Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism.

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential "hypo-priors" theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

Inhibitory Units: An Organizing Nidus for Feature-Selective SubNetworks in Area V1.

Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a limited number of cells that participate in multiple cliques. The principles by which such cliques organize to encode information remain poorly understood. Similarly tuned pyramidal cells that preferentially target each other may form multicellular encoding units performing distinct computational tasks. The existence of such units can reflect upon both spontaneous and stimulus-driven population events.We applied two-photon calcium imaging to study spontaneous population bursts in layer 2/3 of area V1 in male C57BL/6 mice. To identify potential small-world cliques, we searched for pyramidal cells whose calcium events had a consistent temporal relationship with the events of local inhibitory interneurons. This was guided by the intuition that groups of neurons whose synchronous firing represents a temporally coherent computational unit should be inhibited together. Pyramidal members of these interneuron-centered clusters on average displayed stronger functional connectivity between each other than with nonmember pyramidal neurons. The structure of the clusters evolved during postnatal development: cluster size and overlap between clusters decreased with developmental maturation. Pyramidal neurons in a cluster showed higher than chance tuning function similarity between each other and with the linked interneuron. Thus, spontaneous population events in V1 are shaped by small-world subnetworks of pyramidal neurons that share functional properties and work as a coherent unit with a local interneuron. These interneuron-pyramidal cell partnerships may represent a fundamental neocortical unit of computation at the population level.SIGNIFICANCE STATEMENT Neuronal circuit in layer 2/3 of mouse area V1 possesses small-world network architecture, where cliques of densely interconnected neurons ("small worlds") communicate via restricted number of hub cells. We show that: (1) in mouse V1 individual small-world cliques preferably incorporate pyramidal neurons with similar visual feature tuning, and (2) ongoing population activity of such pyramidal neuron clique is temporally linked to the activity of the local interneuron sharing its feature tuning with the clique members. Functional grouping of similarly tuned interneurons and pyramidal cells into cliques may ensure that ensembles of functionally alike pyramidal cells recruited during perceptual tasks and spontaneous activity are also turned off together as a unit, with interneurons serving as organizers of linked pyramidal ensemble activity.

Complex Visual Motion Representation in Mouse Area V1.

Rodent visual cortex has a hierarchical architecture similar to that of higher mammals (Coogan and Burkhalter, 1993; Marshel et al., 2011; Wang et al., 2012). Although notable differences exist between the species in terms or receptive field sizes and orientation map organization (Dräger, 1975; Gattass et al., 1987; Van den Bergh et al., 2010), mouse V1 is thought to respond to local orientation and visual motion elements rather than to global patterns of motion, similar to V1 in higher mammals (Niell and Stryker, 2008; Bonin et al., 2011). However, recent results are inconclusive: some argue mouse V1 is analogous to monkey V1 (Juavinett and Callaway, 2015); others argue that it displays complex motion responses (Muir et al., 2015). We used type I plaids formed by the additive superposition of moving gratings (Adelson and Movshon, 1982; Movshon et al., 1985; Albright and Stoner, 1995) to investigate this question. We show that mouse V1 contains a considerably smaller fraction of component-motion-selective neurons (∼17% vs ∼84%), and a larger fraction of pattern-motion-selective neurons (∼10% vs <1.3%) compared with primate/cat V1. The direction of optokinetic nystagmus correlates with visual perception in higher mammals (Fox et al., 1975; Logothetis and Schall, 1990; Wei and Sun, 1998; Watanabe, 1999; Naber et al., 2011). Measurement of optokinetic responses to plaid stimuli revealed that mice demonstrate bistable perception, sometimes tracking individual stimulus components and others the global pattern of motion. Moreover, bistable optokinetic responses cannot be entirely attributed to subcortical circuitry as V1 lesions alter the fraction of responses occurring along pattern versus component motion. These observations suggest that area V1 input contributes to complex motion perception in the mouse. SIGNIFICANCE STATEMENT: Area V1 in the mouse is hierarchically similar but not necessarily identical to area V1 in cats and primates. Here we demonstrate that area V1 neurons process complex motion plaid stimuli differently in mice versus in cats or primates. Specifically, a smaller proportion of mouse V1 cells are sensitive to component motion, and a larger proportion to pattern motion than are found in area V1 of cats/primates. Furthermore, we demonstrate for the first time that mice exhibit bistable visual perception of plaid stimuli, and that this depends, at least in part, on area V1 input. Finally, we suggest that the relative proportion of component-motion-selective responses to pattern-motion-selective responses in mouse V1 may bias visual perception, as evidenced by changes in the direction of elicited optokinetic responses.

Tug-of-Peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 Duplication Syndrome of Autism.

Extracting common patterns of neural circuit computations in the autism spectrum and confirming them as a cause of specific core traits of autism is the first step toward identifying cell-level and circuit-level targets for effective clinical intervention. Studies in humans with autism have identified functional links and common anatomic substrates between core restricted behavioral repertoire, cognitive rigidity, and overstability of visual percepts during visual rivalry. To study these processes with single-cell precision and comprehensive neuronal population coverage, we developed the visual bistable perception paradigm for mice based on ambiguous moving plaid patterns consisting of two transparent gratings drifting at an angle of 120°. This results in spontaneous reversals of the perception between local component motion (plaid perceived as two separate moving grating components) and integrated global pattern motion (plaid perceived as a fused moving texture). This robust paradigm does not depend on the explicit report of the mouse, since the direction of the optokinetic nystagmus (OKN) is used to infer the dominant percept. Using this paradigm, we found that the rate of perceptual reversals between global and local motion interpretations is reduced in the methyl-CpG-binding protein 2 duplication syndrome (MECP2-ds) mouse model of autism. Moreover, the stability of local motion percepts is greatly increased in MECP2-ds mice at the expense of global motion percepts. Thus, our model reproduces a subclass of the core features in human autism (reduced rate of visual rivalry and atypical perception of visual motion). This further offers a well-controlled approach for dissecting neuronal circuits underlying these core features.

Brain orchestra under spontaneous conditions: Identifying communication modules from the functional architecture of area V1.

We used two-photon imaging to record from granular and supragranular layers in mouse primary visual cortex (V1) under spontaneous conditions and applied an extension of the spike time tiling coefficient (STTC; introduced by Cutts and Eglen) to map functional connectivity architecture within and across layers. We made several observations: Approximately, 19-34% of neuronal pairs within 300 µm of each other exhibit statistically significant functional connections, compared to ~10% at distances of 1mm or more. As expected, neuronal pairs with similar tuning functions exhibit a significant, though relatively small, increase in the fraction of functional inter-neuronal correlations. In contrast, internal state as reflected by pupillary diameter or aggregate neuronal activity appears to play a much stronger role in determining inter-neuronal correlation distributions and topography. Overall, inter-neuronal correlations appear to be slightly more prominent in L4. The first-order functionally connected (i.e., direct) neighbors of neurons determine the hub structure of the V1 microcircuit. L4 exhibits a nearly flat degree of connectivity distribution, extending to higher values than seen in supragranular layers, whose distribution drops exponentially. In all layers, functional connectivity exhibits small-world characteristics and network robustness. The probability of firing of L2/3 pyramidal neurons can be predicted as a function of the aggregate activity in their first-order functionally connected partners within L4, which represent their putative input group. The functional form of this prediction conforms well to a ReLU function, reaching up to firing probability one in some neurons. Interestingly, the properties of L2/3 pyramidal neurons differ based on the size of their L4 functional connectivity group. Specifically, L2/3 neurons with small layer-4 degrees of connectivity appear to be more sensitive to the firing of their L4 functional connectivity partners, suggesting they may be more effective at transmitting synchronous activity downstream from L4. They also appear to fire largely independently from each other, compared to neurons with high layer-4 degrees of connectivity, and are less modulated by changes in pupil size and aggregate population dynamics. Information transmission is best viewed as occurring from neuronal ensembles in L4 to neuronal ensembles in L2/3. Under spontaneous conditions, we were able to identify such candidate neuronal ensembles, which exhibit high sensitivity, precision, and specificity for L4 to L2/3 information transmission. In sum, functional connectivity analysis under spontaneous activity conditions reveals a modular neuronal ensemble architecture within and across granular and supragranular layers of mouse primary visual cortex. Furthermore, modules with different degrees of connectivity appear to obey different rules of engagement and communication across the V1 columnar circuit.

Strengthening of lateral activation in adult rat visual cortex after retinal lesions captured with voltage-sensitive dye imaging in vivo.

Sensory deprivation caused by peripheral injury can trigger functional cortical reorganization across the initially silenced cortical area. It is proposed that intracortical connectivity enables recovery of function within such a lesion projection zone (LPZ), thus substituting lost subcortical input. Here, we investigated retinal lesion-induced changes in the function of lateral connections in the primary visual cortex of the adult rat. Using voltage-sensitive dye recordings, we visualized in millisecond-time resolution spreading synaptic activity across the LPZ. Shortly after lesion, the majority of neurons within the LPZ were subthresholdly activated by delayed propagation of activity that originated from unaffected cortical regions. With longer recovery time, latencies within the LPZ gradually decreased, and activation reached suprathreshold levels. Targeted electrode recordings confirmed that receptive fields of intra-LPZ neurons were displaced to the retinal lesion border while displaying normal orientation and direction selectivity. These results corroborate the view that cortical horizontal connections have a central role in functional reorganization, as revealed here by progressive facilitation of synaptic activity and the traveling wave of excitation that propagates horizontally into the deprived cortical region.

Dictionary Learning for Spontaneous Neural Activity Modeling.

Modeling the activity of an ensemble of neurons can provide critical insights into the workings of the brain. In this work we examine if learning based signal modeling can contribute to a high quality modeling of neuronal signal data. To that end, we employ the sparse coding and dictionary learning schemes for capturing the behavior of neuronal responses into a small number of representative prototypical signals. Performance is measured by the reconstruction quality of clean and noisy test signals, which serves as an indicator of the generalization and discrimination capabilities of the learned dictionaries. To validate the merits of the proposed approach, a novel dataset of the actual recordings from 183 neurons from the primary visual cortex of a mouse in early postnatal development was developed and investigated. The results demonstrate that high quality modeling of testing data can be achieved from a small number of training examples and that the learned dictionaries exhibit significant specificity when introducing noise.