A striking feature of the brain is that, even in early sensory areas, the numbers of inputs from the senses are dwarfed by intrinsic feedback connections from within the brain itself. This contrasts sharply with classical models that see the brain as mostly responding to information from the outside world to generate behavioral responses. As Marcus Raichle(the 2014 Kavli prize laureate in neuroscience)so elegantly phrases it, the intrinsic feedback connectivity is the Dark Matter in the quest to understand the brain. In a recent paper from Dr WANG Wei's group, published online in Cerebral Cortex on December 17th 2016, the researchers used focally specific causal manipulation to study a key feedback connection in the visual system (the corticothalamic loop).

　　This massive reciprocal pathway from primary visual cortex (V1) back to the main thalamic visual relay, the lateral geniculate nucleus (dLGN), demonstrates that only 7% of the inputs to the relay cells come from eye, whereas >60% of the mono– and di–synaptic inputs to this "sensory" relay come from V1 (Figure 1A). Using microionophoresis with carefully controlled ejection currents of a metabotropic GABAB antagonist, they were able to selectively enhance the visually driven response of neurons in a single column of the feedback layer (layer 6) of primary visual cortex (V1). The researchers performed simultaneous recording of the 2D receptive field (RF) of multiple neurons in the dLGN before, during, and after the focally specific modulation of the visual responses in layer 6 of V1.

　　Figure 1: A, schematic of the core reciprocal circuitry studied and experimental procedure. Layer 6 of V1 provides > 60% of the mono– and di–synaptic input to the dLGN. The researchers carefully enhanced the stimulus response of V1 feedback cells using the GABAB antagonist CGP and simultaneously recorded the 2D receptive field maps of multiple dLGN cells. B, example RF maps of V1 and dLGN before, during and after causal manipulation of V1. C,Two recorded dLGN cells showing simultaneous increase (cell 2) and decrease (cell 1) of response gain during V1 causal manipulation. D,The majority of the causal effects were functionally linked to the orientation tuning of the V1 cells.

　　Contemporary optogenetic studies of feedback in the mouse are largely constrained by current limitations of global optical stimulation, and have therefore yielded a wide diversity of potential effects. To truly understand sensory transformations, researchers need to be able to control the sensory–map topography of their perturbation. In this study the authors could precisely control the focal spatial parameters of the causal manipulation. They first found that enhancing the cortical feedback can cause both increases and decreases of response gain in simultaneously recorded dLGN relay neurons (Figure 1C). This contrasts with earlier studies which found facilitation or suppression restricted to a retinotopic Mexican–hat arrangement. Furthermore, the researchers discovered that the majority of the gain changes occurred only when retinotopic relationships between V1 and dLGN were parallel or orthogonal to the orientation preference of the V1 location (Figure 1D). That cortical feedback drives both facilitation and suppression and is linked to its own sensory preferences enables a more flexible functional modulation of incoming sensory information. The researchers also analyzed the fine spatial structure, including the RF size and position during cortical manipulation. They found that there were changes to RF position for some cells, which is consistent with the effects of spatial attention observed in higher cortical areas.

　　Figure 2: Thalamocortical loop as a flexible gatekeeper: the visually selective effects of the feedback match the functional specificity of the feedforward connections. Gain modulation enables both enhancement and suppression of the incoming sensory information, though the full role of the inhibitory perigeniculate nucleus (PGN) is currently unknown.

　　Predictive coding (the dominant variant of the "Bayesian brain") is a high–level network theory of brain function, applicable from synapticconnectivity to complex diseases such as schizophrenia, and provides a framework with which to understand the intrinsic connectivity patterns in the brain. Previous studies (Wang et al., Nat.Neurosci.2006; Andolina et al., PNAS, 2007) by the same authors have been influential for computational modelling of the visual system using predictive coding schemes. The present study adds a further dimension to the potential computations enabled by top-down sensory pathways for models of visual perception.

　　"Focal Gain Control of Thalamic Visual Receptive Fields by Layer 6 Corticothalamic Feedback" by WANG Wei, Ian M. Andolina, LU Yiliangand collaborators, was conducted under National Natural Science Foundation of China (31571078 and 81601628), 973 Project and the State Key Laboratory of Neurosciences, BBSRC grant G022305/1 and MRC grant G0701535.