Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.

BACKGROUND: The etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain's susceptibility is not known. OBJECTIVE: We aimed to determine the mechanism underlying the unique susceptibility to anaphylaxis in C3H/HeJ mice. We tested the role of deleterious Toll-like receptor 4 (Tlr4) or dedicator of cytokinesis 8 (Dock8) mutations in this strain because both genes have been associated with food allergy. METHODS: We generated C3H/HeJ mice with corrected Dock8 or Tlr4 alleles and sensitized and challenged them with peanut. We then characterized the antibody response to sensitization, anaphylaxis response to both oral and systemic peanut challenge, gut microbiome, and biomarkers of gut permeability. RESULTS: In contrast to C3H/HeJ mice, C57BL/6 mice were resistant to anaphylaxis after oral peanut challenge; however, both strains undergo anaphylaxis with intraperitoneal challenge. Restoring Tlr4 or Dock8 function in C3H/HeJ mice did not protect from anaphylaxis. Instead, we discovered enhanced gut permeability resulting in ingested allergens in the bloodstream in C3H/HeJ mice compared to C57BL/6 mice, which correlated with an increased number of goblet cells in the small intestine. CONCLUSIONS: Our work highlights the potential importance of gut permeability in driving anaphylaxis to ingested food allergens; it also indicates that genetic loci outside of Tlr4 and Dock8 are responsible for the oral anaphylactic susceptibility of C3H/HeJ mice.

Shared and distinctive features of the gut microbiome of C57BL/6 mice from different vendors and production sites, and in response to a new vivarium.

Animal models play a critical role in establishing causal relationships between gut microbiota and disease. The laboratory mouse is widely used to study the role of microbes in various disorders; however, differences between mouse vendors, genetic lineages and husbandry protocols have been shown to contribute to variation in phenotypes and to non-reproducibility of experimental results. We sought to understand how gut microbiome profiles of mice vary by vendor, vendor production facility and health status upon receipt into an academic facility and how they change over 12 weeks in the new environment. C57BL/6 mice were sourced from two different production sites for each of three different vendors. Mice were shipped to an academic research vivarium, and fresh-catch stool samples were collected from mice immediately from the shipping box upon receipt, and again after 2, 6 and 12 weeks in the new facility. Substantial variation in bacterial proportional abundance was observed among mice from each vendor at the time of receipt, but shared microbes accounted for most sequence reads. Vendor-specific microbes were generally of low abundance. Microbial profiles of mice from all vendors exhibited shifts over time, highlighting the importance of environmental conditions on microbial dynamics. Our results emphasize the need for continued efforts to account for sources of variation in animal models and understand how they contribute to experimental reproducibility.

A mutation in mouse Krüppel-like factor 15 alters the gut microbiome and response to obesogenic diet.

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high fat diets. HLB444 shares similar phenotypic traits with engineered full- and adipose-specific Klf15 knockout strains; however, some phenotypic differences between this mutant and the other models suggest that the Klf15 mutation in HLB444 is a hypomorphic variant. The HLB444 model will inform further annotation of transcriptional functions of KLF15, especially with respect to the role of the first zinc-finger domain.

Effects of chronic ketamine on hippocampal cross-frequency coupling: implications for schizophrenia pathophysiology.

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30 Hz) phase and high-frequency (30-115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12 Hz) and slow gamma (25-50 Hz) but not fast gamma (65-100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Subthalamic and Cortical Local Field Potentials Associated with Pilocarpine-Induced Oral Tremor in the Rat.

Tremulous jaw movements (TJMs) are rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus. In rodents, TJMs are induced by neurochemical conditions that parallel those seen in human Parkinsonism, including neurotoxic or pharmacological depletion of striatal dopamine (DA), DA antagonism, and cholinomimetic administration. Moreover, TJMs in rodents can be attenuated by antiparkinsonian agents, including levodopa (L-DOPA), DA agonists, muscarinic antagonists, and adenosine A2A antagonists. In human Parkinsonian patients, exaggerated physiological synchrony is seen in the beta frequency band in various parts of the cortical/basal ganglia/thalamic circuitry, and activity in the tremor frequency range (3-7 Hz) also has been recorded. The present studies were undertaken to determine if tremor-related local field potential (LFP) activity could be recorded from motor cortex (M1) or subthalamic nucleus (STN) during the TJMs induced by the muscarinic agonist pilocarpine, which is a well-known tremorogenic agent. Pilocarpine induced a robust TJM response that was marked by rhythmic electromyographic (EMG) activity in the temporalis muscle. Compared to periods with no tremor activity, TJM epochs were characterized by increased LFP activity in the tremor frequency range in both neocortex and STN. Tremor activity was not associated with increased synchrony in the beta frequency band. These studies identified tremor-related LFP activity in parts of the cortical/basal ganglia circuitry that are involved in the pathophysiology of Parkinsonism. This research may ultimately lead to identification of the oscillatory neural mechanisms involved in the generation of tremulous activity, and promote development of novel treatments for tremor disorders.

Theta variation and spatiotemporal scaling along the septotemporal axis of the hippocampus.

Hippocampal theta has been related to locomotor speed, attention, anxiety, sensorimotor integration and memory among other emergent phenomena. One difficulty in understanding the function of theta is that the hippocampus (HPC) modulates voluntary behavior at the same time that it processes sensory input. Both functions are correlated with characteristic changes in theta indices. The current review highlights a series of studies examining theta local field potential (LFP) signals across the septotemporal or longitudinal axis of the HPC. While the theta signal is coherent throughout the entirety of the HPC, the amplitude, but not the frequency, of theta varies significantly across its three-dimensional expanse. We suggest that the theta signal offers a rich vein of information about how distributed neuronal ensembles support emergent function. Further, we speculate that emergent function across the long axis varies with respect to spatiotemporal scale. Thus, septal HPC processes details of the proximal spatiotemporal environment while more temporal aspects process larger spaces and wider time-scales. The degree to which emergent functions are supported by the synchronization of theta across the septotemporal axis is an open question. Our working model is that theta synchrony serves to bind ensembles representing varying resolutions of spatiotemporal information at interdependent septotemporal areas of the HPC. Such synchrony and cooperative interactions along the septotemporal axis likely support memory formation and subsequent consolidation and retrieval.

Novel acoustic stimuli can alter locomotor speed to hippocampal theta relationship.

Hippocampal theta (6-12 Hz) plays a critical role in synchronizing the discharge of action potentials, ultimately orchestrating individual neurons into large-scale ensembles. Alterations in theta dynamics may reflect variations in sensorimotor integration, the flow of sensory input, and/or cognitive processing. Previously we have investigated septotemporal variation in the locomotor speed to theta amplitude relationship as well as how that relationship is systematically altered as a function of novel, physical space. In the present study, we ask, beyond physical space, whether persistent and passive sound delivery can alter septal theta local field potential rhythm dynamics. Results indicate pronounced alterations in the slope of the speed to theta amplitude relationship as a function of sound presentation and location. Further, this reduction in slope habituates across days. The current findings highlight that moment-to-moment alterations in theta amplitude is a rich dynamic index that is quantitatively related to both alterations in motor behavior and sensory experience. The implications of these phenomena are discussed with respect to emergent cognitive functions subserved by hippocampal circuits.

Theta dynamics in rat: speed and acceleration across the Septotemporal axis.

Theta (6-12 Hz) rhythmicity in the local field potential (LFP) reflects a clocking mechanism that brings physically isolated neurons together in time, allowing for the integration and segregation of distributed cell assemblies. Variation in the theta signal has been linked to locomotor speed, sensorimotor integration as well as cognitive processing. Previously, we have characterized the relationship between locomotor speed and theta power and how that relationship varies across the septotemporal (long) axis of the hippocampus (HPC). The current study investigated the relationship between whole body acceleration, deceleration and theta indices at CA1 and dentate gyrus (DG) sites along the septotemporal axis of the HPC in rats. Results indicate that whole body acceleration and deceleration predicts a significant amount of variability in the theta signal beyond variation in locomotor speed. Furthermore, deceleration was more predictive of variation in theta amplitude as compared to acceleration as rats traversed a linear track. Such findings highlight key variables that systematically predict the variability in the theta signal across the long axis of the HPC. A better understanding of the relative contribution of these quantifiable variables and their variation as a function of experience and environmental conditions should facilitate our understanding of the relationship between theta and sensorimotor/cognitive functions.

Novel space alters theta and gamma synchrony across the longitudinal axis of the hippocampus.

Hippocampal theta (6-10 Hz) and gamma (25-50 Hz and 65-100 Hz) local field potentials (LFPs) reflect the dynamic synchronization evoked by inputs impinging upon hippocampal neurons. Novel experience is known to engage hippocampal physiology and promote successful encoding. Does novelty synchronize or desynchronize theta and/or gamma frequency inputs across the septotemporal (long) axis of the hippocampus (HPC)? The present study tested the hypothesis that a novel spatial environment would alter theta power and coherence across the long axis. We compared theta and gamma LFP signals at individual (power) and millimeter distant electrode pairs (coherence) within the dentate gyrus (DG) and CA1 region while rats navigated a runway (1) in a familiar environment, (2) with a modified path in the same environment and (3) in a novel space. Locomotion in novel space was related to increases in theta and gamma power at most CA1 and DG sites. The increase in theta and gamma power was concurrent with an increase in theta and gamma coherence across the long axis of CA1; however, there was a significant decrease in theta coherence across the long axis of the DG. These findings illustrate significant shifts in the synchrony of entorhinal, CA3 and/or neuromodulatory afferents conveying novel spatial information to the dendritic fields of CA1 and DG targets across the long axis of the HPC. This shift suggests that the entire theta/gamma-related input to the CA1 network, and likely output, receives and conveys a more coherent message in response to novel sensory experience. Such may contribute to the successful encoding of novel sensory experience.

Septotemporal variation in dynamics of theta: speed and habituation.

Theta (6-12 Hz) field potentials and the synchronization (coherence) of these potentials present neural network indices of hippocampal physiology. Theta signals within the hippocampal formation may reflect alterations in sensorimotor integration, the flow of sensory input, and/or distinct cognitive operations. While the power and coherence of theta signals vary across lamina within the septal hippocampus, limited information is available about variation in these indices across the septotemporal (long) or areal axis. The present study examined the relationship of locomotor speed to theta indices at CA1 and dentate gyrus (DG) sites across the septotemporal axis as well as in the entorhinal cortex. Our findings demonstrate the dominant relationship of speed to theta indices at septal sites. This relationship diminished systematically with distance from the septal pole of the hippocampus at both CA1 and DG sites. While theta power at entorhinal sites varied in relation to speed, there were no differences across the areal axis of the entorhinal cortex. Locomotor speed was also related to changes in theta coherence along the septotemporal axis as well as between the hippocampus and entorhinal cortex. In addition to the speed-related variation, we observed a decrease in theta power at more temporal hippocampal sites over repeated behavioral testing within a single day that was not observed at septal sites. The results outline a dynamic and distributed pattern of network activity across the septotemporal axis of the hippocampus in relation to locomotor speed and recent past experience.