Lateral inhibition in V1 controls neural & perceptual contrast sensitivity.

Lateral inhibition is a central principle for sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. Much work on the role of inhibition in sensory systems has focused on visual cortex; however, the neurons, computations, and mechanisms underlying cortical lateral inhibition remain debated, and its importance for visual perception remains unknown. Here, we tested how lateral inhibition from PV or SST neurons in mouse primary visual cortex (V1) modulates neural and perceptual sensitivity to stimulus contrast. Lateral inhibition from PV neurons reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from SST neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model identified spatially extensive lateral projections from SST neurons as the key factor, and we confirmed this with direct subthreshold measurements of a larger spatial footprint for SST versus PV lateral inhibition. Together, these results define cell-type specific computational roles for lateral inhibition in V1, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world.

Modular microcircuit organization of the presubicular head-direction map.

Our internal sense of direction is thought to rely on the activity of head-direction (HD) neurons. We find that the mouse dorsal presubiculum (PreS), a key structure in the cortical representation of HD, displays a modular "patch-matrix" organization, which is conserved across species (including human). Calbindin-positive layer 2 neurons within the "matrix" form modular recurrent microcircuits, while inputs from the anterodorsal and laterodorsal thalamic nuclei are non-overlapping and target the "patch" and "matrix" compartments, respectively. The apical dendrites of identified HD cells are largely restricted within the "matrix," pointing to a non-random sampling of patterned inputs and to a precise structure-function architecture. Optogenetic perturbation of modular recurrent microcircuits results in a drastic tonic suppression of firing only in a subpopulation of HD neurons. Altogether, our data reveal a modular microcircuit organization of the PreS HD map and point to the existence of cell-type-specific microcircuits that support the cortical HD representation.

Spatial modulation of dark versus bright stimulus responses in the mouse visual system.

A fundamental task of the visual system is to respond to both increases and decreases of luminance with action potentials (ON and OFF responses1-4). OFF responses are stronger, faster, and more salient than ON responses in primary visual cortex (V1) of both cats5,6 and primates,7,8 but in ferrets9 and mice,10 ON responses can be stronger, weaker,11 or balanced12 in comparison to OFF responses. These discrepancies could arise from differences in species, experimental techniques, or stimulus properties, particularly retinotopic location in the visual field, as has been speculated;9 however, the role of retinotopy for ON/OFF dominance has not been systematically tested across multiple scales of neural activity within species. Here, we measured OFF versus ON responses across large portions of visual space with silicon probe and whole-cell patch-clamp recordings in mouse V1 and lateral geniculate nucleus (LGN). We found that OFF responses dominated in the central visual field, whereas ON and OFF responses were more balanced in the periphery. These findings were consistent across local field potential (LFP), spikes, and subthreshold membrane potential in V1, and were aligned with spatial biases in ON and OFF responses in LGN. Our findings reveal that retinotopy may provide a common organizing principle for spatial modulation of OFF versus ON processing in mammalian visual systems.

Structural Correlates of CA2 and CA3 Pyramidal Cell Activity in Freely-Moving Mice.

Plasticity within hippocampal circuits is essential for memory functions. The hippocampal CA2/CA3 region is thought to be able to rapidly store incoming information by plastic modifications of synaptic weights within its recurrent network. High-frequency spike-bursts are believed to be essential for this process, by serving as triggers for synaptic plasticity. Given the diversity of CA2/CA3 pyramidal neurons, it is currently unknown whether and how burst activity, assessed in vivo during natural behavior, relates to principal cell heterogeneity. To explore this issue, we juxtacellularly recorded the activity of single CA2/CA3 neurons from freely-moving male mice, exploring a familiar environment. In line with previous work, we found that spatial and temporal activity patterns of pyramidal neurons correlated with their topographical position. Morphometric analysis revealed that neurons with a higher proportion of distal dendritic length displayed a higher tendency to fire spike-bursts. We propose that the dendritic architecture of pyramidal neurons might determine burst-firing by setting the relative amount of distal excitatory inputs from the entorhinal cortex.SIGNIFICANCE STATEMENT High-frequency spike-bursts are thought to serve fundamental computational roles within neural circuits. Within hippocampal circuits, spike-bursts are believed to serve as potent instructive signals, which increase the efficiency of information transfer and induce rapid modifications of synaptic efficacies. In the present study, by juxtacellularly recording and labeling single CA2/CA3 neurons in freely-moving mice, we explored whether and how burst propensity relates to pyramidal cell heterogeneity. We provide evidence that, within the CA2/CA3 region, neurons with higher proportion of distal dendritic length display a higher tendency to fire spike-bursts. Thus, the relative amount of entorhinal inputs, arriving onto the distal dendrites, might determine the burst propensity of individual CA2/CA3 neurons in vivo during natural behavior.

Interspike interval analysis and spikelets in presubicular head-direction cells.

Head-direction (HD) neurons are thought to provide the mammalian brain with an internal sense of direction. These cells, which selectively increase their firing when the animal's head points in a specific direction, use the spike rate to encode HD with a high signal-to-noise ratio. In the present work, we analyzed spike train features of presubicular HD cells recorded juxtacellularly in passively rotated rats. We found that HD neurons could be classified into two groups on the basis of their propensity to fire spikes at short interspike intervals. "Bursty" neurons displayed distinct spike waveforms and were weakly but significantly more modulated by HD compared with "nonbursty" cells. In a subset of HD neurons, we observed the occurrence of spikelets, small-amplitude "spike-like" events, whose HD tuning was highly correlated to that of the co-recorded juxtacellular spikes. Bursty and nonbursty HD cells, as well as spikelets, were also observed in freely moving animals during natural behavior. We speculate that spike bursts and spikelets might contribute to presubicular HD coding by enhancing its accuracy and transmission reliability to downstream targets. NEW & NOTEWORTHY We provide evidence that presubicular head-direction (HD) cells can be classified into two classes (bursty and nonbursty) on the basis of their propensity to fire spikes at short interspike intervals. Bursty cells displayed distinct electrophysiological properties and stronger directional tuning compared with nonbursty neurons. We also provide evidence for the occurrence of spikelets in a subset of HD cells. These electrophysiological features (spike bursts and spikelets) might contribute to the precision and robustness of the presubicular HD code.

Manipulating Hippocampal Place Cell Activity by Single-Cell Stimulation in Freely Moving Mice.

Learning critically depends on the ability to rapidly form and store non-overlapping representations of the external world. In line with their postulated role in episodic memory, hippocampal place cells can undergo a rapid reorganization of their firing fields upon contextual manipulations. To explore the mechanisms underlying such global remapping, we juxtacellularly stimulated 42 hippocampal neurons in freely moving mice during spatial exploration. We found that evoking spike trains in silent neurons was sufficient for creating place fields, while in place cells, juxtacellular stimulation induced a rapid remapping of their place fields to the stimulus location. The occurrence of complex spikes was most predictive of place field plasticity. Our data thus indicate that plasticity-inducing stimuli are able to rapidly bias place cell activity, simultaneously suppressing existing place fields. We propose that such competitive place field dynamics could support the orthogonalization of the hippocampal map during global remapping.

Testing the Efficacy of Single-Cell Stimulation in Biasing Presubicular Head Direction Activity.

To support navigation, the firing of head direction (HD) neurons must be tightly anchored to the external space. Indeed, inputs from external landmarks can rapidly reset the preferred direction of HD cells. Landmark stimuli have often been simulated as excitatory inputs from "visual cells" (encoding landmark information) to the HD attractor network; when excitatory visual inputs are sufficiently strong, preferred directions switch abruptly to the landmark location. In the present work, we tested whether mimicking such inputs via juxtacellular stimulation would be sufficient for shifting the tuning of individual presubicular HD cells recorded in passively rotated male rats. We recorded 81 HD cells in a cue-rich environment, and evoked spikes trains outside of their preferred direction (distance range, 11-178°). We found that HD tuning was remarkably resistant to activity manipulations. Even strong stimulations, which induced seconds-long spike trains, failed to induce a detectable shift in directional tuning. HD tuning curves before and after stimulation remained highly correlated, indicating that postsynaptic activation alone is insufficient for modifying HD output. Our data are thus consistent with the predicted stability of an HD attractor network when anchored to external landmarks. A small spiking bias at the stimulus direction could only be observed in a visually deprived environment in which both average firing rates and directional tuning were markedly reduced. Based on this evidence, we speculate that, when attractor dynamics become unstable (e.g., under disorientation), the output of HD neurons could be more efficiently controlled by strong biasing stimuli.SIGNIFICANCE STATEMENT The activity of head direction (HD) cells is thought to provide the mammalian brain with an internal sense of direction. To support navigation, the firing of HD neurons must be anchored to external landmarks, a process thought to be supported by associative plasticity within the HD system. Here, we investigated these plasticity mechanisms by juxtacellular stimulation of single HD neurons in vivo in awake rats. We found that HD coding is strongly resistant to external manipulations of spiking activity. Only in a visually deprived environment was juxtacellular stimulation able to induce a small activity bias in single presubicular neurons. We propose that juxtacellular stimulation can bias HD tuning only when competing anchoring inputs are reduced or not available.

Anatomical organization of presubicular head-direction circuits.

Neurons coding for head-direction are crucial for spatial navigation. Here we explored the cellular basis of head-direction coding in the rat dorsal presubiculum (PreS). We found that layer2 is composed of two principal cell populations (calbindin-positive and calbindin-negative neurons) which targeted the contralateral PreS and retrosplenial cortex, respectively. Layer3 pyramidal neurons projected to the medial entorhinal cortex (MEC). By juxtacellularly recording PreS neurons in awake rats during passive-rotation, we found that head-direction responses were preferentially contributed by layer3 pyramidal cells, whose long-range axons branched within layer3 of the MEC. In contrast, layer2 neurons displayed distinct spike-shapes, were not modulated by head-direction but rhythmically-entrained by theta-oscillations. Fast-spiking interneurons showed only weak directionality and theta-rhythmicity, but were significantly modulated by angular velocity. Our data thus indicate that PreS neurons differentially contribute to head-direction coding, and point to a cell-type- and layer-specific routing of directional and non-directional information to downstream cortical targets.