Faculty Bibliography

Auditory learning is associated with an enhanced representation of acoustic cues in primary auditory cortex, and modulation of inhibitory strength is causally involved in learning. If this inhibitory plasticity is associated with task learning and improvement, its expression should emerge and persist until task proficiency is achieved. We tested this idea by measuring changes to cortical inhibitory synaptic transmission as adult gerbils progressed through the process of associative learning and perceptual improvement. Using either of two procedures, aversive or appetitive conditioning, animals were trained to detect amplitude-modulated noise and then tested daily. Following each training session, a thalamocortical brain slice was generated, and inhibitory synaptic properties were recorded from layer 2/3 pyramidal neurons. Initial associative learning was accompanied by a profound reduction in the amplitude of spontaneous IPSCs (sIPSCs). However, sIPSC amplitude returned to control levels when animals reached asymptotic behavioral performance. In contrast, paired-pulse ratios decreased in trained animals as well as in control animals that experienced unpaired conditioned and unconditioned stimuli. This latter observation suggests that inhibitory release properties are modified during behavioral conditioning, even when an association between the sound and reinforcement cannot occur. These results suggest that associative learning is accompanied by a reduction of postsynaptic inhibitory strength that persists for several days during learning and perceptual improvement.

Synapses are plastic and can be modified by changes in spike timing. Whereas most studies of long-term synaptic plasticity focus on excitation, inhibitory plasticity may be critical for controlling information processing, memory storage, and overall excitability in neural circuits. Here we examine spike-timing-dependent plasticity (STDP) of inhibitory synapses onto layer 5 neurons in slices of mouse auditory cortex, together with concomitant STDP of excitatory synapses. Pairing pre- and postsynaptic spikes potentiated inhibitory inputs irrespective of precise temporal order within approximately 10 ms. This was in contrast to excitatory inputs, which displayed an asymmetrical STDP time window. These combined synaptic modifications both required NMDA receptor activation and adjusted the excitatory-inhibitory ratio of events paired with postsynaptic spiking. Finally, subthreshold events became suprathreshold, and the time window between excitation and inhibition became more precise. These findings demonstrate that cortical inhibitory plasticity requires interactions with co-activated excitatory synapses to properly regulate excitatory-inhibitory balance.

The epidermal growth factor receptor (EGFR) contributes to the pathogenesis of head&neck squamous cell carcinoma (HNSCC). However, only a subset of HNSCC patients benefit from anti-EGFR targeted therapy. By performing an unbiased proteomics screen, we found that the calcium-activated chloride channel ANO1 interacts with EGFR and facilitates EGFR-signaling in HNSCC. Using structural mutants of EGFR and ANO1 we identified the trans/juxtamembrane domain of EGFR to be critical for the interaction with ANO1. Our results show that ANO1 and EGFR form a functional complex that jointly regulates HNSCC cell proliferation. Expression of ANO1 affected EGFR stability, while EGFR-signaling elevated ANO1 protein levels, establishing a functional and regulatory link between ANO1 and EGFR. Co-inhibition of EGFR and ANO1 had an additive effect on HNSCC cell proliferation, suggesting that co-targeting of ANO1 and EGFR could enhance the clinical potential of EGFR-targeted therapy in HNSCC and might circumvent the development of resistance to single agent therapy. HNSCC cell lines with amplification and high expression of ANO1 showed enhanced sensitivity to Gefitinib, suggesting ANO1 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. Taken together, our results introduce ANO1 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC.

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation.

What is the best way to help humans adapt to a distorted sensory input? Interest in this question is more than academic. The answer may help facilitate auditory learning by people who became deaf after learning language and later received a cochlear implant (a neural prosthesis that restores hearing through direct electrical stimulation of the auditory nerve). There is evidence that some cochlear implants (which provide information that is spectrally degraded to begin with) stimulate neurons with higher characteristic frequency than the acoustic frequency of the original stimulus. In other words, the stimulus is shifted in frequency with respect to what the listener expects to hear. This frequency misalignment may have a negative influence on speech perception by CI users. However, a perfect frequency-place alignment may result in the loss of important low frequency speech information. A trade-off may involve a gradual approach: start with correct frequency-place alignment to allow listeners to adapt to the spectrally degraded signal first, and then gradually increase the frequency shift to allow them to adapt to it over time. We used an acoustic model of a cochlear implant to measure adaptation to a frequency-shifted signal, using either the gradual approach or the "standard" approach (sudden imposition of the frequency shift). Listeners in both groups showed substantial auditory learning, as measured by increases in speech perception scores over the course of fifteen one-hour training sessions. However, the learning process was faster for listeners who were exposed to the gradual approach. These results suggest that gradual rather than sudden exposure may facilitate perceptual learning in the face of a spectrally degraded, frequency-shifted input. This article is part of a Special Issue entitled .

OBJECTIVES/HYPOTHESIS: Trauma to intracochlear structures during cochlear implant insertion is associated with poorer hearing outcomes. One way surgeons can influence insertion trauma is by choosing the surgical approach. We seek to compare cochleostomy (CO), peri-round window (PRW), and round window (RW) approaches using a fresh frozen temporal bone model. STUDY DESIGN: Experiments using fresh frozen temporal bones. METHODS: Cochlear implant insertions using the three aforementioned approaches were performed on 15 fresh frozen human temporal bones using a Cochlear 422 electrode. Insertions were evaluated by examining fluoroscopic recordings of histologic sections. RESULTS: Five cochlear implant insertions were performed using each of the three aforementioned approaches. Fluoroscopic examination revealed that none of the CO or PRW insertions contacted the modiolus during insertion, whereas three of five RW insertions did. RW insertions were less linear during insertion when compared to CO and PRW insertions (P < .05). CO insertions had significantly larger angular depth of insertion (487 degrees ) when compared to PRW (413 degrees ) and RW (375 degrees ) (P < .05). Histologic examination revealed one RW insertion resulted in osseous spiral lamina fracture, whereas the remaining insertions had no evidence of trauma. In the damaged specimen, the inserted electrode was observed to rest in the scala vestibuli, whereas the remaining electrodes rested in the scala tympani. CONCLUSIONS: Due to variability in RW anatomy, a CO or PRW window surgical approach appears to minimize the risk for insertion trauma. However, with favorable anatomy, a Cochlear 422 electrode can be inserted with any of the three approaches. LEVEL OF EVIDENCE: NA Laryngoscope, 125:966-971, 2015.

PURPOSE OF REVIEW/OBJECTIVE:This article reviews recent information on outcomes, indications, techniques, and cost of transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). New information on comparisons between TORS, conventional surgery techniques, and chemoradiation is also highlighted. RECENT FINDINGS/RESULTS:Consistent with prior reports, recent studies show excellent oncologic and functional outcomes with TORS for OPSCC. As surgeon experience with this relatively new technique has increased, outcomes continue to improve and complications are rare. TORS may also have a role in management of carcinoma of unknown primary site. Compared with other treatment modalities, TORS for OPSCC may result in similar oncologic outcomes, improved functional outcomes, and decreased cost. SUMMARY/CONCLUSIONS:TORS for OPSCC results in excellent functional and oncologic outcomes. Randomized clinical trials are needed to compare TORS with adjuvant therapy to definitive chemoradiation and will determine whether adjuvant therapy and associated morbidity can be decreased without compromising survival.

OBJECTIVE: The American Thyroid Association (ATA) medullary thyroid cancer (MTC) guidelines group RET variants, in the setting of familial medullary thyroid cancer and multiple endocrine neoplasia type 2, into 4 classes of severity based on epidemiological data. The aim of this study was to determine if genotype correlates with phenotype in RET missense mutations. STUDY DESIGN: In silico mutational tolerance prediction. SETTING: Academic research hospital. SUBJECTS AND METHODS: We analyzed all RET variants currently listed in the ATA guidelines for the management of MTC using 2 computer-based (in silico) mutation tolerance prediction approaches: PolyPhen-2 HumVar and PolyPhen-2 HumDiv. Our analysis also included 27 different RET single-nucleotide polymorphisms resulting in missense variants. RESULTS: There was a statistically significant difference in the overall HumDiv score between ATA groups A and B (P = .025) and a statistically significant different HumVar score between benign polymorphisms and ATA group A (P = .023). Overall, RET variants associated with a less aggressive clinical phenotype generally had a lower Hum Div/Var score. CONCLUSIONS: Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C). In silico genetic analyses, with proper validation, may predict the phenotypic severity of RET variants, providing clinicians with a tool to aid clinical decision making in cases in which the RET variant is currently unknown or little epidemiological data are available.