Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

Landmark-modulated directional coding in postrhinal cortex.

Visual landmarks can anchor an animal's internal sense of orientation to the external world. The rodent postrhinal cortex (POR) may facilitate this processing. Here, we demonstrate that, in contrast to classic head direction (HD) cells, which have a single preferred orientation, POR HD cells develop a second preferred orientation when an established landmark cue is duplicated along another environmental wall. We therefore refer to these cells as landmark-modulated-HD (LM-HD) cells. LM-HD cells discriminate between landmarks in familiar and novel locations, discriminate between visually disparate landmarks, and continue to respond to the previous location of a familiar landmark following its removal. Rats initially exposed to different stable landmark configurations show LM-HD tuning that may reflect the integration of visual landmark information into an allocentric HD signal. These results provide insight into how visual landmarks are integrated into a framework that supports the neural encoding of landmark-based orientation.

How bad could it be? Alcohol dampens stress responses to threat of uncertain intensity.

Stress response dampening is an important motive for alcohol use. However, stress reduction via alcohol (alcohol SRD) is observed inconsistently in the laboratory, and this has raised questions about the precise mechanisms and boundary conditions for these effects. Emerging evidence indicates that alcohol SRD may be observed selectively during uncertain but not certain threats. In a final sample of 89 participants, we measured stress response via potentiation of defensive startle reflex in response to threat of shock in blocks with certain (low and high) and uncertain shock intensity. Our alcohol-administration procedure produced blood alcohol concentrations (BACs) across a broad range (0.00%-0.12%) across participants. Increasing BACs were associated with linearly decreasing startle potentiation and self-reported anxiety. This SRD effect was greater during uncertain than certain threat. More broadly, these results suggest that distinct mechanisms are involved in response to threats of uncertain intensity and threats of certain intensity.