The Fibro-Inflammatory Response in the Glaucomatous Optic Nerve Head.

Glaucoma is a progressive disease and the leading cause of irreversible blindness. The limited therapeutics available are only able to manage the common risk factor of glaucoma, elevated intraocular pressure (IOP), indicating a great need for understanding the cellular mechanisms behind optic nerve head (ONH) damage during disease progression. Here we review the known inflammatory and fibrotic changes occurring in the ONH. In addition, we describe a novel mechanism of toll-like receptor 4 (TLR4) and transforming growth factor beta-2 (TGFß2) signaling crosstalk in the cells of the ONH that contribute to glaucomatous damage. Understanding molecular signaling within and between the cells of the ONH can help identify new drug targets and therapeutics.

TLR4 signaling modulates extracellular matrix production in the lamina cribrosa.

The optic nerve head (ONH) is a place of vulnerability during glaucoma progression due to increased intraocular pressure damaging the retinal ganglion cell axons. The molecular signaling pathways involved in generating glaucomatous ONH damage has not been fully elucidated. There is a great deal of evidence that pro-fibrotic TGFß2 signaling is involved in modulating the ECM environment within the lamina cribrosa (LC) region of the ONH. Here we investigated the role of signaling crosstalk between the TGFß2 pathway and the toll-like receptor 4 (TLR4) pathway within the LC. ECM deposition was examined between healthy and glaucomatous human ONH sections, finding increases in fibronectin and fibronectin extra domain A (FN-EDA) an isoform of fibronectin known to be a damage associated molecular pattern (DAMP) that can activate TLR4 signaling. In human LC cell cultures derived from healthy donor eyes, inhibition of TLR4 signaling blocked TGFß2 induced FN and FN-EDA expression. Activation of TLR4 by cellular FN (cFN) containing the EDA isoform increased both total FN production and Collagen-1 production and this effect was dependent on TLR4 signaling. These studies identify TGFß2-TLR4 signaling crosstalk in LC cells of the ONH as a novel pathway regulating ECM and DAMP production.

Dissociable control of µ-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex.

This study explored potentially dissociable functions of mu-opioid receptor (µ-OR) signaling across different cortical territories in the control of anticipatory activity directed toward palatable food, consumption, and impulsive food-seeking behavior in male rats. The µ-OR agonist, DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), was infused into infralimbic cortex (ILC), prelimbic cortex (PrL), medial and lateral ventral orbitofrontal cortices (VMO, VLO), and agranular/dysgranular insular (AI/DI) cortex of rats. Intra-ILC DAMGO markedly enhanced contact with a see-through screen behind which sucrose pellets were sequestered; in addition, rats having received intra-ILC and intra-VMO DAMGO exhibited locomotor hyperactivity while the screen was in place. Upon screen removal, intra-ILC and -VMO-treated rats emitted numerous, brief sucrose-intake bouts (yielding increased overall intake) interspersed with significant hyperactivity. In contrast, intra-AI/DI-treated rats consumed large amounts of sucrose in long, uninterrupted bouts with no anticipatory hyperactivity pre-screen removal. Intra-PrL and intra-VLO DAMGO altered neither pre-screen behavior nor sucrose intake. Finally, all rats were tested in a sucrose-reinforced differential reinforcement of low rates (DRL) task, which assesses the ability to advantageously withhold premature responses. DAMGO affected (impaired) DRL performance when infused into ILC only. These site-based dissociations reveal differential control of µ-OR-modulated appetitive/approach vs. consummatory behaviors by ventromedial/orbitofrontal and insular networks, respectively, and suggest a unique role of ILC µ-ORs in modulating inhibitory control.