BackgroundSystemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.MethodsPrimary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.ResultsDMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.ConclusionsDMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.

1. Whole-cell current-clamp recordings were made from neurons in the rostral nucleus tractus solitarii (NTS) in an in vitro brain slice preparation in rats. On the basis of previous investigations, these neurons are believed to be involved with processing of gustatory as well as somatosensory information. 2. Rostral NTS neurons had a mean resting membrane potential of -47 mV. The mean input resistance was 336 M omega, and by fitting a double exponential function the membrane time constant had fast (2.3 ms) and slow (20.6 ms) components. 3. Neurons were separated into four different groups on the basis of their responses to a current injection pulse paradigm consisting of membrane hyperpolarization of different magnitudes and durations immediately followed by a long (1.200 ms) depolarizing pulse. The regular repetitive discharge pattern of the first group of neurons (Group I neurons) was changed into an irregular spike train by membrane hyperpolarization. Hyperpolarization of Group II neurons either delayed the occurrence of the first action potential or increased the length of the first interspike interval in the action-potential train produced by membrane depolarization. The length of the delay was related both to the magnitude and duration of the hyperpolarizing prepulse. Hyperpolarization had the least effect on the discharge pattern of Group III neurons. The discharge pattern of Group IV neurons consisted of a short burst of action potentials that was often shortened by prior hyperpolarization of the neuron. 4. Differences exist in other intrinsic properties of the four neuron groups. Group I and III neurons were capable of initiating the highest frequency of action potentials to a 100-pA 1,200-ms depolarizing pulse. In response to a short depolarizing pulse. Group II neurons had the longest latency to the first spike and responded with the fewest action potentials. Group IV neurons tended to have higher input resistance and membrane time constants than the other neuron groups. A subset of neurons in each neuron group showed membrane afterhyperpolarizations (AHP) after depolarization-induced action-potential trains (postburst AHP). Postburst AHP amplitudes ranged from 1.0 to 12.9 mV and were of greatest magnitude in Group II neurons. Postburst AHP durations ranged from 75 to 3,538 ms and were of longest duration in neurons belonging to Group III. Group II neurons, which had the largest postburst AHP magnitude, had the shortest postburst AHP duration. 5. These results demonstrate that neurons in the rostral NTS can be separated on the basis of their intrinsic membrane properties.(ABSTRACT TRUNCATED AT 400 WORDS)

Receptors located in the posterior oral cavity and on the epiglottis play an important role in the initiation of upper airway reflexes such as swallowing, gagging, coughing and apnea. Peripheral nerves which innervate these receptor areas terminate in the nucleus tractus solitarius (NTS). We have recorded the responses of 61 neurons in the lamb NTS to stimulation of the caudal tongue, palate and epiglottis with mechanical, chemical and thermal stimuli and mapped receptive field location. Although there was some overlap in the areas of the NTS from which neurons with oral cavity and epiglottal receptive fields could be recorded, a significant difference was observed in the mean recording sites of the two groups of neurons. Neurons with oral cavity receptive fields were located more rostral, lateral and ventral in the NTS than neurons with receptive fields on the epiglottis. Little convergence of sensory input onto single cells in the NTS was observed between the oral cavity and the epiglottis. Only one NTS neuron had a receptive field in both of these receptor areas. In contrast, a large number of neurons with oral cavity receptive fields received input from two receptor areas. These neurons had a receptive field on the tongue which was located directly beneath the receptive field on the palate. Mechanical stimuli were the most effective for neurons with either oral cavity or epiglottal receptive fields and thermal stimuli were the least effective. Neurons which responded to mechanical stimuli responded better to a moving stimulus than to a punctate one, and large increases in the strength of a punctate stimulus were required to elicit significant increases in response frequency. Most NTS neurons responded to more than one of the stimulus modalities. However, a significant difference in the mean number of stimulus modalities which elicited responses was observed between neurons with oral cavity and epiglottal receptive fields. The number of multimodal neurons with epiglottal receptive fields was higher than those with oral cavity receptive fields. The multimodal nature of neurons which responded to epiglottal or oral cavity stimulation combined with their location in reflexogenic areas of the NTS suggests that these neurons could be important in the integration of afferent input from the oral cavity and upper airway. If these NTS neurons are involved in the control of oral and upper airway reflexes it would be important for them to respond to as many of the stimulus cues as possible and the majority of these neurons do just that.

Afferent and efferent central connections of the lingual-tonsillar branch of the glossopharyngeal nerve (LT-IX) and the superior laryngeal nerve (SLN) in the lamb were traced with horseradish peroxidase (HRP) histochemistry. After entering the brainstem, most LT-IX and SLN afferent fibers turned caudally in the solitary tract (ST). Some afferent fibers of LT-IX terminated in the medial nucleus of the solitary tract slightly caudal to their level of entry. The remaining fibers projected to the dorsolateral, ventrolateral, and interstitial areas of the nucleus of the solitary tract (NST) at the level of the area postrema. Superior laryngeal nerve afferent fibers terminated extensively in the medial and ventral NST at levels near the rostral pole of the area postrema. Further caudal, near the level of obex, SLN afferent terminations were concentrated in the region ventrolateral to the ST and in the interstitial NST. The caudal extent of LT-IX and the rostral extent of SLN terminals projected to similar levels of the NST, but only a relatively small proportion of the total projections overlapped. Lingual-tonsillar and SLN fibers also coursed rostrally to terminate in the caudal pons within and medial to the dorsomedial principal sensory trigeminal nucleus. Other labeled afferent fibers traveled caudally in the dorsal spinal trigeminal tract to terminate in the dorsal two-thirds of the spinal trigeminal nucleus at the level of obex. Large numbers of labeled cells with fibers in the LT-IX or SLN were located in the ipsilateral rostral nucleus ambiguus and surrounding reticular formation. Fewer labeled cells were observed in the inferior salivatory nucleus following HRP application to either the LT-IX or SLN. The LT-IX and SLN projections to areas of the NST associated with upper airway functions, like swallowing and respiration, suggest an important role for these two nerves in the initiation and control of airway reflexes.