Activation of Peroxisome Proliferator-Activated Receptor-ß/δ (PPARß/δ) in Keratinocytes by Endogenous Fatty Acids.

Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARß/δ activity. Fatty acids caused PPARß/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 (Angptl4) mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 (Scd1) mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARß/δ ligands. The activation of PPARß/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing Pparb/d-null keratinocytes. HRAS-expressing Scd1-null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARß/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARß/δ. The results from these studies demonstrate that PPARß/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components.

Bursts of vagus nerve stimulation paired with auditory rehabilitation fail to improve speech sound perception in rats with hearing loss.

Hearing loss can lead to long-lasting effects on the central nervous system, and current therapies, such as auditory training and rehabilitation, show mixed success in improving perception and speech comprehension. Vagus nerve stimulation (VNS) is an adjunctive therapy that can be paired with rehabilitation to facilitate behavioral recovery after neural injury. However, VNS for auditory recovery has not been tested after severe hearing loss or significant damage to peripheral receptors. This study investigated the utility of pairing VNS with passive or active auditory rehabilitation in a rat model of noise-induced hearing loss. Although auditory rehabilitation helped rats improve their frequency discrimination, learn novel speech discrimination tasks, and achieve speech-in-noise performance similar to normal hearing controls, VNS did not enhance recovery of speech sound perception. These results highlight the limitations of VNS as an adjunctive therapy for hearing loss rehabilitation and suggest that optimal benefits from neuromodulation may require restored peripheral signaling.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. METHODS: In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. RESULTS: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. CONCLUSIONS: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Precise sound characteristics drive plasticity in the primary auditory cortex with VNS-sound pairing.

Introduction: Repeatedly pairing a tone with vagus nerve stimulation (VNS) alters frequency tuning across the auditory pathway. Pairing VNS with speech sounds selectively enhances the primary auditory cortex response to the paired sounds. It is not yet known how altering the speech sounds paired with VNS alters responses. In this study, we test the hypothesis that the sounds that are presented and paired with VNS will influence the neural plasticity observed following VNS-sound pairing. Methods: To explore the relationship between acoustic experience and neural plasticity, responses were recorded from primary auditory cortex (A1) after VNS was repeatedly paired with the speech sounds 'rad' and 'lad' or paired with only the speech sound 'rad' while 'lad' was an unpaired background sound. Results: Pairing both sounds with VNS increased the response strength and neural discriminability of the paired sounds in the primary auditory cortex. Surprisingly, pairing only 'rad' with VNS did not alter A1 responses. Discussion: These results suggest that the specific acoustic contrasts associated with VNS can powerfully shape neural activity in the auditory pathway. Methods to promote plasticity in the central auditory system represent a new therapeutic avenue to treat auditory processing disorders. Understanding how different sound contrasts and neural activity patterns shape plasticity could have important clinical implications.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

Background: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods: Neural recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Auditory Brainstem Responses Predict Behavioral Deficits in Rats with Varying Levels of Noise-Induced Hearing Loss.

Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing. Rats can accurately detect and discriminate human speech sounds in the presence of quiet and background noise. Further, it is known that profound hearing loss results in functional deafness in rats. In this study, we generated rats with a range of impairments which model the large range of hearing impairments observed in patients with NIHL. One month after noise exposure, we stratified rats into three distinct deficit groups based on their auditory brainstem response (ABR) thresholds. These groups exhibited markedly different behavioral outcomes across a range of tasks. Rats with moderate hearing loss (30 dB shifts in ABR threshold) were not impaired in speech sound detection or discrimination. Rats with severe hearing loss (55 dB shifts) were impaired at discriminating speech sounds in the presence of background noise. Rats with profound hearing loss (70 dB shifts) were unable to detect and discriminate speech sounds above chance level performance. Across groups, ABR threshold accurately predicted behavioral performance on all tasks. This model of long-term impaired speech discrimination in noise, demonstrated by the severe group, mimics the most common clinical presentation of NIHL and represents a useful tool for developing and improving interventions to target restoration of hearing.

Vagus nerve stimulation paired with tones restores auditory processing in a rat model of Rett syndrome.

BACKGROUND: Rett syndrome is a rare neurological disorder associated with a mutation in the X-linked gene MECP2. This disorder mainly affects females, who typically have seemingly normal early development followed by a regression of acquired skills. The rodent Mecp2 model exhibits many of the classic neural abnormalities and behavioral deficits observed in individuals with Rett syndrome. Similar to individuals with Rett syndrome, both auditory discrimination ability and auditory cortical responses are impaired in heterozygous Mecp2 rats. The development of therapies that can enhance plasticity in auditory networks and improve auditory processing has the potential to impact the lives of individuals with Rett syndrome. Evidence suggests that precisely timed vagus nerve stimulation (VNS) paired with sound presentation can drive robust neuroplasticity in auditory networks and enhance the benefits of auditory therapy. OBJECTIVE: The aim of this study was to investigate the ability of VNS paired with tones to restore auditory processing in Mecp2 transgenic rats. METHODS: Seventeen female heterozygous Mecp2 rats and 8 female wild-type (WT) littermates were used in this study. The rats were exposed to multiple tone frequencies paired with VNS 300 times per day for 20 days. Auditory cortex responses were then examined following VNS-tone pairing therapy or no therapy. RESULTS: Our results indicate that Mecp2 mutation alters auditory cortex responses to sounds compared to WT controls. VNS-tone pairing in Mecp2 rats improves the cortical response strength to both tones and speech sounds compared to untreated Mecp2 rats. Additionally, VNS-tone pairing increased the information contained in the neural response that can be used to discriminate between different consonant sounds. CONCLUSION: These results demonstrate that VNS-sound pairing may represent a strategy to enhance auditory function in individuals with Rett syndrome.

Pairing vagus nerve stimulation with tones drives plasticity across the auditory pathway.

Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with sounds can enhance the primary auditory cortex (A1) response to the paired sound. The neural response to sounds following VNS-sound pairing in other subcortical and cortical auditory fields has not been documented. We predicted that VNS-tone pairing would increase neural responses to the paired tone frequency across the auditory pathway. In this study, we paired VNS with the presentation of a 9-kHz tone 300 times a day for 20 days. We recorded neural responses to tones from 2,950 sites in the inferior colliculus (IC), A1, anterior auditory field (AAF), and posterior auditory field (PAF) 24 h after the last pairing session in anesthetized rats. We found that VNS-tone pairing increased the percentage of IC, A1, AAF, and PAF that responds to the paired tone frequency. Across all tested auditory fields, the response strength to tones was strengthened in VNS-tone paired rats compared with control rats. VNS-tone pairing reduced spontaneous activity, frequency selectivity, and response threshold across the auditory pathway. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing. Our findings suggest that VNS paired with sound presentation is an effective method to enhance auditory processing.NEW & NOTEWORTHY Previous studies have reported primary auditory cortex plasticity following vagus nerve stimulation (VNS) paired with a sound. This study extends previous findings by documenting that fields across the auditory pathway are altered by VNS-tone pairing. VNS-tone pairing increases the percentage of each field that responds to the paired tone frequency. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing.

Regulatory mechanisms mediated by peroxisome proliferator-activated receptor-ß/δ in skin cancer.

Considerable progress has been made during the past 20 years towards elucidating the role of peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) in skin cancer. In 1999, the original notion that PPARß/δ was involved with epithelial cell function was postulated based on a correlation between PPARß/δ expression and the induction of messenger RNAs encoding proteins that mediate terminal differentiation in keratinocytes. Subsequent studies definitively revealed that PPARß/δ could induce terminal differentiation and inhibit proliferation of keratinocytes. Molecular mechanisms have since been discovered to explain how this nuclear receptor can be targeted for preventing and treating skin cancer. This includes the regulation of terminal differentiation, mitotic signaling, endoplasmic reticulum stress, and cellular senescence. Interestingly, the effects of activating PPARß/δ can preferentially target keratinocytes with genetic mutations associated with skin cancer. This review provides the history and current understanding of how PPARß/δ can be targeted for both nonmelanoma skin cancer and melanoma and postulates how future approaches that modulate PPARß/δ signaling may be developed for the prevention and treatment of these diseases.

Vagus Nerve Stimulation Rate and Duration Determine whether Sensory Pairing Produces Neural Plasticity.

Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an auditory stimulus drives reorganization of primary auditory cortex (A1), and the magnitude of this VNS-dependent plasticity is dependent on the stimulation parameters, including intensity and pulse rate. However, there is currently little data to guide the selection of VNS train durations, an easily adjusted parameter that could influence the effect of VNS-based therapies. Here, we tested the effect of varying the duration of the VNS train on the extent of VNS-dependent cortical plasticity. Rats were exposed to a 9 kHz tone 300 times per day for 20 days. Coincident with tone presentation, groups received trains of 4, 16, or 64 pulses of VNS delivered at 30 Hz, corresponding to train durations of 0.125 s, 0.5 s, and 2.0 s, respectively. High-density microelectrode mapping of A1 revealed that 0.5 s duration VNS trains significantly increased the number of neurons in A1 that responded to tones near the paired tone frequency. Trains lasting 0.125 or 2.0 s failed to alter A1 responses, indicating that both shorter and longer stimulation durations are less effective at enhancing plasticity. A second set of experiments evaluating the effect of delivering 4 or 64 pulses in a fixed 0.5 s VNS train duration paired with tone presentation reveal that both slower and faster stimulation rates are less effective at enhancing plasticity. We incorporated these results with previous findings describing the effect of stimulation parameters on VNS-dependent plasticity and activation of neuromodulatory networks to generate a model of synaptic activation by VNS.

Varying Stimulation Parameters to Improve Cortical Plasticity Generated by VNS-tone Pairing.

Pairing vagus nerve stimulation (VNS) with movements or sounds can direct robust plasticity in motor or auditory cortex, respectively. The degree of map plasticity is influenced by the intensity and pulse width of VNS, number of VNS-event pairings, and the interval between each pairing. It is likely that these parameters interact, influencing optimal implementation of VNS pairing protocols. We varied VNS intensity, number of stimulations, and inter-stimulation interval (ISI) to test for interactions among these parameters. Rats were implanted with a vagus nerve stimulating cuff and randomly assigned to one of three treatment groups to receive 20 days of VNS paired with a 9-kHz tone: (1) Fast VNS: 50 daily pairings of 400-µA VNS with a 30-s ISI; (2) Dispersed VNS: 50 daily pairings of 400-µA VNS with a 180-s ISI; and (3) Standard VNS: 300 daily pairings of 800-µA VNS with a 30-s ISI. Following 20 days of VNS-tone pairing, multi-unit recordings were conducted in primary auditory cortex (A1) and receptive field properties were analyzed. Increasing ISI (Dispersed VNS) did not lead to an enhancement of cortical plasticity. Reducing the current intensity and number of stimulations (Fast VNS) resulted in robust cortical plasticity, using 6 times fewer VNS pairings than the Standard protocol. These findings reveal an interaction between current intensity, stimulation number, and ISI and identify a novel VNS paradigm that is substantially more efficient than the previous standard paradigm.

Inhibition of tumorigenesis by peroxisome proliferator-activated receptor (PPAR)-dependent cell cycle blocks in human skin carcinoma cells.

To examine the functional role of peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) and PPARγ in skin cancer, stable cell lines were created in the A431 human squamous cell carcinoma cell line. Expression of PPAR target genes was greatly enhanced in response to ligand activation of PPARß/δ or PPARγ in A431 cells expressing these receptors. PPARß/δ expression blocked the cell cycle at the G2/M phase, and this effect was increased by ligand activation. Ligand activation of PPARß/δ markedly inhibited clonogenicity as compared to vehicle-treated controls. Similarly, ligand activation of PPARγ in A431 cells expressing PPARγ resulted in reduced clonogenicity. Expression of either PPARß/δ or PPARγ markedly reduced tumor volume in ectopic xenografts, while ligand activation of these receptors had little further influence on tumor volume. Collectively, these studies demonstrate that stable expression and activation of PPARß/δ or PPARγ in A431 cells led to reduced tumorigenicity. Importantly, PPAR expression or ligand activation had major impacts on clonogenicity and/or tumor volume. Thus, PPARß/δ or PPARγ could be therapeutically targeted for the treatment of squamous cell carcinomas.

The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity.

Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult. Development of VNS delivery paradigms that reduce therapy duration and maximize efficacy would facilitate clinical translation. The goal of the current study was to determine whether primary auditory cortex (A1) plasticity can be generated more quickly by shortening the interval between VNS-tone pairing events or by delivering fewer VNS-tone pairing events. While shortening the inter-stimulus interval between VNS-tone pairing events resulted in significant A1 plasticity, reducing the number of VNS-tone pairing events failed to alter A1 responses. Additionally, shortening the inter-stimulus interval between VNS-tone pairing events failed to normalize neural and behavioral responses following acoustic trauma. Extending the interval between VNS-tone pairing events yielded comparable A1 frequency map plasticity to the standard protocol, but did so without increasing neural excitability. These results indicate that the duration of the VNS-event pairing session is an important parameter that can be adjusted to optimize neural plasticity for different clinical needs.

The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation.

BACKGROUND: Repeatedly pairing a tone with a brief burst of vagus nerve stimulation (VNS) results in a reorganization of primary auditory cortex (A1). The plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response to stimulation intensity, in which moderate intensity currents yield greater effects than low or high intensity currents. It is not known how other stimulation parameters effect the plasticity-enhancing effects of VNS. OBJECTIVE: We sought to investigate the effect of pulse-width and intensity on VNS efficacy. Here, we used the extent of plasticity induced by VNS-tone pairing to assess VNS efficacy. METHODS: Rats were exposed to a 9 kHz tone paired to VNS with varying current intensities and pulse widths. Cortical plasticity was measured as changes in the percent of area of primary auditory cortex responding to a range of sounds in VNS-treated rats relative to naïve rats. RESULTS: We find that a combination of low current intensity (200 µA) and short pulse duration (100 µs) is insufficient to drive cortical plasticity. Increasing the pulse duration to 500 µs results in a reorganization of receptive fields in A1 auditory cortex. The extent of plasticity engaged under these conditions is less than that driven by conditions previously reported to drive robust plasticity (800 µA with 100 µs wide pulses). CONCLUSION: These results suggest that the plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response of stimulation current that is influenced by pulse width. Furthermore, shorter pulse widths may offer a clinical advantage when determining optimal stimulation current. These findings may facilitate determination of optimal VNS parameters for clinical application.

Shank3-deficient rats exhibit degraded cortical responses to sound.

Individuals with SHANK3 mutations have severely impaired receptive and expressive language abilities. While brain responses are known to be abnormal in these individuals, the auditory cortex response to sound has remained largely understudied. In this study, we document the auditory cortex response to speech and non-speech sounds in the novel Shank3-deficient rat model. We predicted that the auditory cortex response to sounds would be impaired in Shank3-deficient rats. We found that auditory cortex responses were weaker in Shank3 heterozygous rats compared to wild-type rats. Additionally, Shank3 heterozygous responses had less spontaneous auditory cortex firing and were unable to respond well to rapid trains of noise bursts. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome. Autism Res 2018, 11: 59-68. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Individuals with SHANK3 mutations have severely impaired language abilities, yet the auditory cortex response to sound has remained largely understudied. In this study, we found that auditory cortex responses were weaker and were unable to respond well to rapid sounds in Shank3-deficient rats compared to control rats. The rat model of the auditory impairments in SHANK3 mutation could be used to test potential rehabilitation or drug therapies to improve the communication impairments observed in individuals with Phelan-McDermid syndrome.

Editor's Highlight: PPARß/δ and PPARγ Inhibit Melanoma Tumorigenicity by Modulating Inflammation and Apoptosis.

Skin tumorigenesis results from DNA damage, increased inflammation, and evasion of apoptosis. The peroxisome proliferator-activated receptors (PPARs) can modulate these mechanisms in non-melanoma skin cancer. However, limited data exists regarding the role of PPARs in melanoma. This study examined the effect of proliferator-activated receptor-ß/δ (PPARß/δ) and PPARγ on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the UACC903 human melanoma cell line. Stable overexpression of either PPARß/δ or PPARγ enhanced ligand-induced expression of a PPARß/δ/PPARγ target gene in UACC903 cell lines as compared with controls. The induction of target gene expression by ligand activation of PPARγ was not altered by overexpression of PPARß/δ, or vice versa. Stable overexpression of either PPARß/δ or PPARγ reduced the percentage of cells in the G1 and S phase of the cell cycle, and increased the percentage of cells in the G2/M phase of the cell cycle in UACC903 cell lines as compared with controls. Ligand activation of PPARß/δ did not further alter the distribution of cells within each phase of the cell cycle. By contrast, ligand activation of PPARγ enhanced these changes in stable UACC903 cells overexpressing PPARγ compared with controls. Stable overexpression of either PPARß/δ or PPARγ and/or ligand activation of either PPARß/δ or PPARγ inhibited cell proliferation, and anchorage-dependent clonogenicity of UACC903 cell lines as compared with controls. Further, overexpression of either PPARß/δ or PPARγ and/or ligand activation of either PPARß/δ or PPARγ inhibited ectopic xenograft tumorigenicity derived from UACC903 melanoma cells as compared with controls, and this was likely due in part to induction of apoptosis. Results from these studies demonstrate the antitumorigenic effects of both PPARß/δ and PPARγ and suggest that targeting these receptors may be useful for primary or secondary melanoma chemoprevention.

Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome.

Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial.

Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex.

The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (single acute injections of lipopolysaccharide, LPS, 10mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-signaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic α7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or - in wild-type animals - upon application sgp130Fc. Similar results were obtained by activating the "anti-inflammatory reflex" - a neural circuit regulating peripheral immune response - by stimulation of the vagal nerve or through peripheral administration of the α7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-signaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depression.

Lattice design challenges for fourth-generation storage-ring light sources.

Third-generation low-emittance storage-ring light sources based on double- and triple-bend cells and undulator magnets have been in operation around the world for more than two decades. On the horizon is a new generation based on the multi-bend achromat (MBA) lattice concept promising two to three orders of magnitude higher brightness than is available in today's sources. In this paper, the challenges inherent in designing MBA lattices, as well as potential solutions, are described. Topics covered include lattice concepts, scaling of storage-ring performance, brightness optimization, nonlinear dynamics, beam lifetime and injection schemes.