An Anatomically Constrained Model of V1 Simple Cells Predicts the Coexistence of Push-Pull and Broad Inhibition.

The spatial organization and dynamic interactions between excitatory and inhibitory synaptic inputs that define the receptive field (RF) of simple cells in the cat primary visual cortex (V1) still raise the following paradoxical issues: (1) stimulation of simple cells in V1 with drifting gratings supports a wiring schema of spatially segregated sets of excitatory and inhibitory inputs activated in an opponent way by stimulus contrast polarity and (2) in contrast, intracellular studies using flashed bars suggest that although ON and OFF excitatory inputs are indeed segregated, inhibitory inputs span the entire RF regardless of input contrast polarity. Here, we propose a biologically detailed computational model of simple cells embedded in a V1-like network that resolves this seeming contradiction. We varied parametrically the RF-correlation-based bias for excitatory and inhibitory synapses and found that a moderate bias of excitatory neurons to synapse onto other neurons with correlated receptive fields and a weaker bias of inhibitory neurons to synapse onto other neurons with anticorrelated receptive fields can explain the conductance input, the postsynaptic membrane potential, and the spike train dynamics under both stimulation paradigms. This computational study shows that the same structural model can reproduce the functional diversity of visual processing observed during different visual contexts.SIGNIFICANCE STATEMENT Identifying generic connectivity motives in cortical circuitry encoding for specific functions is crucial for understanding the computations implemented in the cortex. Indirect evidence points to correlation-based biases in the connectivity pattern in V1 of higher mammals, whereby excitatory and inhibitory neurons preferentially synapse onto neurons respectively with correlated and anticorrelated receptive fields. A recent intracellular study questions this push-pull hypothesis, failing to find spatial anticorrelation patterns between excitation and inhibition across the receptive field. We present here a spiking model of V1 that integrates relevant anatomic and physiological constraints and shows that a more versatile motif of correlation-based connectivity with selectively tuned excitation and broadened inhibition is sufficient to account for the diversity of functional descriptions obtained for different classes of stimuli.

Inhibition in Simple Cell Receptive Fields Is Broad and OFF-Subregion Biased.

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with in vivo intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings.SIGNIFICANCE STATEMENT The wiring of excitatory and inhibitory neurons in cortical circuits is key to determining the response properties in sensory cortex. In the visual cortex, the first cells that receive visual input are simple cells in layer 4. The underlying circuitry responsible for the response properties of simple cells is not yet known. In this study, we challenge a long-held view concerning the pattern of inhibitory input and provide results that agree with current known anatomy. We show here that inhibition is evoked broadly across the receptive fields of simple cells, and we identify a surprising bias in inhibition within the receptive field. Our findings represent a step toward a unified view of inhibition across different species and sensory systems.

Intracellular, In Vivo, Dynamics of Thalamocortical Synapses in Visual Cortex.

Seminal studies of the thalamocortical circuit in the visual system of the cat have been central to our understanding of sensory encoding. However, thalamocortical synaptic properties remain poorly understood. We used paired recordings, in the lateral geniculate nucleus (LGN) and primary visual cortex (V1), to provide the first in vivo characterization of sensory-driven thalamocortical potentials in V1. The amplitudes of EPSPs we characterized were smaller than those previously reported in vitro Consistent with prior findings, connected LGN-V1 pairs were only found when their receptive fields (RFs) overlapped, and the probability of connection increased steeply with degree of RF overlap and response similarity. However, surprisingly, we found no relationship between EPSP amplitudes and the similarity of RFs or responses, suggesting different connectivity models for intracortical and thalamocortical circuits. Putative excitatory regular-spiking (RS) and inhibitory fast-spiking (FS) V1 cells had similar EPSP characteristics, showing that in the visual system, feedforward excitation and inhibition are driven with equal strength by the thalamus. Similar to observations in the somatosensory cortex, FS V1 cells received less specific input from LGN. Finally, orientation tuning in V1 was not inherited from single presynaptic LGN cells, suggesting that it must emerge exclusively from the combined input of all presynaptic LGN cells. Our results help to decipher early visual encoding circuits and have immediate utility in providing physiological constraints to computational models of the visual system.SIGNIFICANCE STATEMENT To understand how the brain encodes the visual environment, we must understand the transfer of visual signals between various regions of the brain. Therefore, understanding synaptic dynamics is critical to our understanding of sensory encoding. This study provides the first characterization of visually evoked synaptic potentials between the visual thalamus and visual cortex in an intact animal. To record these potentials, we simultaneously recorded the extracellular potential of presynaptic thalamic cells and the intracellular potential of postsynaptic cortical cells in input layers of primary visual cortex. Our characterization of synaptic potentials in vivo disagreed with prior findings in vitro This study will increase our understanding of thalamocortical circuits and will improve computational models of visual encoding.

Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion.

Neurological symptoms in tuberous sclerosis complex (TSC) and associated brain lesions are thought to arise from abnormal embryonic neurogenesis due to inherited mutations in Tsc1 or Tsc2. Neurogenesis persists postnatally in the human subventricular zone (SVZ) where slow-growing tumors containing Tsc-mutant cells are generated in TSC patients. However, whether Tsc-mutant neurons from the postnatal SVZ contribute to brain lesions and abnormal circuit remodeling in forebrain structures remain unexplored. Here, we report the formation of olfactory lesions following conditional genetic Tsc1 deletion in the postnatal SVZ using transgenic mice or targeted single-cell electroporation. These lesions include migratory heterotopias and olfactory micronodules containing neurons with a hypertrophic dendritic tree. Most significantly, our data identify migrating glial and neuronal precursors that are re-routed and infiltrate forebrain structures (e.g. cortex) and become glia and neurons. These data show that Tsc1-mutant cells from the neonatal and juvenile SVZ generate brain lesions and structural abnormalities, which would not be visible using conventional non-invasive imaging. These findings also raise the hypothesis that micronodules and the persistent infiltration of cells to forebrain structures may contribute to network malfunction leading to progressive neuropsychiatric symptoms in TSC.

NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development.

Signaling through GABA(A) receptors controls neural progenitor cell (NPC) development in vitro and is altered in schizophrenic and autistic individuals. However, the in vivo function of GABA(A) signaling on neural stem cell proliferation, and ultimately neurogenesis, remains unknown. To examine GABA(A) function in vivo, we electroporated plasmids encoding short-hairpin (sh) RNA against the Na-K-2Cl cotransporter NKCC1 (shNKCC1) in NPCs of the neonatal subventricular zone in mice to reduce GABA(A)-induced depolarization. Reduced GABA(A) depolarization identified by a loss of GABA(A)-induced calcium responses in most electroporated NPCs led to a 70% decrease in the number of proliferative Ki67(+) NPCs and a 60% reduction in newborn neuron density. Premature loss of GABA(A) depolarization in newborn neurons resulted in truncated dendritic arborization at the time of synaptic integration. However, by 6 weeks the dendritic tree had partially recovered and displayed a small, albeit significant, decrease in dendritic complexity but not total dendritic length. To further examine GABA(A) function on NPCs, we treated animals with a GABA(A) allosteric agonist, pentobarbital. Enhancement of GABA(A) activity in NPCs increased the number of proliferative NPCs by 60%. Combining shNKCC1 and pentobarbital prevented the shNKCC1 and the pentobarbital effects on NPC proliferation, suggesting that these manipulations affected NPCs through GABA(A) receptors. Thus, dysregulation in GABA(A) depolarizing activity delayed dendritic development and reduced NPC proliferation resulting in decreased neuronal density.

Neurotransmitters couple brain activity to subventricular zone neurogenesis.

Adult neurogenesis occurs in two privileged microenvironments, the hippocampal subgranular zone of the dentate gyrus and the subventricular zone (SVZ) along the lateral ventricle. This review focuses on accumulating evidence suggesting that the activity of specific brain regions or bodily states influences SVZ cell proliferation and neurogenesis. Neuromodulators such as dopamine and serotonin have been shown to have long-range effects through neuronal projections into the SVZ. Local γ-aminobutyric acid and glutamate signaling have demonstrated effects on SVZ proliferation and neurogenesis, but an extra-niche source of these neurotransmitters remains to be explored and options will be discussed. There is also accumulating evidence that diseases and bodily states such as Alzheimer's disease, seizures, sleep and pregnancy influence SVZ cell proliferation. With such complex behavior and environmentally-driven factors that control subregion-specific activity, it will become necessary to account for overlapping roles of multiple neurotransmitter systems on neurogenesis when developing cell therapies or drug treatments.