Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis.

One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis.

Frontal midline θ power as an index of listening effort.

Attempts to identify physiological correlates of listening effort have mainly focused on peripheral measures (e.g. pupillometry) and auditory-evoked/event-related potentials. Although nonauditory studies have suggested that sustained time-frequency electroencephalographic (EEG) features in the θ-band (4-7 Hz) are correlated with domain-general mental effort, little work has characterized such features during effortful listening. Here, high-density EEG data was collected while listeners performed a sentence-recognition task in noise, the signal-to-noise ratio (SNR) of which varied across blocks. Frontal midline θ (Fmθ), largely driven by sources localized in or near the medial frontal cortex, showed greater power with decreasing SNR and was positively correlated with self-reports of effort. Increased Fmθ was present before speech onset and during speech presentation. Fmθ power also differed across SNRs when including only trials in which all words were recognized, suggesting that the effects were unrelated to performance differences. Results suggest that frontal cortical networks play a larger role in listening as acoustic signals are increasingly masked. Further, sustained time-frequency EEG features may usefully supplement previously used peripheral and event-related potential measures in psychophysiological investigations of effortful listening.