Functional coupling between target selection and acquisition in the superior colliculus.

Survival in unpredictable environments requires that animals continuously evaluate their surroundings for behavioral targets, direct their movements toward those targets, and terminate movements once a target is reached. The ability to select, move toward, and acquire spatial targets depends on a network of brain regions, but it remains unknown how these goal-directed processes are linked by neural circuits. Within this network, common circuits in the midbrain superior colliculus (SC) mediate the selection and initiation of movements to spatial targets. However, SC activity often persists throughout movement, suggesting that the same SC circuits underlying target selection and movement initiation may also contribute to "target acquisition": stopping the movement at the selected target. Here, we examine the hypothesis that SC functional circuitry couples target selection and acquisition using a "default motor plan" generated by selection-related neuronal activity. Recordings from intermediate and deep layer SC neurons in mice performing a spatial choice task demonstrate that choice-predictive neurons, including optogenetically identified GABAergic neurons whose activity mediates target selection, exhibit increased activity during movement to the target. By recording from rostral and caudal SC in separate groups of mice, we also revealed higher activity in rostral than caudal neurons during target acquisition. Finally, we used an attractor model to examine how-invoking only SC circuitry-caudal SC activity related to selecting an eccentric target could generate higher rostral than caudal acquisition-related activity. Overall, our results suggest a functional coupling between SC circuits for target selection and acquisition, elucidating a key mechanism for goal-directed behavior.NEW & NOTEWORTHY How do neural circuits ensure that selected targets are successfully acquired? Here, we examine whether choice-related activity in the superior colliculus (SC) promotes a motor plan for target acquisition. By demonstrating that choice-predictive SC neurons-including GABAergic neurons-remain active throughout movement, while the activity of rostral SC neurons increases during acquisition, and by recapitulating these dynamics with an attractor model, our results support a role for SC circuits in coupling target selection and acquisition.

PVT1 dependence in cancer with MYC copy-number increase.

'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.

Dynamic membrane depolarization is an early regulator of ependymoglial cell response to spinal cord injury in axolotl.

Salamanders, such as the Mexican axolotl, are some of the few vertebrates fortunate in their ability to regenerate diverse structures after injury. Unlike mammals they are able to regenerate a fully functional spinal cord after injury. However, the molecular circuitry required to initiate a pro-regenerative response after spinal cord injury is not well understood. To address this question we developed a spinal cord injury model in axolotls and used in vivo imaging of labeled ependymoglial cells to characterize the response of these cells to injury. Using in vivo imaging of ion sensitive dyes we identified that spinal cord injury induces a rapid and dynamic change in the resting membrane potential of ependymoglial cells. Prolonged depolarization of ependymoglial cells after injury inhibits ependymoglial cell proliferation and subsequent axon regeneration. Using transcriptional profiling we identified c-Fos as a key voltage sensitive early response gene that is expressed specifically in the ependymoglial cells after injury. This data establishes that dynamic changes in the membrane potential after injury are essential for regulating the specific spatiotemporal expression of c-Fos that is critical for promoting faithful spinal cord regeneration in axolotl.

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

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.

Spatial representations in the superior colliculus are modulated by competition among targets.

Selecting and moving to spatial targets are critical components of goal-directed behavior, yet their neural bases are not well understood. The superior colliculus (SC) is thought to contain a topographic map of contralateral space in which the activity of specific neuronal populations corresponds to particular spatial locations. However, these spatial representations are modulated by several decision-related variables, suggesting that they reflect information beyond simply the location of an upcoming movement. Here, we examine the extent to which these representations arise from competitive spatial choice. We recorded SC activity in male mice performing a behavioral task requiring orienting movements to targets for a water reward in two contexts. In "competitive" trials, either the left or right target could be rewarded, depending on which stimulus was presented at the central port. In "noncompetitive" trials, the same target (e.g., left) was rewarded throughout an entire block. While both trial types required orienting movements to the same spatial targets, only in competitive trials do targets compete for selection. We found that in competitive trials, pre-movement SC activity predicted movement to contralateral targets, as expected. However, in noncompetitive trials, some neurons lost their spatial selectivity and in others activity predicted movement to ipsilateral targets. Consistent with these findings, unilateral optogenetic inactivation of pre-movement SC activity ipsiversively biased competitive, but not noncompetitive, trials. Incorporating these results into an attractor model of SC activity points to distinct pathways for orienting movements under competitive and noncompetitive conditions, with the SC specifically required for selecting among multiple potential targets.

Warning! Dopaminergic Modulation of the Superior Colliculus.

Recent work by Bolton et al. describes a dopaminergic input to the superior colliculus (SC) from the zona incerta, as well as the organization of D1- and D2-receptor expression in the SC. We discuss a potential role for this input in modulating SC-mediated behavior, particularly in response to aversive stimuli.