Gidon Felsen

A natural approach to studying vision

An ultimate goal of systems neuroscience is to understand how sensory stimuli encountered in the natural environment are processed by neural circuits. Achieving this goal requires knowledge of both the characteristics of natural stimuli and the response properties of sensory neurons under natural stimulation. Most of our current notions of sensory processing have come from experiments using simple, parametric stimulus sets. However, a growing number of researchers have begun to question whether this approach alone is sufficient for understanding the real-life sensory tasks performed by the organism. Here, focusing on the early visual pathway, we argue that the use of natural stimuli is vital for advancing our understanding of sensory processing.

Neural substrates of sensory-guided locomotor decisions in the rat superior colliculus.

Deciding in which direction to move is a ubiquitous feature of animal behavior, but the neural substrates of locomotor choices are not well understood. The superior colliculus (SC) is a midbrain structure known to be important for controlling the direction of gaze, particularly when guided by visual or auditory cues, but which may play a more general role in behavior involving spatial orienting. To test this idea, we recorded and manipulated activity in the SC of freely moving rats performing an odor-guided spatial choice task. In this context, not only did a substantial majority of SC neurons encode choice direction during goal-directed locomotion, but many also predicted the upcoming choice and maintained selectivity for it after movement completion. Unilateral inactivation of SC activity profoundly altered spatial choices. These results indicate that the SC processes information necessary for spatial locomotion, suggesting a broad role for this structure in sensory-guided orienting and navigation.

Light scattering properties vary across different regions of the adult mouse brain.

Recently developed optogenetic tools provide powerful approaches to optically excite or inhibit neural activity. In a typical in-vivo experiment, light is delivered to deep nuclei via an implanted optical fiber. Light intensity attenuates with increasing distance from the fiber tip, determining the volume of tissue in which optogenetic proteins can successfully be activated. However, whether and how this volume of effective light intensity varies as a function of brain region or wavelength has not been systematically studied. The goal of this study was to measure and compare how light scatters in different areas of the mouse brain. We delivered different wavelengths of light via optical fibers to acute slices of mouse brainstem, midbrain and forebrain tissue. We measured light intensity as a function of distance from the fiber tip, and used the data to model the spread of light in specific regions of the mouse brain. We found substantial differences in effective attenuation coefficients among different brain areas, which lead to substantial differences in light intensity demands for optogenetic experiments. The use of light of different wavelengths additionally changes how light illuminates a given brain area. We created a brain atlas of effective attenuation coefficients of the adult mouse brain, and integrated our data into an application that can be used to estimate light scattering as well as required light intensity for optogenetic manipulation within a given volume of tissue.

How the Neuroscience of Decision Making Informs Our Conception of Autonomy

Autonomy, the ability to make decisions for ourselves about ourselves, is among the most prized of human liberties. In this review we reconsider the key conditions necessary for autonomous decision making, long debated by moral philosophers and ethicists, in light of current neuroscientific evidence. The most widely accepted criteria for autonomy are that decisions are made by a rationally deliberative and reflective agent and that these decisions are free of undue external influences. The corpus of neuroscientific data suggest that human brains are capable of the hierarchical control required for reflective thought, but that decisions conventionally perceived as autonomous may not be rational with respect to the deliberative process itself, and are rarely free from covert external influences. These findings cast doubt upon the capacity for autonomy as traditionally defined, and suggest that we reconsider valorizing the right to autonomy in order to align our moral values with neuroscientific naturalism.

Activity in mouse pedunculopontine tegmental nucleus reflects action and outcome in a decision-making task.

Recent studies across several mammalian species have revealed a distributed network of cortical and subcortical brain regions responsible for sensorimotor decision making. Many of these regions have been shown to be interconnected with the pedunculopontine tegmental nucleus (PPTg), a brain stem structure characterized by neuronal heterogeneity and thought to be involved in several cognitive and behavioral functions. However, whether this structure plays a general functional role in sensorimotor decision making is unclear. We hypothesized that, in the context of a sensorimotor task, activity in the PPTg would reflect task-related variables in a similar manner as do the cortical and subcortical regions with which it is anatomically associated. To examine this hypothesis, we recorded PPTg activity in mice performing an odor-cued spatial choice task requiring a stereotyped leftward or rightward orienting movement to obtain a reward. We studied single-neuron activity during epochs of the task related to movement preparation, execution, and outcome (i.e., whether or not the movement was rewarded). We found that a substantial proportion of neurons in the PPTg exhibited direction-selective activity during one or more of these epochs. In addition, an overlapping population of neurons reflected movement direction and reward outcome. These results suggest that the PPTg should be considered within the network of brain areas responsible for sensorimotor decision making and lay the foundation for future experiments to examine how the PPTg interacts with other regions to control sensory-guided motor output.

Optogenetic investigation of the role of the superior colliculus in orienting movements

In vivo studies have demonstrated that the superior colliculus (SC) integrates sensory information and plays a role in controlling orienting motor output. However, how the complex microcircuitry within the SC, as documented by slice studies, subserves these functions is unclear. Optogenetics affords the potential to examine, in behaving animals, the functional roles of specific neuron types that comprise heterogeneous nuclei. As a first step toward understanding how SC microcircuitry underlies motor output, we applied optogenetics to mice performing an odor discrimination task in which sensory decisions are reported by either a leftward or rightward SC-dependent orienting movement. We unilaterally expressed either channelrhodopsin-2 or halorhodopsin in the SC and delivered light in order to excite or inhibit motor-related SC activity as the movement was planned. We found that manipulating SC activity predictably affected the direction of the selected movement in a manner that depended on the difficulty of the odor discrimination. This study demonstrates that the SC plays a similar role in directional orienting movements in mice as it does in other species, and provides a framework for future investigations into how specific SC cell types contribute to motor control.

ePPR: a new strategy for the characterization of sensory cells from input/output data

A central goal of systems neuroscience is to characterize the transformation of sensory input to spiking output in single neurons. This problem is complicated by the large dimensionality of the inputs. To cope with this problem, previous methods have estimated simplified versions of a generic linear-nonlinear (LN) model and required, in most cases, stimuli with constrained statistics. Here we develop the extended Projection Pursuit Regression (ePPR) algorithm that allows the estimation of all of the parameters, in space and time, of a generic LN model using arbitrary stimuli. We first prove that ePPR models can uniformly approximate, to an arbitrary degree of precision, any continuous function. To test this generality empirically, we use ePPR to recover the parameters of models of cortical cells that cannot be represented exactly with an ePPR model. Next we evaluate ePPR with physiological data from primary visual cortex, and show that it can characterize both simple and complex cells, from their responses to both natural and random stimuli. For both simulated and physiological data, we show that ePPR compares favorably to spike-triggered and information-theoretic techniques. To the best of our knowledge, this article contains the first demonstration of a method that allows the estimation of an LN model of visual cells, containing multiple spatio-temporal filters, from their responses to natural stimuli.

An integrative role for the superior colliculus in selecting targets for movements

A fundamental goal of systems neuroscience is to understand the neural mechanisms underlying decision making. The midbrain superior colliculus (SC) is known to be central to the selection of one among many potential spatial targets for movements, which represents an important form of decision making that is tractable to rigorous experimental investigation. In this review, we first discuss data from mammalian models-including primates, cats, and rodents-that inform our understanding of how neural activity in the SC underlies the selection of targets for movements. We then examine the anatomy and physiology of inputs to the SC from three key regions that are themselves implicated in motor decisions-the basal ganglia, parabrachial region, and neocortex-and discuss how they may influence SC activity related to target selection. Finally, we discuss the potential for methodological advances to further our understanding of the neural bases of target selection. Our overarching goal is to synthesize what is known about how the SC and its inputs act together to mediate the selection of targets for movements, to highlight open questions about this process, and to spur future studies addressing these questions.

Optogenetic cholinergic modulation of the mouse superior colliculus in vivo

The superior colliculus (SC) plays a critical role in orienting movements, in part by integrating modulatory influences on the sensorimotor transformations it performs. Many species exhibit a robust brain stem cholinergic projection to the intermediate and deep layers of the SC arising mainly from the pedunculopontine tegmental nucleus (PPTg), which may serve to modulate SC function. However, the physiological effects of this input have not been examined in vivo, preventing an understanding of its functional role. Given the data from slice experiments, cholinergic input may have a net excitatory effect on the SC. Alternatively, the input could have mixed effects, via activation of inhibitory neurons within or upstream of the SC. Distinguishing between these possibilities requires in vivo experiments in which endogenous cholinergic input is directly manipulated. Here we used anatomical and optogenetic techniques to identify and selectively activate brain stem cholinergic terminals entering the intermediate and deep layers of the awake mouse SC and recorded SC neuronal responses. We first quantified the pattern of the cholinergic input to the mouse SC, finding that it was predominantly localized to the intermediate and deep layers. We then found that optogenetic stimulation of cholinergic terminals in the SC significantly increased the activity of a subpopulation of SC neurons. Interestingly, cholinergic input had a broad range of effects on the magnitude and timing of SC responses, perhaps reflecting both monosynaptic and polysynaptic innervation. These findings begin to elucidate the functional role of this cholinergic projection in modulating the processing underlying sensorimotor transformations in the SC.

Rats can make relative perceptual judgments about sequential stimuli

In their natural environment, animals often make decisions based on abstract relationships among multiple stimulus representations. Humans and other primates can determine not only whether a sensory stimulus differs from a remembered sensory representation, but also how they differ along a particular dimension. However, much remains unknown about how such relative comparisons are made, and which species share this capacity, in part because most studies of sensory-guided decision making have utilized instrumental tasks in which choices are based on very simple stimulus–response associations. Here, we used a two-stimulus-interval discrimination task to test whether rats could determine how two sequentially presented stimuli were related along the dimension of odor quality (i.e., what the stimulus smells like). At a central port, rats sampled and compared two odor mixtures that consisted of spearmint and caraway in different ratios, separated by a 2–4-s interval, and then entered the left or right reward port. Water was delivered at the left if the first mixture consisted of more spearmint than the second did, and at the right otherwise. We found that the difference in mixture ratio predicted choice accuracy. Control experiments suggest that rats were indeed basing their choices on a comparison of odor quality across mixtures and were not using associative strategies. This study is the first demonstration of the use of a sequential “more than versus less than” rule in rats and provides a well-controlled paradigm for studying abstract comparisons in a rodent model system.