Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data.

Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1ß, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold.

Corticothalamic feedback sculpts visual spatial integration in mouse thalamus.

En route from the retina to the cortex, visual information passes through the dorsolateral geniculate nucleus (dLGN) of the thalamus, where extensive corticothalamic (CT) feedback has been suggested to modulate spatial processing. How this modulation arises from direct excitatory and indirect inhibitory CT feedback pathways remains enigmatic. Here, we show that in awake mice, retinotopically organized cortical feedback sharpens receptive fields (RFs) and increases surround suppression in the dLGN. Guided by a network model indicating that widespread inhibitory CT feedback is necessary to reproduce these effects, we targeted the visual sector of the thalamic reticular nucleus (visTRN) for recordings. We found that visTRN neurons have large RFs, show little surround suppression and exhibit strong feedback-dependent responses to large stimuli. These features make them an ideal candidate for mediating feedback-enhanced surround suppression in the dLGN. We conclude that cortical feedback sculpts spatial integration in the dLGN, likely via recruitment of neurons in the visTRN.

Effects of locomotion extend throughout the mouse early visual system.

BACKGROUND: Neural responses in visual cortex depend not only on sensory input but also on behavioral context. One such context is locomotion, which modulates single-neuron activity in primary visual cortex (V1). How locomotion affects neuronal populations across cortical layers and in precortical structures is not well understood. RESULTS: We performed extracellular multielectrode recordings in the visual system of mice during locomotion and stationary periods. We found that locomotion influenced activity of V1 neurons with a characteristic laminar profile and shaped the population response by reducing pairwise correlations. Although the reduction of pairwise correlations was restricted to cortex, locomotion slightly but consistently increased firing rates and controlled tuning selectivity already in the dorsolateral geniculate nucleus (dLGN) of the thalamus. At the level of the eye, increases in locomotion speed were associated with pupil dilation. CONCLUSIONS: These findings document further, nonmultiplicative effects of locomotion, reaching earlier processing stages than cortex.

Spatial integration in mouse primary visual cortex.

Responses of many neurons in primary visual cortex (V1) are suppressed by stimuli exceeding the classical receptive field (RF), an important property that might underlie the computation of visual saliency. Traditionally, it has proven difficult to disentangle the underlying neural circuits, including feedforward, horizontal intracortical, and feedback connectivity. Since circuit-level analysis is particularly feasible in the mouse, we asked whether neural signatures of spatial integration in mouse V1 are similar to those of higher-order mammals and investigated the role of parvalbumin-expressing (PV+) inhibitory interneurons. Analogous to what is known from primates and carnivores, we demonstrate that, in awake mice, surround suppression is present in the majority of V1 neurons and is strongest in superficial cortical layers. Anesthesia with isoflurane-urethane, however, profoundly affects spatial integration: it reduces the laminar dependency, decreases overall suppression strength, and alters the temporal dynamics of responses. We show that these effects of brain state can be parsimoniously explained by assuming that anesthesia affects contrast normalization. Hence, the full impact of suppressive influences in mouse V1 cannot be studied under anesthesia with isoflurane-urethane. To assess the neural circuits of spatial integration, we targeted PV+ interneurons using optogenetics. Optogenetic depolarization of PV+ interneurons was associated with increased RF size and decreased suppression in the recorded population, similar to effects of lowering stimulus contrast, suggesting that PV+ interneurons contribute to spatial integration by affecting overall stimulus drive. We conclude that the mouse is a promising model for circuit-level mechanisms of spatial integration, which relies on the combined activity of different types of inhibitory interneurons.

Physical modeling of cell geometric order in an epithelial tissue.

In multicellular organisms, cells pack together to form tissues of intricate and well defined morphology. How such cell-packing geometries arise is an important open question in biology, because the functionality of many differentiated tissues depends on their reliable formation. We show that combining adhesive forces due to E- and N-cadherin with a quantitative description of cell membrane elasticity in an interfacial energy model explains not only the qualitative neighbor relations, but also the detailed geometry of a tissue. The characteristic cellular geometries in the eyes of both wild-type Drosophila and genetic mutants are accurately reproduced by using a fixed set of few, physically motivated parameters. The model predicts adhesion strengths in the eye epithelium, quantifies their role relative to membrane elasticity, and reveals how simple minimization of interfacial energy can give rise to complex geometric patterns of important biological functionality.