Development of Parallel Auditory Thalamocortical Pathways for Two Different Behaviors

Auditory thalamocortical connections are organized as parallel pathways that originate in different divisions of the medial geniculate body (MGB). These pathways may be involved in different functions. Surprisingly little is known about the development of these connections. Here we review studies of the organization and development of auditory thalamocortical pathways in the pallid bat. The pallid bat depends primarily on passive hearing of prey-generated noise for localizing prey, while reserving echolocation for general orientation and obstacle avoidance. In the inferior colliculus (IC) and the auditory cortex, physiological studies show that noise and echolocation calls are processed in segregated regions. Injection of retrograde tracers in physiologically characterized cortical sites show that the ventral division of the MGB (MGBv) projects to the cortical region selective for noise. The cortical region selective for echolocation calls receives input from the suprageniculate (SG) nucleus in the dorsal MGB, but not from the MGBv. Taken together, these studies reveal parallel IC–MGB–cortex pathways involved in echolocation and passive listening. There is overlap of thalamocortical pathways during development. At 2-weeks postnatal, when the bat begins to exhibit adult-like hearing thresholds, the SG projects to both noise- and echolocation call-selective regions. The MGBv, as in adults, projects only to the noise-selective region. The connections become adult-like only after 2-months postnatal. These data suggest that parallel auditory thalamocortical pathways may segregate in an experience-dependent fashion, a hypothesis that remains to be tested in any species

Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice.

BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS

Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice.

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs

The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders

Perineuronal nets (PNN) are extracellular matrix (ECM) assemblies that preferentially ensheath parvalbumin (PV) expressing interneurons. Converging evidence indicates that PV cells and PNN are impaired in a variety of neurological disorders. PNN development and maintenance is necessary for a number of processes within the CNS, including regulation of GABAergic cell function, protection of neurons from oxidative stress, and closure of developmental critical period plasticity windows. Understanding PNN functions may be essential for characterizing the mechanisms of altered cortical excitability observed in neurodegenerative and neurodevelopmental disorders. Indeed, PNN abnormalities have been observed in post-mortem brain tissues of patients with schizophrenia and Alzheimer’s disease. There is impaired development of PNNs and enhanced activity of its key regulator matrix metalloproteinase-9 (MMP-9) in Fragile X Syndrome, a common genetic cause of autism. MMP-9, a protease that cleaves ECM, is differentially regulated in a number of these disorders. Despite this, few studies have addressed the interactions between PNN expression, MMP-9 activity and neuronal excitability. In this review, we highlight the current evidence for PNN abnormalities in CNS disorders associated with altered network function and MMP-9 levels, emphasizing the need for future work targeting PNNs in pathophysiology and therapeutic treatment of neurological disorders

Detecting and Quantifying Topography in Neural Maps

Topographic maps are an often-encountered feature in the brains of many species, yet there are no standard, objective procedures for quantifying topography. Topographic maps are typically identified and described subjectively, but in cases where the scale of the map is close to the resolution limit of the measurement technique, identifying the presence of a topographic map can be a challenging subjective task. In such cases, an objective topography detection test would be advantageous. To address these issues, we assessed seven measures (Pearson distance correlation, Spearman distance correlation, Zrehen's measure, topographic product, topological correlation, path length and wiring length) by quantifying topography in three classes of cortical map model: linear, orientation-like, and clusters. We found that all but one of these measures were effective at detecting statistically significant topography even in weakly-ordered maps, based on simulated noisy measurements of neuronal selectivity and sparse sampling of the maps. We demonstrate the practical applicability of these measures by using them to examine the arrangement of spatial cue selectivity in pallid bat A1. This analysis shows that significantly topographic arrangements of interaural intensity difference and azimuth selectivity exist at the scale of individual binaural clusters

Reusable Multielectrode Array Technique for Electroencephalography in Awake Freely Moving Mice

Translational comparison of rodent models of neurological and neuropsychiatric diseases to human electroencephalography (EEG) biomarkers in these conditions will require multisite rodent EEG on the skull surface, rather than local area electrocorticography (ECoG) or multisite local field potential (LFP) recording. We have developed a technique for planar multielectrode array (MEA) implantation on the mouse skull surface, which enables multisite EEG in awake and freely moving mice and reusability of the MEA probes. With this method, we reliably obtain 30-channel low-noise EEG from awake mice. Baseline and stimulus-evoked EEG recordings can be readily obtained and analyzed. For example, we have demonstrated EEG responses to auditory stimuli. Broadband noise elicits reliable 30-channel auditory event-related potentials (ERPs), and chirp stimuli induce phase-locked EEG responses just as in human sound presentation paradigms. This method is unique in achieving chronic implantation of novel MEA technology onto the mouse skull surface for chronic multisite EEG recordings. Furthermore, we demonstrate a reliable method for reusing MEA probes for multiple serial implantations without loss of EEG quality. This skull surface MEA methodology can be used to obtain simultaneous multisite EEG recordings and to test EEG biomarkers in diverse mouse models of human neurological and neuropsychiatric diseases. Reusability of the MEA probes makes it more cost-effective to deploy this system for various studies

Effects of sound intensity on temporal properties of inhibition in the pallid bat auditory cortex

Auditory neurons in bats that use frequency modulated (FM) sweeps for echolocation are selective for the behaviorally-relevant rates and direction of frequency change. Such selectivity arises through spectrotemporal interactions between excitatory and inhibitory components of the receptive field. In the pallid bat auditory system, the relationship between FM sweep direction/rate selectivity and spectral and temporal properties of sideband inhibition have been characterized. Of note is the temporal asymmetry in sideband inhibition, with low-frequency inhibition (LFI) exhibiting faster arrival times compared to high-frequency inhibition (HFI). Using the two-tone inhibition over time stimulus paradigm, this study investigated the interactions between two sound parameters in shaping sideband inhibition: intensity and time. Specifically, the impact of changing relative intensities of the excitatory and inhibitory tones on arrival time of inhibition was studied. Using this stimulation paradigm, single unit data from the auditory cortex of pentobarbital-anesthetized cortex show that the threshold for LFI is on average ~8 dB lower than HFI. For equal intensity tones near threshold, LFI is stronger than HFI. When the inhibitory tone intensity is increased further from threshold, the strength asymmetry decreased. The temporal asymmetry in LFI versus HFI arrival time is strongest when the excitatory and inhibitory tones are of equal intensities or if excitatory tone is louder. As inhibitory tone intensity is increased, temporal asymmetry decreased suggesting that the relative magnitude of excitatory and inhibitory inputs shape arrival time of inhibition and FM sweep rate and direction selectivity. Given that most FM bats use downward sweeps as echolocation calls, a similar asymmetry in threshold and strength of LFI versus HFI may be a general adaptation to enhance direction selectivity while maintaining sweep-rate selective responses to downward sweeps

Behavioral Effects of Administering CTEP Treatment in a Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS) is a genetic neurodevelopmental disorder that causes autism and intellectual disabilities: exhibiting hyperactivity, elevated anxiety, and impaired cognitive/sensory processing. These deficits result from mutations in the X-linked gene Fragile X messenger ribonucleoprotein 1 (Fmr1). Fmr1-knock- out (KO) mouse models have shown consistency with observations in humans, displaying seizures and sensory processing deficits. Utilizing Fmr1-KO mice to identify a potential treatment for these symptoms, we administered a drug called 2-chloro-4-((2,5-dimethyl-1-(4-trifluoromethoxy)phenyl)-1H-imidazole-4-yl) ethynyl)pyridine (CTEP) to KO mice and measured behavioral changes. CTEP in- hibits metabotropic glutamate receptor pathways, which are upregulated in FXS. Two types of experiments were run: open field test (OFT) and elevated plus maze (EPM), commonly used to study anxiety and hyperactivity. Experimental mice with higher anxiety depict decreased exploration and more time spent near the arena’s wall or closed arms. We found that CTEP reduces the distance traveled in the OFT across both wild-type (WT) and KO groups, suggesting reduced locomotion. There were no statistically significant differences in time spent in EPM closed arms between WT and KO mice, indicating no treatment of anxiety. These results suggest that more effective intervention is needed to target anxiety deficits related to FXS

Mix design method for self compacting metakaolin concrete with different properties of coarse aggregate

This study deals with a proposed mix design method for SCC utilizing different properties of coarse aggregate. The work was conducted in three phases, i.e. paste, mortar and concrete to facilitate the mix design process. Initial investigation on cement paste determined the basis for water cement ratio and superplasticizer dosage for the concrete. For the study on mortar, metakaolin (MK) as pozzolan was used at replacement levels of 5, 10, 15, and 20 by weight of cement. Self compactability of mortars was obtained by adding suitable materials such as mineral admixtures and superplasticizer which provided a sufficient balance between flowability and viscosity of the mix. The optimum MK replacement level for cement was 10 from the viewpoint of workability and strength. Flowability of mortar decreased with the use of metakaolin. Moreover, strength of mortar increased when the optimum replacement level of pozzolan was used. Different fresh concrete tests were adopted. The results obtained for fresh concrete properties showed that flowability of concrete increased with increase flowability of mortar. The mixes which contained coarse aggregate with lower volume, small size, and continuous grading affected positively the fresh properties of SCC. Finally, the mix design method used was successful in producing SCC with different coarse aggregate properties. © 2013 Elsevier Ltd