Removal of microglial-specific MyD88 signaling alters dentate gyrus doublecortin and enhances opioid addiction-like behaviors.

Drugs of abuse promote a potent immune response in central nervous system (CNS) via the activation of microglia and astrocytes. However, the molecular mechanisms underlying microglial activation during addiction are not well known. We developed and functionally characterized a novel transgenic mouse (Cx3cr1-CreBTtg/0:MyD88f/f [Cretg/0]) wherein the immune signaling adaptor gene, MyD88, was specifically deleted in microglia. To test the downstream effects of loss of microglia-specific MyD88 signaling in morphine addiction, Cretg/0 and Cre0/0 mice were tested for reward learning, extinction, and reinstatement using a conditioned place preference (CPP) paradigm. There were no differences in drug acquisition, but Cretg/0 mice had prolonged extinction and enhanced reinstatement compared to Cre0/0 controls. Furthermore, morphine-treated Cretg/0 mice showed increased doublecortin (DCX) signal relative to Cre0/0 control mice in the hippocampus, indicative of increased number of immature neurons. Additionally, there was an increase in colocalization of microglial lysosomal marker CD68 with DCX+cells in morphine-treated Cretg/0 mice but not in Cre0/0 or drug-naїve mice, suggesting a specific role for microglial MyD88 signaling in neuronal phagocytosis in the hippocampus. Our results show that MyD88 deletion in microglia may negatively impact maturing neurons within the adult hippocampus and thus reward memories, suggesting a novel protective role for microglia in opioid addiction.

Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.

Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD.

Morphological differences affect speech transmission over bone conduction.

In bone conduction (BC), acoustic signals travel through an individual's bones and soft tissues rather than travelling through the air. While bone conduction hearing and communication are important in everyday life, nature, and technology, little is known about how individual differences affect the transmission of bone-conducted sound. Individuals differ in the sizes, shapes, and proportions of their craniofacial bones, leading to potentially different bone-conducted sound transmission effects in different individuals. Individual differences may influence the audibility and quality of bone-conducted sound, and this was studied using speech intelligibility as an assessment criterion for bone-conducted sound transmission. Thirty-two human participants were first subjected to a series of anthropometric craniofacial measurements. Eight morphologically diverse talkers were recorded with bone microphones placed at different skull locations, and 24 morphologically diverse listeners listened to these samples over bone conduction headphones. Modified Rhyme Test results suggest that skull morphology influences BC speech intelligibility and does so differently at different skull locations. Understanding morphological effects can improve bone conduction sound transmission models and may help to enhance BC technology for a diverse user population.

Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core.

BACKGROUND: As a more detailed picture of nervous system function emerges, diversity of astrocyte function becomes more widely appreciated. While it has been shown that cocaine experience impairs astroglial glutamate uptake and release in the nucleus accumbens (NAc), few studies have explored effects of self-administration on the structure and physiology of astrocytes. We investigated the effects of extinction from daily cocaine self-administration on astrocyte characteristics including glial fibrillary acidic protein (GFAP) expression, surface area, volume, and colocalization with a synaptic marker. METHODS: Cocaine or saline self-administration and extinction were paired with GFAP Westerns, immunohistochemistry, and fluorescent imaging of NAc core astrocytes (30 saline-administering and 36 cocaine-administering male Sprague Dawley rats were employed). Imaging was performed using a membrane-tagged lymphocyte protein tyrosine kinase-green fluorescent protein (Lck-GFP) driven by the GFAP promoter, coupled with synapsin I immunohistochemistry. RESULTS: GFAP expression was significantly reduced in the NAc core following cocaine self-administration and extinction. Similarly, we observed an overall smaller surface area and volume of astrocytes, as well as reduced colocalization with synapsin I, in cocaine-administering animals. Cocaine-mediated reductions in synaptic contact were reversed by the ß-lactam antibiotic ceftriaxone. CONCLUSIONS: Multiple lines of investigation indicate that NAc core astrocytes exist in a hyporeactive state following cocaine self-administration and extinction. Decreased association with synaptic elements may be particularly meaningful, as cessation of chronic cocaine use is associated with changes in synaptic strength and resistance to the induction of synaptic plasticity. We hypothesize that the reduced synaptic colocalization of astrocytes represents an important maladaptive cellular response to cocaine and the mechanisms underlying relapse vulnerability.

The effect of vocal and demographic traits on speech intelligibility over bone conduction.

Bone conduction (BC) communication systems provide benefits over air conduction systems but are not in widespread use, partly due to problems with speech intelligibility. Contributing factors like device location and background noise have been explored, but little attention has been paid to the role of individual user differences. Because BC signals travel through an individual's skull and facial tissues, demographic factors such as user age, sex, race, or regional origin may influence sound transmission. Vocal traits such as pitch, spectral tilt, jitter, and shimmer may also play a role. Along with microphone placement and background noise, these factors can affect BC speech intelligibility. Eight diverse talkers were recorded with bone microphones on two different skull locations and in different background noise conditions. Twenty-four diverse listeners listened to these samples over BC and completed Modified Rhyme Tests for speech intelligibility. Forehead bone recordings were more intelligible than condyle recordings. In condyle recordings, female talkers, talkers with high fundamental frequency, and talkers in background noise were understood better, as were communications between talkers and listeners of the same regional origin. Listeners' individual traits had no significant effects. Thoughtful application of this knowledge can help improve BC communication for diverse users.

Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.

Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.

Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism.

In recent years, interactions between neurons and glia have been evaluated as mediators of neuropsychiatric diseases, including drug addiction. In particular, compounds that increase expression of the astroglial glutamate transporter GLT-1 (N-acetylcysteine and ceftriaxone) can decrease measures of drug seeking. However, it is unknown whether the compounds that influence broad measures of glial physiology can influence behavioral measures of drug relapse, nor is it clear whether the upregulated GLT-1 is functionally important for suppressing of drug seeking. To address these questions, we sought to determine whether the glial modulator and neuroprotective agent propentofylline (PPF) modifies drug seeking in rats using a reinstatement model of cocaine relapse. We found that 7 days of chronic (but not acute) administration of PPF significantly decreased both cue- and cocaine-induced reinstatement of cocaine seeking. We next determined whether the effect of systemic PPF on reinstatement depended upon its ability to restore expression of GLT-1 in the nucleus accumbens. PPF restored the cocaine-induced decrease in GLT-1 in the accumbens core; then, using an antisense strategy against glutamate transporter GLT-1, we found that restored transporter expression was necessary for PPF to inhibit cue-primed cocaine seeking. These findings indicate that modulating glial physiology with atypical xanthine derivatives like PPF is a potential avenue for developing new medications for cocaine abuse, and support the hypothesis that neuron-glial interactions contribute to mechanisms of psychostimulant addiction, particularly via expression and function of astroglial glutamate transporters.

The effect of bone conduction microphone placement on intensity and spectrum of transmitted speech items.

Speech signals can be converted into electrical audio signals using either conventional air conduction (AC) microphone or a contact bone conduction (BC) microphone. The goal of this study was to investigate the effects of the location of a BC microphone on the intensity and frequency spectrum of the recorded speech. Twelve locations, 11 on the talker's head and 1 on the collar bone, were investigated. The speech sounds were three vowels (/u/, /a/, /i/) and two consonants (/m/, /∫/). The sounds were produced by 12 talkers. Each sound was recorded simultaneously with two BC microphones and an AC microphone. Analyzed spectral data showed that the BC recordings made at the forehead of the talker were the most similar to the AC recordings, whereas the collar bone recordings were most different. Comparison of the spectral data with speech intelligibility data collected in another study revealed a strong negative relationship between BC speech intelligibility and the degree of deviation of the BC speech spectrum from the AC spectrum. In addition, the head locations that resulted in the highest speech intelligibility were associated with the lowest output signals among all tested locations. Implications of these findings for BC communication are discussed.

A free-field method to calibrate bone conduction transducers.

Bone conduction communication systems employ a variety of transducers with different physical and electroacoustic properties, and these transducers may be worn at various skull locations. Testing these systems thus requires a reliable means of transducer calibration that can be implemented across different devices, skull locations, and settings. Unfortunately, existing calibration standards do not meet these criteria. Audiometric bone conduction standards focus on only one device model and on limited skull locations. Furthermore, while mechanical couplers may be used for calibration, the general human validity of their results is suspect. To address the need for more flexible, human-centered calibration methods, the authors investigated a procedure for bone transducer calibration, analogous to free-field methods for calibrating air conduction headphones. Participants listened to1s third-octave noise bands (125-12,500 Hz) alternating between a bone transducer and a loudspeaker and adjusted the bone transducer to match the perceived loudness of the loudspeaker at each test frequency. Participants tested two transducer models and two skull locations. Intra- and inter-subject reliability was high, and the resulting data differed by transducer, by location, and from the mechanical coupler. The described procedure is flexible to transducer model and skull location, requires only basic equipment, and directly yields perceptual data.

The effect of head-related transfer function measurement methodology on localization performance in spatial audio interfaces.

OBJECTIVE: Four head-related transfer function (HRTF) data sets were compared to determine the effect of HRTF measurement methodology on the localization of spatialized auditory stimuli. BACKGROUND: Spatial audio interfaces typically require HRTF data sets to generate the spatialized auditory stimuli. HRTF measurement is accomplished using a variety of techniques that can require several nearly arbitrary decisions about methodology. The effects of these choices upon the resulting spatial audio interface are unclear. METHOD: Sixteen participants completed a sound localization task that included real-world, broadband stimuli spatialized at eight locations on the horizontal plane. Four different HRTF data sets were utilized to spatialize the stimuli: two publicly available HRTF data sets and two data sets obtained using different in-house measurement systems. All HRTFs were obtained from the Knowles Electronics Mannequin for Acoustics Research. RESULTS: Unsigned localization error and proportion of front/back reversals did not differ significantly across HRTF data sets. Poorest accuracy was observed in locations near the medial (front/back) axis of the listener, mainly because of the relatively large proportions of reversals at these locations. CONCLUSION: This study suggests that the particular generalized HRTF data set chosen for spatialization is of minimal importance to the localizability of the resulting stimuli. APPLICATION: This result will inform the design of many spatial audio interfaces that are based upon generalized HRTFs, including wayfaring devices, communication systems, and virtual reality systems.

Loudspeaker equalization for auditory research.

The equalization of loudspeaker frequency response is necessary to conduct many types of well-controlled auditory experiments. This article introduces a program that includes functions to measure a loudspeaker's frequency response, design equalization filters, and apply the filters to a set of stimuli to be used in an auditory experiment. The filters can compensate for both magnitude and phase distortions introduced by the loudspeaker. A MATLAB script is included in the Appendix to illustrate the details of the equalization algorithm used in the program.