Mammalian visual behaviors, as well as responses in the neural systems underlying these behaviors, are driven by luminance and color contrast. With constantly improving tools for measuring activity in cell-type-specific populations in the mouse during visual behavior, it is important to define the extent of luminance and color information that is behaviorally accessible to the mouse. A non-uniform distribution of cone opsins in the mouse retina potentially complicates both luminance and color sensitivity; opposing gradients of short (UV-shifted) and middle (blue/green) cone opsins suggest that color discrimination and wavelength-specific luminance contrast sensitivity may differ with retinotopic location. Here we ask how well mice can discriminate color and wavelength-specific luminance changes across visuotopic space. We found that mice were able to discriminate color and were able to do so more broadly across visuotopic space than expected from the cone-opsin distribution. We also found wavelength-band-specific differences in luminance sensitivity.

Transgenic mouse lines are invaluable tools for neuroscience but, as with any technique, care must be taken to ensure that the tool itself does not unduly affect the system under study. Here we report aberrant electrical activity, similar to interictal spikes, and accompanying fluorescence events in some genotypes of transgenic mice expressing GCaMP6 genetically encoded calcium sensors. These epileptiform events have been observed particularly, but not exclusively, in mice with Emx1-Cre and Ai93 transgenes, of either sex, across multiple laboratories. The events occur at >0.1 Hz, are very large in amplitude (>1.0 mV local field potentials, >10% df/f widefield imaging signals), and typically cover large regions of cortex. Many properties of neuronal responses and behavior seem normal despite these events, although rare subjects exhibit overt generalized seizures. The underlying mechanisms of this phenomenon remain unclear, but we speculate about possible causes on the basis of diverse observations. We encourage researchers to be aware of these activity patterns while interpreting neuronal recordings from affected mouse lines and when considering which lines to study.

Cortical circuits can flexibly change with experience and learning, but the effects on specific cell types, including distinct inhibitory types, are not well understood. Here we investigated how excitatory and VIP inhibitory cells in layer 2/3 of mouse visual cortex were impacted by visual experience in the context of a behavioral task. Mice learned a visual change detection task with a set of eight natural scene images. Subsequently, during 2-photon imaging experiments, mice performed the task with these familiar images and three sets of novel images. Strikingly, the temporal dynamics of VIP activity differed markedly between novel and familiar images: VIP cells were stimulus-driven by novel images but were suppressed by familiar stimuli and showed ramping activity when expected stimuli were omitted from a temporally predictable sequence. This prominent change in VIP activity suggests that these cells may adopt different modes of processing under novel versus familiar conditions.

Electrical microstimulation has been widely used to artificially activate neural circuits on fast time scales. Despite the ubiquity of its use, little is known about precisely how it activates neural pathways. Current is typically delivered to neural tissue in a manner that provides a locally balanced injection of positive and negative charge, resulting in negligible net charge delivery to avoid the neurotoxic effects of charge accumulation. Modeling studies have suggested that the most common approach, using a temporally symmetric current pulse waveform as the base unit of stimulation, results in preferential activation of axons, causing diffuse activation of neurons relative to the stimulation site. Altering waveform shape and using an asymmetric current pulse waveform theoretically reverses this bias and preferentially activates cell bodies, providing increased specificity. In separate studies, measurements of downstream cortical activation from sub-cortical microstimulation are consistent with this hypothesis, as are recent measurements of behavioral detection threshold currents from cortical microstimulation. Here, we compared the behavioral and electrophysiological effects of symmetric vs. asymmetric current waveform shape in cortical microstimulation. Using a go/no-go behavioral task, we found that microstimulation waveform shape significantly shifts psychometric performance, where a larger current pulse was necessary when applying an asymmetric waveform to elicit the same behavioral response, across a large range of behaviorally relevant current amplitudes. Using voltage-sensitive dye imaging of cortex in anesthetized animals with simultaneous cortical microstimulation, we found that altering microstimulation waveform shape shifted the cortical activation in a manner that mirrored the behavioral results. Taken together, these results are consistent with the hypothesis that asymmetric stimulation preferentially activates cell bodies, albeit at a higher threshold, as compared to symmetric stimulation. These findings demonstrate the sensitivity of the pathway to varying electrical stimulation parameters and underscore the importance of designing electrical stimuli for optimal activation of neural circuits.

Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

To study the mechanisms of perception and cognition, neural measurements must be made during behavior. A goal of the Allen Brain Observatory is to map the activity of distinct cortical cell classes underlying visual and behavioral processing. Here we describe standardized methodology for training head-fixed mice on a visual change detection task, and we use our paradigm to characterize learning and behavior of five GCaMP6-expressing transgenic lines. We used automated training procedures to facilitate comparisons across mice. Training times varied, but most transgenic mice learned the behavioral task. Motivation levels also varied across mice. To compare mice in similar motivational states we subdivided sessions into over-, under-, and optimally motivated periods. When motivated, the pattern of perceptual decisions were highly correlated across transgenic lines, although overall performance (d-prime) was lower in one line labeling somatostatin inhibitory cells. These results provide important context for using these mice to map neural activity underlying perception and behavior.