Muscleblind1, but Not Dmpk or Six5, Contributes to a Complex Phenotype of Muscular and Motivational Deficits in Mouse Models of Myotonic Dystrophy

Assessment of molecular defects that underlie cognitive deficits observed in mendelian disorders provides a unique opportunity to identify key regulators of human cognition. Congenital Myotonic Dystrophy 1 (cDM1), a multi-system disorder is characterized by both cognitive deficits and a spectrum of behavioral abnormalities, which include visuo-spatial memory deficits, anxiety and apathy. Decreased levels of DMPK (Dystrophia Myotonica-protein kinase), SIX5, a transcription factor or MBNL1 (Muscleblind-like 1), an RNA splice regulator have been demonstrated to contribute to distinct features of cDM1. Mouse strains in which either Dmpk, Six5 or Mbnl1 are inactivated were therefore studied to determine the relative contribution of each gene to these cognitive functions. The open field and elevated plus maze tasks were used to examine anxiety, sucrose consumption was used to assess motivation, whereas the water maze and context fear conditioning were used to examine spatial learning and memory. Cognitive and behavioral abnormalities were observed only in Mbnl1 deficient mice, which demonstrate behavior consistent with motivational deficits in the Morris water maze, a complex visuo-spatial task and in the sucrose consumption test for anhedonia. All three models of cDM1 exhibit normal spatial learning and memory. These data identify MBNL1 as a potential regulator of emotional state with decreased MBNL1 levels underlying the motivational deficits observed in cDM1

Three New Outcome Measures That Tap Into Cognitive Processes Required for Real-Life Communication

To increase the ecological validity of outcomes from laboratory evaluations of hearing and hearing devices, it is desirable to introduce more realistic outcome measures in the laboratory. This article presents and discusses three outcome measures that have been designed to go beyond traditional speech-in-noise measures to better reflect realistic everyday challenges. The outcome measures reviewed are: the Sentence-final Word Identification and Recall (SWIR) test that measures working memory performance while listening to speech in noise at ceiling performance; a neural tracking method that produces a quantitative measure of selective speech attention in noise; and pupillometry that measures changes in pupil dilation to assess listening effort while listening to speech in noise. According to evaluation data, the SWIR test provides a sensitive measure in situations where speech perception performance might be unaffected. Similarly, pupil dilation has also shown sensitivity in situations where traditional speech-in-noise measures are insensitive. Changes in working memory capacity and effort mobilization were found at positive signal-to-noise ratios (SNR), that is, at SNRs that might reflect everyday situations. Using stimulus reconstruction, it has been demonstrated that neural tracking is a robust method at determining to what degree a listener is attending to a specific talker in a typical cocktail party situation. Using both established and commercially available noise reduction schemes, data have further shown that all three measures are sensitive to variation in SNR. In summary, the new outcome measures seem suitable for testing hearing and hearing devices under more realistic and demanding everyday conditions than traditional speech-in-noise tests.Funding Agencies|Oticon Foundation; EU H2020-ICT COCOHA (Cognitive Control of a Hearing Aid) [644732]; Swedish Research Council (Vetenskapsradet, Mekanismer och behandling vid aldersrelaterad horselnedsattning) [VR 2017-06092]; Linnaeus Centre HEAD excellence center grant [349-2007-8654]</p

Muscleblind1, but not Dmpk or Six5, contributes to a complex phenotype of muscular and motivational deficits in mouse models of myotonic dystrophy.

Assessment of molecular defects that underlie cognitive deficits observed in mendelian disorders provides a unique opportunity to identify key regulators of human cognition. Congenital Myotonic Dystrophy 1 (cDM1), a multi-system disorder is characterized by both cognitive deficits and a spectrum of behavioral abnormalities, which include visuo-spatial memory deficits, anxiety and apathy. Decreased levels of DMPK (Dystrophia Myotonica-protein kinase), SIX5, a transcription factor or MBNL1 (Muscleblind-like 1), an RNA splice regulator have been demonstrated to contribute to distinct features of cDM1. Mouse strains in which either Dmpk, Six5 or Mbnl1 are inactivated were therefore studied to determine the relative contribution of each gene to these cognitive functions. The open field and elevated plus maze tasks were used to examine anxiety, sucrose consumption was used to assess motivation, whereas the water maze and context fear conditioning were used to examine spatial learning and memory. Cognitive and behavioral abnormalities were observed only in Mbnl1 deficient mice, which demonstrate behavior consistent with motivational deficits in the Morris water maze, a complex visuo-spatial task and in the sucrose consumption test for anhedonia. All three models of cDM1 exhibit normal spatial learning and memory. These data identify MBNL1 as a potential regulator of emotional state with decreased MBNL1 levels underlying the motivational deficits observed in cDM1

Effects of Hearing Aid Noise Reduction on Early and Late Cortical Representations of Competing Talkers in Noise

Objectives Previous research using non-invasive (magnetoencephalography, MEG) and invasive (electrocorticography, ECoG) neural recordings has demonstrated the progressive and hierarchical representation and processing of complex multi-talker auditory scenes in the auditory cortex. Early responses (&amp;lt;85 ms) in primary-like areas appear to represent the individual talkers with almost equal fidelity and are independent of attention in normal-hearing (NH) listeners. However, late responses (&amp;gt;85 ms) in higher-order non-primary areas selectively represent the attended talker with significantly higher fidelity than unattended talkers in NH and hearing-impaired (HI) listeners. Motivated by these findings, the objective of this study was to investigate the effect of a noise reduction scheme (NR) in a commercial hearing aid (HA) on the representation of complex multi-talker auditory scenes in distinct hierarchical stages of the auditory cortex by using high-density electroencephalography (EEG). Design We addressed this issue by investigating early (&amp;lt;85 ms) and late (&amp;gt;85 ms) EEG responses recorded in 34 HI subjects fitted with HAs. The HA noise reduction (NR) was either on or off while the participants listened to a complex auditory scene. Participants were instructed to attend to one of two simultaneous talkers in the foreground while multi-talker babble noise played in the background (+3 dB SNR). After each trial, a two-choice question about the content of the attended speech was presented. Results Using a stimulus reconstruction approach, our results suggest that the attention-related enhancement of neural representations of target and masker talkers located in the foreground, as well as suppression of the background noise in distinct hierarchical stages is significantly affected by the NR scheme. We found that the NR scheme contributed to the enhancement of the foreground and of the entire acoustic scene in the early responses, and that this enhancement was driven by better representation of the target speech. We found that the target talker in HI listeners was selectively represented in late responses. We found that use of the NR scheme resulted in enhanced representations of the target and masker speech in the foreground and a suppressed representation of the noise in the background in late responses. We found a significant effect of EEG time window on the strengths of the cortical representation of the target and masker. Conclusion Together, our analyses of the early and late responses obtained from HI listeners support the existing view of hierarchical processing in the auditory cortex. Our findings demonstrate the benefits of a NR scheme on the representation of complex multi-talker auditory scenes in different areas of the auditory cortex in HI listeners

Neural Representation Enhanced for Speech and Reduced for Background Noise With a Hearing Aid Noise Reduction Scheme During a Selective Attention Task

Objectives Selectively attending to a target talker while ignoring multiple interferers (competing talkers and background noise) is more difficult for hearing-impaired (HI) individuals compared to normal-hearing (NH) listeners. Such tasks also become more difficult as background noise levels increase. To overcome these difficulties, hearing aids (HAs) offer noise reduction (NR) schemes. The objective of this study was to investigate the effect of NR processing (inactive, where the NR feature was switched off,vs.active, where the NR feature was switched on) on the neural representation of speech envelopes across two different background noise levels [+3 dB signal-to-noise ratio (SNR) and +8 dB SNR] by using a stimulus reconstruction (SR) method. Design To explore how NR processing supports the listeners selective auditory attention, we recruited 22 HI participants fitted with HAs. To investigate the interplay between NR schemes, background noise, and neural representation of the speech envelopes, we used electroencephalography (EEG). The participants were instructed to listen to a target talker in front while ignoring a competing talker in front in the presence of multi-talker background babble noise. Results The results show that the neural representation of the attended speech envelope was enhanced by the active NR scheme for both background noise levels. The neural representation of the attended speech envelope at lower (+3 dB) SNR was shifted, approximately by 5 dB, toward the higher (+8 dB) SNR when the NR scheme was turned on. The neural representation of the ignored speech envelope was modulated by the NR scheme and was mostly enhanced in the conditions with more background noise. The neural representation of the background noise was modulated (i.e., reduced) by the NR scheme and was significantly reduced in the conditions with more background noise. The neural representation of the net sum of the ignored acoustic scene (ignored talker and background babble) was not modulated by the NR scheme but was significantly reduced in the conditions with a reduced level of background noise. Taken together, we showed that the active NR scheme enhanced the neural representation of both the attended and the ignored speakers and reduced the neural representation of background noise, while the net sum of the ignored acoustic scene was not enhanced. Conclusion Altogether our results support the hypothesis that the NR schemes in HAs serve to enhance the neural representation of speech and reduce the neural representation of background noise during a selective attention task. We contend that these results provide a neural index that could be useful for assessing the effects of HAs on auditory and cognitive processing in HI populations

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field