general categories of methods and components:
- 1.
Animal restraint: The simultaneous measurement of neural activity and behavior in VR requires restricting the animal so that the stimuli can be sensed while providing enough freedom of mobility for the animal to move in response to the environment. Progress towards this goal was built on efforts to develop high resolution functional neural recording
VR to study the neural activity underlying behavior
While the powerful combination of VR, behavior, and high precision functional recording and/or stimulation have thus far only been accomplished in mice (see below); these methods offer great future promise for understanding the neural basis of behavior in other genetic model systems. Recent progress on many fronts suggests that these are only the early days of a rapidly growing field that will soon expand to flies, fish, and possibly worms. In this section, we cover the recent results from
Considerations for VR experiments
By design, VR experiments are implemented as closed-loop systems and as a consequence, scientists who pursue these methods must grapple with the often non-intuitive properties of feedback systems. In particular all feedback systems must be ‘tuned’ in some way; classical feedback systems are parameterized to allow the designer to balance the speed and the stability of the closed-loop system. The simplest form of coupling between the animal's measured motor output and subsequent stimuli
Outlook
Several recent studies in genetic model organisms have provided new evidence that the activity levels [18•, 35] and even the tuning and encoding properties of neurons [51, 52, 71] are modulated by the behavioral state of the animal. In general the neurons recorded in these studies were found to be more active while the animals are actively locomoting, and in one study this modulation was shown to be graded, that is the more the animals walked, the greater the enhancement in neuronal activity [52
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
References (83)
- et al.
The human hippocampus and spatial and episodic memory
Neuron
(2002) - et al.
Human spatial navigation: cognitive maps, sexual dimorphism, and neural substrates
Curr Opin Neurobiol
(1999) - et al.
From response to stimulus: adaptive sampling in sensory physiology
Curr Opin Neurobiol
(2007) - et al.
Genetic dissection of neural circuits
Neuron
(2008) - et al.
Troponin C-based biosensors: a new family of genetically encoded indicators for in vivo calcium imaging in the nervous system
Cell Calcium
(2007) - et al.
Modulation of visual responses by behavioral state in mouse visual cortex
Neuron
(2010) - et al.
Reflective surfaces for panoramic imaging
Appl Opt
(1997) - et al.
The neural basis of temporal processing
Annu Rev Neurosci
(2004) - et al.
Optogenetic manipulation of neural activity in freely moving Caenorhabditis elegans
Nat Methods
(2011) - et al.
Cellular networks underlying human spatial navigation
Nature
(2003)