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.

The detection of novel stimuli is critical to learn and survive in a dynamic environment. Though novel stimuli powerfully affect brain activity, their impact on specific cell types and circuits is not well understood. Disinhibition is one candidate mechanism for novelty-induced enhancements in activity. Here we characterize the impact of stimulus novelty on disinhibitory circuit components using longitudinal 2-photon calcium imaging of Vip, Sst, and excitatory populations in the mouse visual cortex. Mice learn a behavioral task with stimuli that become highly familiar, then are tested on both familiar and novel stimuli. Mice consistently perform the task with novel stimuli, yet responses to stimulus presentations and stimulus omissions are dramatically altered. Further, we find that novelty modifies coding of visual as well as behavioral and task information. At the population level, the direction of these changes is consistent with engagement of the Vip-Sst disinhibitory circuit. At the single cell level, we identify separate clusters of Vip, Sst, and excitatory cells with unique patterns of novelty-induced coding changes. This study and the accompanying open-access dataset reveals the impact of novelty on sensory and behavioral representations in visual cortical circuits and establishes novelty as a key driver of cellular functional diversity.

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, 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, though 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.

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.

The maintenance of short-term memories is critical for survival in a dynamically changing world. Previous studies suggest that this memory can be stored in the form of persistent neural activity or using a synaptic mechanism, such as with short-term plasticity. Here, we compare the predictions of these two mechanisms to neural and behavioral measurements in a visual change detection task. Mice were trained to respond to changes in a repeated sequence of natural images while neural activity was recorded using two-photon calcium imaging. We also trained two types of artificial neural networks on the same change detection task as the mice. Following fixed pre-processing using a pretrained convolutional neural network, either a recurrent neural network (RNN) or a feedforward neural network with short-term synaptic depression (STPNet) was trained to the same level of performance as the mice. While both networks are able to learn the task, the STPNet model contains units whose activity are more similar to the in vivo data and produces errors which are more similar to the mice. When images are omitted, an unexpected perturbation which was absent during training, mice often do not respond to the omission but are more likely to respond to the subsequent image. Unlike the RNN model, STPNet produces a similar pattern of behavior. These results suggest that simple neural adaptation mechanisms may serve as an important bottom-up memory signal in this task, which can be used by downstream areas in the decision-making process.

Cortical circuits are flexible and can change with experience and learning. However, the effects of experience on specific cell types including distinct inhibitory types are not well understood. Here we studied 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 to perform an image 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 additional sets of novel images. Familiar images evoked less overall activity in both excitatory and VIP populations, and excitatory cells showed higher selectivity for familiar images. The temporal dynamics of VIP cells differed markedly between novel and familiar images: VIP cells were stimulus-driven for novel images but displayed ramping activity during the inter-stimulus interval for familiar images. Moreover, when a familiar stimulus was omitted, VIP cells showed extended ramping activity until the subsequent image flash. This prominent shift in response dynamics suggests that VIP cells may adopt different modes of processing during familiar versus novel conditions. HIGHLIGHTS• Experience with natural images in a change detection task reduces overall activity of cortical excitatory and VIP inhibitory cells • Encoding of natural images is sharpened with experience in excitatory neurons • VIP cells are stimulus-driven by novel images but show pre-stimulus ramping for familiar images • VIP cells show strong ramping activity during the omission of an expected stimulus RESULTS Visual change detection task with familiar and novel imagesWe trained GCaMP6f-expressing transgenic mice to perform a go/no-go visual change detection task with natural scene stimuli ( Figure 1A). In this task, mice are presented with a continuous stream of flashing stimuli (250 ms image flash separated by 500 ms gray screen; Figure 1B). On 'go' trials, a change in image identity occurs at a time unknown to the animal. To earn water rewards, mice must report the image change by licking a reward spout within a 750 ms response window. False alarms are quantified during 'catch' trials in which the repeated image does not change, but licking behavior is measured in a similar time window ( Figure 1B; see Methods). Behavioral training proceeded through a series of stages: mice first learned task rules with simple full-field gratings of two different orientations with no intervening gray period, followed by introduction of a 500ms gray screen period between grating flashes, and lastly, training of natural scene stimuli ( Figure 1C). During the natural image stage, mice were trained with one set of eight images (image set A) for an extended number of sessions (range = 6-46 sessions with image set A, median = 17 sessions; Figure 1F, Supplemental Figure 1A). Mice viewed each of the eight scenes from the familiar image set an average of 10,350 times prior to the 2-photon imaging stage (range: ...

The maintenance of short-term memories is critical for survival in a dynamically changing world. Previous studies suggest that this memory can be stored in the form of persistent neural activity or using a synaptic mechanism, such as with short-term plasticity. Here, we compare the predictions of these two mechanisms to neural and behavioral measurements in a visual change detection task. Mice were trained to respond to changes in a repeated sequence of natural images while neural activity was recorded using two-photon calcium imaging. We trained two different models to perform the same visual change detection task. Compared to a recurrent neural network (RNN), we find that a feedforward neural network with short-term synaptic depression (STPNet) is more consistent with the pattern of behavioral responses to image changes in mice and the observed adaptation in neural responses across repeated image presentations. These results suggest that simple neural adaptation mechanisms may serve as an important bottom-up memory signal in this task, which can be used by downstream areas in the decision-making process.