Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

Summary Lactate shuttled from blood, astrocytes, and/or oligodendrocytes may serve as the major glucose alternative in brain energy metabolism. However, its effectiveness in fueling neuronal information processing underlying complex cortex functions like perception and memory is unclear. We show that sole lactate disturbs electrical gamma and theta-gamma oscillations in hippocampal networks by either attenuation or neural bursts. Bursting is suppressed by elevating the glucose fraction in substrate supply. By contrast, lactate does not affect electrical sharp wave-ripple activity featuring lower energy use. Lactate increases the oxygen consumption during the network states, reflecting enhanced oxidative ATP synthesis in mitochondria. Finally, lactate attenuates synaptic transmission in excitatory pyramidal cells and fast-spiking, inhibitory interneurons by reduced neurotransmitter release from presynaptic terminals, whereas action potential generation in the axon is regular. In conclusion, sole lactate is less effective and potentially harmful during gamma-band rhythms by omitting obligatory ATP delivery through fast glycolysis at the synapse.

Cortical information processing comprises various activity states emerging from timed synaptic excitation and inhibition. However, the underlying energy metabolism is widely unknown. We determined the cerebral metabolic rate of oxygen (CMRO) along a tissue depth of <0.3 mm in the hippocampal CA3 region during various network activities, including gamma oscillations and sharp wave-ripples that occur during wakefulness and sleep. These physiological states associate with sensory perception and memory formation, and critically depend on perisomatic GABA inhibition. Moreover, we modelled vascular oxygen delivery based on quantitative microvasculature analysis. (1) Local CMRO was highest during gamma oscillations (3.4 mM/min), medium during sharp wave-ripples, asynchronous activity and isoflurane application (2.0-1.6 mM/min), and lowest during tetrodotoxin application (1.4 mM/min). (2) Energy expenditure of axonal and synaptic signaling accounted for >50% during gamma oscillations. (3) CMRO positively correlated with number and synchronisation of activated synapses, and neural multi-unit activity. (4) The median capillary distance was 44 µm. (5) The vascular oxygen partial pressure of 33 mmHg was needed to sustain oxidative phosphorylation during gamma oscillations. We conclude that gamma oscillations featuring high energetics require a hemodynamic response to match oxygen consumption of respiring mitochondria, and that perisomatic inhibition significantly contributes to the brain energy budget.

Gamma oscillations (30-100 Hz) reflect a fast brain rhythm that provides a fundamental mechanism of complex neuronal information processing in the hippocampus and in the neocortex in vivo. Gamma oscillations have been implicated in higher brain functions, such as sensory perception, motor activity, and memory formation. Experimental studies on synaptic transmission and bioenergetics underlying gamma oscillations have primarily used acute slices of the hippocampus. This study tests whether organotypic hippocampal slice cultures of the rat provide an alternative model for cortical gamma oscillations in vitro. Our findings are that 1) slice cultures feature well-preserved laminated architecture and neuronal morphology; 2) slice cultures of different maturation stages (7-28 days in vitro) reliably express gamma oscillations at about 40 Hz as induced by cholinergic (acetylcholine) or glutamatergic (kainate) receptor agonists; 3) the peak frequency of gamma oscillations depends on the temperature, with an increase of 3.5 Hz per degree Celsius for the range of 28-36 C; 4) most slice cultures show persistent gamma oscillations for 1 hr during electrophysiological local field potential recordings, and later alterations may occur; and 5) in slice cultures, glucose at a concentration of 5 mM in the recording solution is sufficient to power gamma oscillations, and additional energy substrate supply with monocarboxylate metabolite lactate (2 mM) exclusively increases the peak frequency by 4 Hz. This study shows that organotypic hippocampal slice cultures provide a reliable model to study agonistinduced gamma oscillations at glucose levels near the physiological range. V C 2015 Wiley Periodicals, Inc.

Fast neuronal network oscillations in the gamma-frequency band (30–−100 Hz) provide a fundamental mechanism of complex neuronal information processing in the hippocampus and neocortex of mammals. Gamma oscillations have been implicated in higher brain functions such as sensory perception, motor activity, and memory formation. The oscillations emerge from precise synapse interactions between excitatory principal neurons such as pyramidal cells and inhibitory GABAergic interneurons, and they are associated with high energy expenditure. However, both energy substrates and metabolic pathways that are capable to power cortical gamma oscillations have been less defined. Here, we investigated the energy sources fueling persistent gamma oscillations in the CA3 subfield of organotypic hippocampal slice cultures of the rat. This preparation permits superior oxygen supply as well as fast application of glucose, glycolytic metabolites or drugs such as glycogen phosphorylase inhibitor during extracellular recordings of the local field potential. Our findings are: (i) gamma oscillations persist in the presence of glucose (10 mmol/L) for greater than 60 min in slice cultures while (ii) lowering glucose levels (2.5 mmol/L) significantly reduces the amplitude of the oscillation. (iii) Gamma oscillations are absent at low concentration of lactate (2 mmol/L). (iv) Gamma oscillations persist at high concentration (20 mmol/L) of either lactate or pyruvate, albeit showing significant reductions in the amplitude. (v) The breakdown of glycogen significantly delays the decay of gamma oscillations during glucose deprivation. However, when glucose is present, the turnover of glycogen is not essential to sustain gamma oscillations. Our study shows that fast neuronal network oscillations can be fueled by different energy-rich substrates, with glucose being most effective.