Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes ...across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.
Altering the diet to treat disease dates to c. 400 BC when starvation was used to reduce seizures in persons with epilepsy. The current diversity of symptomology and mechanisms underlying autism ...spectrum disorders (ASDs) and a corresponding lack of disorder-specific effective treatments prompts an evaluation of diet as a therapeutic approach to improve symptoms of ASDs. In this review article, we summarize the main findings of nutritional studies in ASDs, with an emphasis on the most common monogenic cause of autism, Fragile X Syndrome (FXS), and the most studied dietary intervention, the ketogenic diet as well as other dietary interventions. We also discuss the gut microbiota in relation to pre- and probiotic therapies and provide insight into future directions that could aid in understanding the mechanism(s) underlying dietary efficacy.
Recent technical advancements in neural engineering allow for precise recording and control of neural circuits simultaneously, opening up new opportunities for closed-loop neural control. In this ...work, a rapid spike sorting system was developed based on template matching to rapidly calculate instantaneous firing rates for each neuron in a multi-unit extracellular recording setting. Cluster templates were first generated by a desktop computer using a non-parameter spike sorting algorithm (Super-paramagnetic clustering) and then transferred to a field-programmable gate array digital circuit for rapid sorting through template matching. Two different matching techniques-Euclidean distance (ED) and correlational matching (CM)-were compared for the accuracy of sorting and the performance of calculating firing rates. The performance of the system was first verified using publicly available artificial data and was further confirmed with pre-recorded neural spikes from an anesthetized Mongolian gerbil. Real-time recording and sorting from an awake mouse were also conducted to confirm the system performance in a typical behavioral neuroscience experimental setting. Experimental results indicated that high sorting accuracies were achieved for both template-matching methods, but CM can better handle spikes with non-Gaussian spike distributions, making it more robust for in vivo recording. The technique was also compared to several other off-line spike sorting algorithms and the results indicated that the sorting accuracy is comparable but sorting time is significantly shorter than these other techniques. A low sorting latency of under 2 ms and a maximum spike sorting rate of 941 spikes/second have been achieved with our hybrid hardware/software system. The low sorting latency and fast sorting rate allow future system developments of neural circuit modulation through analyzing neural activities in real-time.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parasites exert a profound effect on biological processes. In animal communication, parasite effects on signalers are well-known drivers of the evolution of communication systems. Receiver behavior ...is also likely to be altered when they are parasitized or at risk of parasitism, but these effects have received much less attention. Here, we present a broad framework for understanding the consequences of parasitism on receivers for behavioral, ecological, and evolutionary processes. First, we outline the different kinds of effects parasites can have on receivers, including effects on signal processing from the many parasites that inhabit, occlude, or damage the sensory periphery and the central nervous system or that affect physiological processes that support these organs, and effects on receiver response strategies. We then demonstrate how understanding parasite effects on receivers could answer important questions about the mechanistic causes and functional consequences of variation in animal communication systems. Variation in parasitism levels is a likely source of among-individual differences in response to signals, which can affect receiver fitness and, through effects on signaler fitness, impact population levels of signal variability. The prevalence of parasitic effects on specific sensory organs may be an important selective force for the evolution of elaborate and multimodal signals. Finally, host-parasite coevolution across heterogeneous landscapes will generate geographic variation in communication systems, which could ultimately lead to evolutionary divergence. We discuss applications of experimental techniques to manipulate parasitism levels and point the way forward by calling for integrative research collaborations between parasitologists, neurobiologists, and behavioral and evolutionary ecologists.
Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR ...signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1
mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.
•First characterization of behavior for all available system xc- mouse mutants.•First demonstration that the subtle gray (sut) mutation is a protein null.•First measurement of brain extracellular ...glutamate levels in sut mutants.•Highlights importance of looking at multiple mutant alleles for behavioral studies.
The slc7a11 gene encodes xCT, an essential component of ‘system xc-’, a plasma membrane exchanger that imports cystine and exports glutamate. Slc7a11 is expressed primarily in the brain, but its role there is not clear. We performed behavioral tests on two different strains of homozygous slc7a11 mutant mice (’sut’ and ‘xCT’), as well as heteroallelic offspring of these two strains (‘xCT/sut’) and their associated genetic backgrounds. Homozygous sut mutant males showed reduced spontaneous alternation in spontaneous alternation tasks as well as reduced movement in an open field maze, but xCT and xCT/sut strains did not show significant changes in these tasks compared to appropriate controls. Neither xCT nor sut mutants showed differences from controls in rotarod tests. Female behavioral phenotypes were independent of estrus cycle stage. To ensure that homozygous xCT, sut, and xCT/sut strains all represent protein null alleles, we measured whole brain xCT protein levels using immunoblots. xCT, sut and xCT/sut strains showed no detectable xCT protein expression, confirming them as null alleles. Previously published microdialysis experiments showed reduced striatal glutamate in xCT mutants. Using the same methods, we measured reduced interstitial glutamate levels in the striatum but not cerebellum of sut mutants. However, we detected no glutamate change in the striatum or cerebellum of sut/xCT mice. We detected no changes in whole brain EAAT-1, -2, or -3 expression. We conclude that the behavioral and chemical differences exist between slc7a11 mutant strains, but we were unable to definitively attribute any of these differences to loss of system xc-.
Hyperexcitability and the imbalance of excitation/inhibition are one of the leading causes of abnormal sensory processing in Fragile X syndrome (FXS). The precise timing and distribution of ...excitation and inhibition is crucial for auditory processing at the level of the auditory brainstem, which is responsible for sound localization ability. Sound localization is one of the sensory abilities disrupted by loss of the Fragile X Mental Retardation 1 (Fmr1) gene. Using triple immunofluorescence staining we tested whether there were alterations in the number and size of presynaptic structures for the three primary neurotransmitters (glutamate, glycine, and GABA) in the auditory brainstem of Fmr1 knockout mice. We found decreases in either glycinergic or GABAergic inhibition to the medial nucleus of the trapezoid body (MNTB) specific to the tonotopic location within the nucleus. MNTB is one of the primary inhibitory nuclei in the auditory brainstem and participates in the sound localization process with fast and well‐timed inhibition. Thus, a decrease in inhibitory afferents to MNTB neurons should lead to greater inhibitory output to the projections from this nucleus. In contrast, we did not see any other significant alterations in balance of excitation/inhibition in any of the other auditory brainstem nuclei measured, suggesting that the alterations observed in the MNTB are both nucleus and frequency specific. We furthermore show that glycinergic inhibition may be an important contributor to imbalances in excitation and inhibition in FXS and that the auditory brainstem is a useful circuit for testing these imbalances.
Using triple immunofluorescence the authors show nucleus specific and frequency specific changes in inhibitory presynaptic markers (GABA and glycine) in the auditory brainstem of Fmr1−/− mice, specifically the medial nucleus of the trapezoid body (MNTB). These alterations in inhibitory inputs to nuclei may underlie deficits in sound localization seen in Fragile X syndrome patients.
Auditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that ...lead to these symptoms are under explored. In this study, we examined whether there are defects in myelination in the auditory brainstem circuitry. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a myelination defects in the auditory brainstem that may underly auditory phenotypes in FXS.
A global online register of women scientists, ready to share their science, was established by a cohort of volunteer women from the grassroots organization 500 Women Scientists on January 17th, 2018. ...In less than one year, the database "Request a Woman Scientist" comprised over 7,500 women from 174 scientific disciplines and 133 countries. The database is built upon a voluntary questionnaire regarding career stage, degree, scientific discipline, geographic location, and other self-identifying dimensions of representation. The information was visualized using the software platform Tableau, with dropdown menus that help query the database and output a list of names, email addresses, and websites. The biological sciences and women scientists from the United States of America were best represented in the database. A survey of women in the database conducted in November 2018 showed that of 1,278 respondents, 11% had been contacted since signing up for a variety of engagements, including media, peer review, panel participation, educational outreach, and professional/research connections. These engagements resulted in consultations for articles, video chats with students, and speaking opportunities at conferences and events. With improved functionality and marketing, outreach in the global south, and future translation in other languages, this database will further promote the profile and participation of women scientists across society, which in turn will benefit the advancement of science.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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