Elaine Tring

A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex.

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Fast-spiking interneurons have an initial orientation bias that is lost with vision

We found that in mice, following eye opening, fast-spiking, parvalbumin-positive GABAergic interneurons had well-defined orientation tuning preferences and that subsequent visual experience broadened this tuning. Broad inhibitory tuning was not required for the developmental sharpening of excitatory tuning but did precede binocular matching of excitatory orientation tuning. We propose that experience-dependent broadening of inhibition is a candidate for initiating the critical period of excitatory binocular plasticity in developing visual cortex.

Spatial clustering of tuning in mouse primary visual cortex

The primary visual cortex of higher mammals is organized into two-dimensional maps, where the preference of cells for stimulus parameters is arranged regularly on the cortical surface. In contrast, the preference of neurons in the rodent appears to be arranged randomly, in what is termed a salt-and-pepper map. Here we revisited the spatial organization of receptive fields in mouse primary visual cortex by measuring the tuning of pyramidal neurons in the joint orientation and spatial frequency domain. We found that the similarity of tuning decreases as a function of cortical distance, revealing a weak but statistically significant spatial clustering. Clustering was also observed across different cortical depths, consistent with a columnar organization. Thus, the mouse visual cortex is not strictly a salt-and-pepper map. At least on a local scale, it resembles a degraded version of the organization seen in higher mammals, hinting at a possible common origin.

Enhanced Spatial Resolution During Locomotion and Heightened Attention in Mouse Primary Visual Cortex

We do not fully understand how behavioral state modulates the processing and transmission of sensory signals. Here, we studied the cortical representation of the retinal image in mice that spontaneously switched between a state of rest and a constricted pupil, and one of active locomotion and a dilated pupil, indicative of heightened attention. We measured the selectivity of neurons in primary visual cortex for orientation and spatial frequency, as well as their response gain, in these two behavioral states. Consistent with prior studies, we found that preferred orientation and spatial frequency remained invariant across states, whereas response gain increased during locomotion relative to rest. Surprisingly, relative gain, defined as the ratio between the gain during locomotion and the gain during rest, was not uniform across the population. Cells tuned to high spatial frequencies showed larger relative gain compared with those tuned to lower spatial frequencies. The preferential enhancement of high-spatial-frequency information was also reflected in our ability to decode the stimulus from population activity. Finally, we show that changes in gain originate from shifts in the operating point of neurons along a spiking nonlinearity as a function of behavioral state. Differences in the relative gain experienced by neurons with high and low spatial frequencies are due to corresponding differences in how these cells shift their operating points between behavioral states. SIGNIFICANCE STATEMENT How behavioral state modulates the processing and transmission of sensory signals remains poorly understood. Here, we show that the mean firing rate and neuronal gain increase during locomotion as a result in a shift of the operating point of neurons. We define relative gain as the ratio between the gain of neurons during locomotion and rest. Interestingly, relative gain is higher in cells with preferences for higher spatial frequencies than those with low-spatial-frequency selectivity. This means that, during a state of locomotion and heightened attention, the population activity in primary visual cortex can support better spatial acuity, a phenomenon that parallels the improved spatial resolution observed in human subjects during the allocation of spatial attention.

An inhibitory pull-push circuit in frontal cortex

Push–pull is a canonical computation of excitatory cortical circuits. By contrast, we identify a pull–push inhibitory circuit in frontal cortex that originates in vasoactive intestinal polypeptide (VIP)-expressing interneurons. During arousal, VIP cells rapidly and directly inhibit pyramidal neurons; VIP cells also indirectly excite these pyramidal neurons via parallel disinhibition. Thus, arousal exerts a feedback pull–push influence on excitatory neurons—an inversion of the canonical push–pull of feedforward input.

Pattern and not magnitude of neural activity determines dendritic spine stability in awake mice

The stability of dendritic spines in the neocortex is profoundly influenced by sensory experience, which determines the magnitude and pattern of neural firing. By optically manipulating the temporal structure of neural activity in vivo using channelrhodopsin-2 and repeatedly imaging dendritic spines along these stimulated neurons over a period of weeks, we show that the specific pattern, rather than the total amount of activity, determines spine stability in awake mice.

Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism

Significance Advances in human genetics have identified many gene alterations that cause autism, but how these mutations lead to cortical dysfunction is not understood. Mutations in the gene phosphatase and tensin homolog on chromosome ten (PTEN) cause autism and intellectual disability. We have discovered that single-copy deletion of Pten results in overexpression of the small-conductance calcium-activated potassium channel in cortical neurons. This overexpression leads to decreased sensitivity of cortical neurons to incoming inputs. In vivo, this diminished excitability leads to decreased primary visual cortical responsiveness to visual stimuli. We hypothesize that diminished cortical responses in primary sensory regions lead to poor recruitment of secondary sensory cortices, leading to sensory processing deficits. Our findings identify a unique target for potential pharmacological intervention. De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets.

Local tuning biases in mouse primary visual cortex

Neurons in primary visual cortex are selective to the orientation and spatial frequency of sinusoidal gratings. In the classic model of cortical organization, a population of neurons responding to the same region of the visual field but tuned to all possible feature combinations provides a detailed representation of the local image. Such a functional module is assumed to be replicated across primary visual cortex to provide a uniform representation of the image across the entire visual field. In contrast, it has been hypothesized that the tiling properties of ON- and OFF-center receptive fields in the retina, largely mirrored in the geniculate, may constrain cortical tuning at each location in the visual field. This model predicts the existence of local biases in tuning that vary across the visual field and would prevent the cortex from developing a uniform, modular representation as postulated by the classic model. Here, we confirm the existence of local tuning biases in the primary visual cortex of the mouse, lending support to the notion that cortical tuning may be constrained by signals from the periphery. NEW & NOTEWORTHY Populations of cortical neurons responding to the same part of the visual field are shown to have similar tuning. Such local biases are consistent with the hypothesis that cortical tuning, in mouse primary visual cortex, is constrained by signals from the periphery.

Pten and EphB4 regulate the establishment of perisomatic inhibition in mouse visual cortex

Perisomatic inhibition of pyramidal neurons is established by fast-spiking, parvalbumin-expressing interneurons (PV cells). Failure to assemble adequate perisomatic inhibition is thought to underlie the aetiology of neurological dysfunction in seizures, autism spectrum disorders and schizophrenia. Here we show that in mouse visual cortex, strong perisomatic inhibition does not develop if PV cells lack a single copy of Pten. PTEN signalling appears to drive the assembly of perisomatic inhibition in an experience-dependent manner by suppressing the expression of EphB4; PV cells hemizygous for Pten show an ∼2-fold increase in expression of EphB4, and over-expression of EphB4 in adult PV cells causes a dismantling of perisomatic inhibition. These findings implicate a molecular disinhibitory mechanism driving the establishment of perisomatic inhibition whereby visual experience enhances Pten signalling, resulting in the suppression of EphB4 expression; this relieves a native synaptic repulsion between PV cells and pyramidal neurons, thereby promoting the assembly of perisomatic inhibition.

On the Subspace Invariance of Population Responses

The response of a neural population in cat primary visual cortex to the linear combination of two sinusoidal gratings (a plaid) can be well approximated by a weighted sum of the population responses to the individual gratings – a property we refer to as subspace invariance. We tested subspace invariance in mouse primary visual cortex by measuring the angle between the population response to a plaid and the plane spanned by the population responses to its individual components. We found robust violations of subspace invariance, represented by a median angular deviation of ~55 deg. The cause of this departure is a strong, negative correlation between the mean responses a neuron to the individual gratings and its response to the plaid. We suggest that an early nonlinearity may distort the power distribution of grating and plaid stimuli such that plaids have a prominent power component at ±45 deg off the fundamental orientations. We conclude that subspace invariance does not hold in mouse V1. This finding rules out a large class of possible models of population coding, including vector averaging and gain control.