Unique Spatial Integration in Mouse Primary Visual Cortex and Higher Visual Areas.

Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes. Neurons in PM, compared with V1 or the other HVAs, have significantly larger RF sizes and less surround suppression, independent of stimulus eccentricity or contrast. To understand how this specialization of RFs arises in the HVAs, we measured the spatial properties of V1 inputs to each area. Spatial integration of V1 axons was remarkably similar across areas and significantly different from the tuning of neurons in their target HVAs. Thus, unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Further, the differences in RF properties could not be explained by differences in convergence of V1 inputs to the HVAs. Instead, our data suggest that distinct inputs from other areas or connectivity within PM may support the area's unique ability to encode global features of the visual scene, whereas V1, LM, and AL may be more specialized for processing local features.SIGNIFICANCE STATEMENT Surround suppression is a common feature of visual processing whereby large stimuli are less effective at driving neuronal responses than smaller stimuli. This is thought to enhance efficiency in the population code and enable higher-order processing of visual information, such as figure-ground segregation. However, this comes at the expense of global computations. Here we find that surround suppression is not equally represented across mouse visual areas: primary visual cortex has substantially more surround suppression than higher visual areas, and one higher area has significantly less suppression than two others examined, suggesting that these areas have distinct functional roles. Thus, we have identified a novel dimension of specialization in the mouse visual cortex that may enable both local and global computations.

Glutathione S-transferases promote proinflammatory astrocyte-microglia communication during brain inflammation.

Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione S-transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Knocking down GSTM1 in astrocytes also attenuated LPS-induced production of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by microglia when the two cell types were cocultured. In astrocytes, GSTM1 was required for the activation of nuclear factor κB (NF-κB) and the production of proinflammatory mediators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif chemokine ligand 2 (CCL2), both of which enhance microglia activation. Our study suggests that GSTs play a proinflammatory role in priming astrocytes and enhancing microglia activation in a microglia-astrocyte positive feedback loop during brain inflammation.

Dysregulated gene expressions of MEX3D, FOS and BCL2 in human induced-neuronal (iN) cells from NF1 patients: a pilot study.

Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells.

Infection and characterization of Toxoplasma gondii in human induced neurons from patients with brain disorders and healthy controls.

Toxoplasma gondii is a protozoan parasite capable of establishing persistent infection within the brain. Serological studies in humans have linked exposure to Toxoplasma to neuropsychiatric disorders. However, serological studies have not elucidated the related molecular mechanisms within neuronal cells. To address this question, we used human induced neuronal cells derived from peripheral fibroblasts of healthy individuals and patients with genetically-defined brain disorders (i.e. childhood-onset schizophrenia with disease-associated copy number variations). Parasite infection was characterized by differential detection of tachyzoites and tissue cysts in induced neuronal cells. This approach may aid study of molecular mechanisms underlying individual predisposition to Toxoplasma infection linked to neuropathology of brain disorders.

Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities.

The novel technology of induced neuronal cells (iN cells) is promising for translational neuroscience, as it allows the conversion of human fibroblasts into cells with postmitotic neuronal traits. However, a major technical barrier is the low conversion rate. To overcome this problem, we optimized the conversion media. Using our improved formulation, we studied how major mental illness-associated chromosomal abnormalities may impact the characteristics of iN cells. We demonstrated that our new iN cell culture protocol enabled us to obtain more precise measurement of neuronal cellular phenotypes than previous iN cell methods. Thus, this iN cell culture provides a platform to efficiently obtain possible cellular phenotypes caused by genetic differences, which can be more thoroughly studied in research using other human cell models such as induced pluripotent stem cells.

Visual circuits get the VIP treatment.

Behavioral state, specifically locomotion, has been shown to enhance sensory responses in primary visual cortex. In this issue of Cell, Fu et al. reveal the circuit elements that mediate this plasticity and suggest that these circuits may serve a general modulatory function across primary sensory areas.