Responses to Pattern-Violating Visual Stimuli Evolve Differently Over Days in Somata and Distal Apical Dendrites.

Scientists have long conjectured that the neocortex learns patterns in sensory data to generate top-down predictions of upcoming stimuli. In line with this conjecture, different responses to pattern-matching vs pattern-violating visual stimuli have been observed in both spiking and somatic calcium imaging data. However, it remains unknown whether these pattern-violation signals are different between the distal apical dendrites, which are heavily targeted by top-down signals, and the somata, where bottom-up information is primarily integrated. Furthermore, it is unknown how responses to pattern-violating stimuli evolve over time as an animal gains more experience with them. Here, we address these unanswered questions by analyzing responses of individual somata and dendritic branches of layer 2/3 and layer 5 pyramidal neurons tracked over multiple days in primary visual cortex of awake, behaving female and male mice. We use sequences of Gabor patches with patterns in their orientations to create pattern-matching and pattern-violating stimuli, and two-photon calcium imaging to record neuronal responses. Many neurons in both layers show large differences between their responses to pattern-matching and pattern-violating stimuli. Interestingly, these responses evolve in opposite directions in the somata and distal apical dendrites, with somata becoming less sensitive to pattern-violating stimuli and distal apical dendrites more sensitive. These differences between the somata and distal apical dendrites may be important for hierarchical computation of sensory predictions and learning, since these two compartments tend to receive bottom-up and top-down information, respectively.

Responses of pyramidal cell somata and apical dendrites in mouse visual cortex over multiple days.

The apical dendrites of pyramidal neurons in sensory cortex receive primarily top-down signals from associative and motor regions, while cell bodies and nearby dendrites are heavily targeted by locally recurrent or bottom-up inputs from the sensory periphery. Based on these differences, a number of theories in computational neuroscience postulate a unique role for apical dendrites in learning. However, due to technical challenges in data collection, little data is available for comparing the responses of apical dendrites to cell bodies over multiple days. Here we present a dataset collected through the Allen Institute Mindscope's OpenScope program that addresses this need. This dataset comprises high-quality two-photon calcium imaging from the apical dendrites and the cell bodies of visual cortical pyramidal neurons, acquired over multiple days in awake, behaving mice that were presented with visual stimuli. Many of the cell bodies and dendrite segments were tracked over days, enabling analyses of how their responses change over time. This dataset allows neuroscientists to explore the differences between apical and somatic processing and plasticity.

A Standardized Nonvisual Behavioral Event Is Broadcasted Homogeneously across Cortical Visual Areas without Modulating Visual Responses.

Multiple recent studies have shown that motor activity greatly impacts the activity of primary sensory areas like V1. Yet, the role of this motor related activity in sensory processing is still unclear. Here, we dissect how these behavior signals are broadcast to different layers and areas of the visual cortex. To do so, we leveraged a standardized and spontaneous behavioral fidget event in passively viewing mice. Importantly, this behavior event had no relevance to any ongoing task allowing us to compare its neuronal correlates with visually relevant behaviors (e.g., running). A large two-photon Ca2+ imaging database of neuronal responses uncovered four neural response types during fidgets that were consistent in their proportion and response patterns across all visual areas and layers of the visual cortex. Indeed, the layer and area identity could not be decoded above chance level based only on neuronal recordings. In contrast to running behavior, fidget evoked neural responses that were independent to visual processing. The broad availability of visually orthogonal standardized behavior signals could be a key component in how the cortex selects, learns and binds local sensory information with motor outputs. Contrary to behaviorally relevant motor outputs, irrelevant motor signals could project to separate local neural subspaces.

Measuring Stimulus-Evoked Neurophysiological Differentiation in Distinct Populations of Neurons in Mouse Visual Cortex.

Despite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis-quantifying distinct patterns of neurophysiological activity-has been proposed as an "inside-out" approach that addresses this question. This methodology contrasts with "outside-in" approaches such as feature tuning and decoding analyses, which are defined in terms of extrinsic experimental variables. Here, we used two-photon calcium imaging in mice of both sexes to systematically survey stimulus-evoked neurophysiological differentiation (ND) in excitatory neuronal populations in layers (L)2/3, L4, and L5 across five visual cortical areas (primary, lateromedial, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater ND than scrambled stimuli specifically in L2/3 of the anterolateral and anteromedial areas, and that this effect is modulated by arousal state and locomotion. By contrast, decoding performance was far above chance and did not vary substantially across areas and layers. Differentiation also differed within the unscrambled stimulus set, suggesting that differentiation analysis may be used to probe the ethological relevance of individual stimuli.

VIP interneurons in mouse primary visual cortex selectively enhance responses to weak but specific stimuli.

Vasoactive intestinal peptide-expressing (VIP) interneurons in the cortex regulate feedback inhibition of pyramidal neurons through suppression of somatostatin-expressing (SST) interneurons and, reciprocally, SST neurons inhibit VIP neurons. Although VIP neuron activity in the primary visual cortex (V1) of mouse is highly correlated with locomotion, the relevance of locomotion-related VIP neuron activity to visual coding is not known. Here we show that VIP neurons in mouse V1 respond strongly to low contrast front-to-back motion that is congruent with self-motion during locomotion but are suppressed by other directions and contrasts. VIP and SST neurons have complementary contrast tuning. Layer 2/3 contains a substantially larger population of low contrast preferring pyramidal neurons than deeper layers, and layer 2/3 (but not deeper layer) pyramidal neurons show bias for front-to-back motion specifically at low contrast. Network modeling indicates that VIP-SST mutual antagonism regulates the gain of the cortex to achieve sensitivity to specific weak stimuli without compromising network stability.

Aberrant Cortical Activity in Multiple GCaMP6-Expressing Transgenic Mouse Lines.

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.

Effects of prefrontal cortex and hippocampal NMDA NR1-subunit deletion on complex cognitive and social behaviors.

Glutamate N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC) and hippocampus may play an integral role in complex cognitive and social deficits associated with a number of psychiatric illnesses including autism, mood disorders, and schizophrenia. We used localized infusions of adeno-associated virus Cre-recombinase in adult, targeted knock-in mice with loxP sites flanking exons 11-22 of the NR1 gene to investigate the effects of chronic NMDAR dysfunction in the mPFC and CA3 hippocampus on cognitive and social behavior. A 5-choice serial reaction time task (5-CSRTT) was used to monitor aspects of cognitive function that included attention and response inhibition. Social behavior was assessed using Crowley׳s sociability and preference for social novelty protocol. Chronic NMDAR dysfunction localized to the anterior cingulate/prelimbic mPFC or dorsal CA3 hippocampus differentially affected the response inhibition and social interaction. mPFC NR1-deletion increased perseverative responding in the 5-CSRTT and enhanced preference for social novelty, whereas CA3 NR1-deletion increased premature responding in the 5-CSRTT and decreased social approach behavior. These findings suggest that mPFC and CA3 NMDARs play selective roles in regulating compulsive and impulsive behavior, respectively. Furthermore, these findings are consistent with emerging evidence that these behaviors are mediated by distinct, albeit overlapping, neural circuits. Our data also suggest that NMDARs in these regions uniquely contribute to the expression of normal social behavior. In this case, mPFC and CA3 NMDARs appear to inhibit and facilitate aspects of social interaction, respectively. The latter dissociation raises the possibility that distinct circuits contribute to the expression of social intrusiveness and impoverished social interaction.