The ability to suppress actions that lead to a negative outcome and explore alternative actions is necessary for optimal decision making. Although the basal ganglia have been implicated in these processes1–5, the circuit mechanisms underlying action selection and exploration remain unclear. Here, using a simple lateralized licking task, we show that indirect striatal projection neurons (iSPN) in the basal ganglia contribute to these processes through modulation of the superior colliculus (SC). Optogenetic activation of iSPNs suppresses contraversive licking and promotes ipsiversive licking. Activity in lateral superior colliculus (lSC), a region downstream of the basal ganglia, is necessary for task performance and predicts lick direction. Furthermore, iSPN activation suppresses ipsilateral lSC, but surprisingly excites contralateral lSC, explaining the emergence of ipsiversive licking. Optogenetic inactivation reveals inter-collicular competition whereby each hemisphere of the superior colliculus inhibits the other, thus allowing the indirect pathway to disinhibit the contralateral lSC and trigger licking. Finally, inactivating iSPNs impairs suppression of devalued but previously rewarded licking and reduces exploratory licking. Our results reveal that iSPNs engage the competitive interaction between lSC hemispheres to trigger a motor action and suggest a general circuit mechanism for exploration during action selection. Indirect striatal projection neurons in the basal ganglia modulate activity in the superior colliculus, thereby controlling selection and exploration of actions in response to a  reward omission.

Striatal indirect pathway mediates exploration via collicular competition.

Optogenetics, a field concentrating on controlling cellular functions by means of light-activated proteins, has shown tremendous potential in neuroscience. It possesses superior spatiotemporal resolution compared to the surgical, electrical, and pharmacological methods traditionally used in studying brain function. A multitude of optogenetic tools for neuroscience have been created that, for example, enable the control of action potential generation via light-activated ion channels. Other optogenetic proteins have been used in the brain, for example, to control long-term potentiation or to ablate specific subtypes of neurons. In in vivo applications, however, the majority of optogenetic tools are operated with blue, green, or yellow light, which all have limited penetration in biological tissues compared to red light and especially infrared light. This difference is significant, especially considering the size of the rodent brain, a major research model in neuroscience. Our review will focus on the utilization of red light-operated optogenetic tools in neuroscience. We first outline the advantages of red light for in vivo studies. Then we provide a brief overview of the red light-activated optogenetic proteins and systems with a focus on new developments in the field. Finally, we will highlight different tools and applications, which further facilitate the use of red light optogenetics in neuroscience.

Red Light Optogenetics in Neuroscience

Abstract The superior colliculus (SC), one of the most well-characterized midbrain sensorimotor structures where visual, auditory, and somatosensory information are integrated to initiate motor commands, is highly conserved across vertebrate evolution. Moreover, cell-type-specific SC neurons integrate afferent signals within local networks to generate defined output related to innate and cognitive behaviors. This review focuses on the recent progress in understanding of phenotypic diversity amongst SC neurons and their intrinsic circuits and long-projection targets. We further describe relevant neural circuits and specific cell types in relation to behavioral outputs and cognitive functions. The systematic delineation of SC organization, cell types, and neural connections is further put into context across species as these depend upon laminar architecture. Moreover, we focus on SC neural circuitry involving saccadic eye movement, and cognitive and innate behaviors. Overall, the review provides insight into SC functioning and represents a basis for further understanding of the pathology associated with SC dysfunction. 

https://link.springer.com/content/pdf/10.1007/s12264-022-00858-1.pdf

The Superior Colliculus: Cell Types, Connectivity, and Behavior

Motion sensing is a critical aspect of vision. We studied the representation of motion in mouse retinal bipolar cells and found that some bipolar cells are radially direction selective, preferring the origin of small object motion trajectories. Using a glutamate sensor, we directly observed bipolar cells synaptic output and found that there are radial direction selective and non-selective bipolar cell types, the majority being selective, and that radial direction selectivity relies on properties of the center-surround receptive field. We used these bipolar cell receptive fields along with connectomics to design biophysical models of downstream cells. The models and additional experiments demonstrated that bipolar cells pass radial direction selective excitation to starburst amacrine cells, which contributes to their directional tuning. As bipolar cells provide excitation to most amacrine and ganglion cells, their radial direction selectivity may contribute to motion processing throughout the visual system. 

/pdf/center-surround-interactions-underlie-bipolar-cell-motion-1gdqjis4.pdf

Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina

Covert visual attention is accomplished by a cascade of mechanisms distributed across multiple brain regions. Visual cortex is associated with enhanced representations of relevant stimulus features, whereas the contributions of subcortical circuits are less well understood but have been associated with selection of relevant spatial locations and suppression of distracting stimuli. As a step toward understanding these subcortical circuits, here we identified how neuronal activity in the intermediate layers of the superior colliculus (SC) of head-fixed mice is modulated during covert visual attention. We found that spatial cues modulated both firing rate and spike-count correlations. Crucially, the cue-related modulation in firing rate was due to enhancement of activity at the cued spatial location rather than suppression at the uncued location, indicating that SC neurons in our task were modulated by an excitatory or disinhibitory circuit mechanism focused on the relevant location, rather than broad inhibition of irrelevant locations. This modulation improved the neuronal discriminability of visual-change-evoked activity, but only when assessed for neuronal activity between the contralateral and ipsilateral SC. Together, our findings indicate that neurons in the mouse SC can contribute to covert visual selective attention by biasing processing in favor of locations expected to contain task-relevant information. 

/pdf/neuronal-modulation-in-the-mouse-superior-colliculus-during-2qq1dkxv.pdf

Neuronal modulation in the mouse superior colliculus during covert visual selective attention

Decision making is a cognitive process that mediates behaviors critical for survival. Choosing spatial targets is an experimentally-tractable form of decision making that depends on the midbrain superior colliculus (SC). While physiological and computational studies have uncovered the functional topographic organization of the SC, the role of specific SC cell types in spatial choice is unknown. Here, we leveraged behavior, optogenetics, neural recordings and modeling to directly examine the contribution of GABAergic SC neurons to the selection of opposing spatial targets. Although GABAergic SC neurons comprise a heterogeneous population with local and long-range projections, our results demonstrate that GABAergic SC neurons do not locally suppress premotor output, suggesting that functional long-range inhibition instead plays a dominant role in spatial choice. An attractor model requiring only intrinsic SC circuitry was sufficient to account for our experimental observations. Overall, our study elucidates the role of GABAergic SC neurons in spatial choice.

/pdf/inhibitory-neurons-in-the-superior-colliculus-mediate-vvncmb0i3m.pdf

Inhibitory neurons in the superior colliculus mediate selection of spatially-directed movements.

Abstract Antagonistic interactions between center and surround receptive field (RF) components lie at the heart of the computations performed in the visual system. Circularly symmetric center-surround RFs are thought to enhance responses to spatial contrasts (i.e., edges), but how visual edges affect motion processing is unclear. Here, we addressed this question in retinal bipolar cells, the first visual neuron with classic center-surround interactions. We found that bipolar glutamate release emphasizes objects that emerge in the RF; their responses to continuous motion are smaller, slower, and cannot be predicted by signals elicited by stationary stimuli. In our hands, the alteration in signal dynamics induced by novel objects was more pronounced than edge enhancement and could be explained by priming of RF surround during continuous motion. These findings echo the salience of human visual perception and demonstrate an unappreciated capacity of the center-surround architecture to facilitate novel object detection and dynamic signal representation. 

/pdf/classical-center-surround-receptive-fields-facilitate-novel-2pkvt17g.pdf

Classical center-surround receptive fields facilitate novel object detection in retinal bipolar cells

Decision making is critical for survival but its neural basis is unclear. Here we examine how functional neural circuitry in the output layers of the midbrain superior colliculus (SC) mediates spatial choice, an SC-dependent tractable form of decision making. We focus on the role of inhibitory SC neurons, using optogenetics to record and manipulate their activity in behaving mice. Based on data from SC slice experiments and on a canonical role of inhibitory neurons in cortical microcircuits, we hypothesized that inhibitory SC neurons locally inhibit premotor output neurons that represent contralateral targets. However, our experimental results refuted this hypothesis. An attractor model revealed that our results were instead consistent with inhibitory neurons providing long-range inhibition between the two SCs, and terminal activation experiments supported this architecture. Our study provides mechanistic evidence for competitive inhibition between populations representing discrete choices, a common motif in theoretical models of decision making.

/pdf/inhibitory-midbrain-neurons-mediate-decision-making-1bsa3ylwau.pdf

Inhibitory midbrain neurons mediate decision making

Our project is motivated by the question of how the brain suppresses perception sometimes. Specifically, during motion signals of motion that we voluntarily generate with our eyes. To have a model for answering this question, we first need to reliably elicit these voluntary eye movements. Presenting a drifting grating, the Felsen and Poleg‐Polsky labs did that in mice except the eye movements were involuntary. Presenting a moving center that radiates dots, other scientists did that in primates and the eye movements were voluntary. We want the same stimulus to work on mice because they’re more ethical subjects. Therefore, we hypothesized that that a mice‐adapted stimulus would work on mice. We discovered that the moving center of our stimulus elicited eye movements. Next, we discovered the moving center of the stimulus elicited involuntary eye movements. Next, we discovered the moving center of the stimulus elicited more eye movements when on the left side of the screen. Since this came from expanding dots, a next step should be to try contracting dots. Ultimately, our data doesn't support the hypothesis that our mice‐adapted optic flow stimulus would elicit voluntary eye movements. We could expect difficulty in eliciting voluntary eye movements in mice because they have such large field of vision and spread out photoreceptors that they may not need voluntary eye movements. Our results were relevant because they say something about the potential of mice as models to understand how we make sense of a moving world when we ourselves move in it.

Joshua B. Hunt

Papers

Inhibitory neurons in the superior colliculus mediate selection of spatially-directed movements.

Classical center-surround receptive fields facilitate novel object detection in retinal bipolar cells

Inhibitory midbrain neurons mediate decision making

Triggering eye movements in mice to understand stable visual perception