Summary Purpose The role of granule cell axon (mossy fiber) sprouting in temporal lobe epileptogenesis is unclear and controversial. Rapamycin suppresses mossy fiber sprouting, but its reported effects on seizure frequency are mixed. The present study used high-dose rapamycin to more completely block mossy fiber sprouting and measure the effect on seizure frequency. Methods Mice were treated with pilocarpine to induce status epilepticus. Beginning 24 h later and continuing for 2 months, vehicle or rapamycin (10 mg/kg/d) was administered. Starting 1 month after status epilepticus, mice were video-monitored 9 h/d every day for 1 month to measure the frequency of spontaneous motor seizures. At the end of seizure monitoring, a subset of mice was prepared for anatomical analysis. Mossy fiber sprouting was measured as the proportion of the granule cell layer and molecular layer that displayed black labeling in Timm-stained sections. Key findings Extensive mossy fiber sprouting developed in mice that experienced status epilepticus and were treated with vehicle. In rapamycin-treated mice, mossy fiber sprouting was blocked almost to the level of naïve controls. Seizure frequency was similar in vehicle- and rapamycin-treated mice. Significance These findings suggest mossy fiber sprouting is not necessary for epileptogenesis in the mouse pilocarpine model. They also reveal that rapamycin does not have anti-seizure or anti-epileptogenic effects in this model.

Objectives/Hypothesis: The goal of this study was to objectively examine vocal fold (VF) motion dynamics after iatrogenic recurrent laryngeal nerve (RLN) injury in a mouse surgical model. Furthermore, we sought to identify a method of inducing injury with a consistent recovery pattern from which we can begin to evaluate spontaneous recovery and test therapeutic interventions.Study Design: Animal model. Methods: The right RLN in C57BL/6J mice was crushed for 30 seconds using an aneurysm clip with 1.3-N closing force. Transoral laryngoscopy enabled visualization of VF movement prior to surgery, immediately post-crush, and at two endpoints: 3 days (n = 5) and 2 weeks (n = 5). VF motion was quantified with our custom motion-analysis software. At each endpoint, RLN samples were collected for transmission electron microscopy for correlation with VF motion dynamics.Results: Our VF tracking software permitted automated quantification of several measures of VF dynamics, such as range and frequency of motion. By 2 weeks post-injury, the frequency of VF movement on the right (injured) side equaled the left, yet range of motion only partially recovered. These objective outcome measures enabled detection of VF dysfunction that persisted at 2 weeks post-crush. Transmission electron microscopy images revealed RLN degeneration 3 days post-crush and partial regeneration at 2 weeks, consistent with functional results obtained with automated VF tracking.Conclusions: Our motion-analysis software provides novel objective, quantitative, and repeatable metrics to detect and describe subtle VF dysfunction in mice that corresponds with underlying RLN degeneration and recovery. Adaptation of our tracking software for use with human patients is underway.

Pilocarpine-treated mice are an increasingly used model of temporal lobe epilepsy. However, outcomes of treatment can be disappointing, because many mice die or fail to develop status epilepticus. To improve animal welfare and outcomes of future experiments we analyzed results of previous pilocarpine treatments to identify factors that correlate with development of status epilepticus and survival. All treatments were performed by one investigator with mice of the FVB background strain. Results from 2413 mice were evaluated for effects of sex, age, body weight, and latency between administration of atropine methyl bromide and pilocarpine. All parameters correlated with effects on outcomes. Best results were obtained from male mice, 6–7 weeks old, and 21–25 g, with pilocarpine administered 18–30 min after atropine methyl bromide. In that group only 23% failed to develop status epilepticus, and 64% developed status epilepticus and survived. Those results are substantially better than that of the total sample in which 31% failed to develop status epilepticus and only 34% developed status epilepticus and survived.

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The vagus nerve, the tenth and longest cranial nerve in the body, innervates numerous structures including the larynx, pharynx, heart, lungs, and gastrointestinal tract. The vagus nerve is composed of thousands of axons that work to provide a vast majority of the autonomic innervation in the body. 39,70 This nerve plays a large role in interoceptive awareness and is often regarded as the body's 'sixth sense.' 12,61,73 Although the function of the vagus nerve is largely parasympathetic, it also provides somatic innervation, mainly to the muscles responsible for swallowing and upper airway function. 6 The vagus nerve comprises A, B, and C fiber types, all of which are characterized by different conduction velocities and stimulation thresholds. 14,39,55,60 This nerve consists of both afferent (80%) and efferent (20%) fibers that provide sensory and motor information to maintain homeostasis in nearly every organ system in mammals. 12,39,43,54,65,70 Given the vagus nerve's wide-ranging anatomic targets and neuromodulatory effects, targeted manipulation of this nerve has a broad range of potential experimental and therapeutic applications. In fact, vagal nerve stimulation (VNS) has been used experimentally to establish the contribution of the vagus nerve to numerous behaviors, including immune function, mood, pain, and memory. 70 Furthermore, there is immense interest in using implantable and noninvasive VNS devices to modulate essential functions within the body. 39 VNS has been shown as an effective therapeutic strategy for diverse disorders, and various forms of VNS are currently FDA-approved for treating refractory epilepsy, depression, migraines, cluster headaches, and obesity. 12,30,51,55,60,70-72 In addition, this technology is currently being explored in a multitude of other disorders, including arthritis, asthma, heart failure, gastroparesis, and inflammatory bowel disease, among many others. 30,54,70 Despite the effectiveness of VNS as a treatment strategy, the richness and complexity of the information transmitted along the vagus nerve raises serious challenges that must be considered before widespread use of VNS. 39 Because the vagus nerve innervates multiple organ systems, it is imperative to examine how using VNS to treat a disorder of one organ system might affect healthy function in another. Numerous studies have been conducted on the safety of VNS in regard to cardiovascular and respiratory function. 6,8,10,30 However, although studies have examined the effects of VNS on gastrointestinal function, 45,46,50 no published study has investigated how VNS might influence gastrointestinal microbial populations. 12 This dearth is surprising, given that the vagus nerve is the direct link between the CNS and gastrointestinal tract, serving as a complex bidirectional line of communication

The prevailing dogma is that thermogenic brown adipose tissue (BAT) contributes to improvements in glucose homeostasis in obesogenic animal models; though, much of the evidence supporting this premise is from thermostressed rodents. Whether modulation of the BAT morphology/function drives changes in glucoregulation at thermoneutrality requires further investigation. We utilized loss and gain‐of‐function approaches including genetic manipulation of the lipolytic enzyme Pnpla2, change in environmental temperature, and lifestyle interventions to comprehensively test the premise that a thermogenic‐like BAT phenotype is coupled with enhanced glucose tolerance in female mice. In contrast to this hypothesis, we found that: (i) compared to mice kept at thermoneutrality, enhanced activation of BAT and its thermogenic phenotype via chronic mild cold stress does not improve glucose tolerance in obese mice; (ii) silencing of the Pnpla2 in interscapular BAT causes a brown‐to‐white phenotypic shift but does not disturb glucose tolerance in lean mice; and (iii) exercise and low‐fat diet improve glucose tolerance in obese mice but these effects do not track with a thermogenic BAT phenotype. Collectively, these findings indicate that a thermogenic‐like BAT phenotype is not linked to heightened glucose tolerance in female mice. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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The intricate sensorimotor neural circuits that control swallowing are heavily reliant on serotonin (5-hydroxytryptamine [5-HT]); however, the impact of 5-HT deficiency on swallow function remains largely unexplored. We investigated this using mice deficient in tryptophan-hydroxylase-2 (TPH2), the enzyme catalyzing the rate-limiting step in 5-HT synthesis. Videofluoroscopy was utilized to characterize the swallowing function of TPH2 knockout ( TPH2-/-) mice as compared with littermate controls ( TPH2+/+). Results showed that 5-HT deficiency altered all 3 stages of swallowing. As compared with controls, TPH2-/- mice had significantly slower lick and swallow rates and faster esophageal transit times. Future studies with this model are necessary to determine if 5-HT replacement may rescue abnormal swallowing function. If so, supplemental 5-HT therapy may have vast applications for a large population of patients with a variety of neurologic disorders resulting in life-diminishing dysphagia, particularly amyotrophic lateral sclerosis and Parkinson’s disease, for which 5-HT deficiency is implicated in the disease pathogenesis.