Estrogens rapidly shape synaptic and intrinsic properties to regulate the temporal precision of songbird auditory neurons.

Sensory neurons parse millisecond-variant sound streams like birdsong and speech with exquisite precision. The auditory pallial cortex of vocal learners like humans and songbirds contains an unconventional neuromodulatory system: neuronal expression of the estrogen synthesis enzyme aromatase. Local forebrain neuroestrogens fluctuate when songbirds hear a song, and subsequently modulate bursting, gain, and temporal coding properties of auditory neurons. However, the way neuroestrogens shape intrinsic and synaptic properties of sensory neurons remains unknown. Here, using a combination of whole-cell patch clamp electrophysiology and calcium imaging, we investigate estrogenic neuromodulation of auditory neurons in a region resembling mammalian auditory association cortex. We found that estradiol rapidly enhances the temporal precision of neuronal firing via a membrane-bound G-protein coupled receptor and that estradiol rapidly suppresses inhibitory synaptic currents while sparing excitation. Notably, the rapid suppression of intrinsic excitability by estradiol was predicted by membrane input resistance and was observed in both males and females. These findings were corroborated by analysis of in vivo electrophysiology recordings, in which local estrogen synthesis blockade caused acute disruption of the temporal correlation of song-evoked firing patterns. Therefore, on a modulatory timescale, neuroestrogens alter intrinsic cellular properties and inhibitory neurotransmitter release to regulate the temporal precision of higher-order sensory neurons.

Consensus statement on smoking cessation in patients with pain.

Smoking is closely associated with the development of various cancers and tobacco-related illnesses such as cardiovascular and respiratory disorders. However, data are scarce on the relationship between smoking and both acute and chronic pain. In addition to nicotine, tobacco smoke contains more than 4000 different compounds. Although nicotine is not the sole cause of smoking-induced diseases, it plays a critical role in pain-related pathophysiology. Despite the acute analgesic effects of nicotine, long-term exposure leads to tolerance and increased pain sensitivity due to nicotinic acetylcholine receptor desensitization and neuronal plastic changes. The purpose of smoking cessation interventions in smoking patients with pain is primarily not only to reduce their pain and associated limitations in activities of daily living, but also to improve the outcomes of underlying pain-causing conditions and reduce the risks of tobacco-related disorders. This statement aims to summarize the available evidence on the impact of smoking on pain and to inform medical professionals of the significance of smoking cessation in patients with pain.

Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain).

We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.

A retrospective observational cohort study investigating the association between acute kidney injury and all-cause mortality among patients undergoing endovascular repair of abdominal aortic aneurysms.

BACKGROUND: Acute kidney injury (AKI) has been found to be associated with short- and long-term mortality and morbidity in various clinical settings. However, it is unknown whether AKI after endovascular repair of abdominal aortic aneurysms (EVAR) is associated with postoperative mortality. METHODS: This observational study analyzed patients who underwent EVAR. The primary outcome was all-cause mortality. The outcomes of patients with and without postoperative AKI were compared using the Kaplan-Meier method and log-rank test. Factors with P < 0.05 on the univariate analysis were entered into the multivariate Cox regression model. Predictors of AKI were also determined using Cox univariate and multivariate analysis. The identified predictors of AKI were excluded from multivariate analysis for all-cause mortality because these factors could intermediate outcome. RESULTS: There were 490 eligible patients. After a follow-up of 28.3 (16.8) months [mean (standard deviation)], 62 patients (12.7%) died. AKI occurred in 59 patients (12.0%). AKI was found by the log-rank test to be associated with a significant increase of all-cause mortality (P < 0.001). Preoperative estimated glomerular filtration rate, preoperative peripheral vascular disease, and emergency surgery were found to be independent predictors of AKI and these variables were excluded from the main analysis. Multivariate analysis showed AKI [hazard ratio (HR) = 1.19, 95% confidence interval (CI) 1.01-3.60, P = 0.045] and transfusion (HR = 1.05, 95% CI 1.01-1.09, P = 0.011) were independent predictors of mortality. CONCLUSIONS: In the present study, AKI and transfusion were associated with significant increases in all-cause mortality after EVAR.

Temporal plasticity involved in recovery from manual dexterity deficit after motor cortex lesion in macaque monkeys.

The question of how intensive motor training restores motor function after brain damage or stroke remains unresolved. Here we show that the ipsilesional ventral premotor cortex (PMv) and perilesional primary motor cortex (M1) of rhesus macaque monkeys are involved in the recovery of manual dexterity after a lesion of M1. A focal lesion of the hand digit area in M1 was made by means of ibotenic acid injection. This lesion initially caused flaccid paralysis in the contralateral hand but was followed by functional recovery of hand movements, including precision grip, during the course of daily postlesion motor training. Brain imaging of regional cerebral blood flow by means of H2 (15)O-positron emission tomography revealed enhanced activity of the PMv during the early postrecovery period and increased functional connectivity within M1 during the late postrecovery period. The causal role of these areas in motor recovery was confirmed by means of pharmacological inactivation by muscimol during the different recovery periods. These findings indicate that, in both the remaining primary motor and premotor cortical areas, time-dependent plastic changes in neural activity and connectivity are involved in functional recovery from the motor deficit caused by the M1 lesion. Therefore, it is likely that the PMv, an area distant from the core of the lesion, plays an important role during the early postrecovery period, whereas the perilesional M1 contributes to functional recovery especially during the late postrecovery period.

Acute inhibition of a cortical motor area impairs vocal control in singing zebra finches.

Genetically targeted approaches that permit acute and reversible manipulation of neuronal circuit activity have enabled an unprecedented understanding of how discrete neuronal circuits control animal behavior. Zebra finch singing behavior has emerged as an excellent model for studying neuronal circuit mechanisms underlying the generation and learning of behavioral motor sequences. We employed a newly developed, reversible, neuronal silencing system in zebra finches to test the hypothesis that ensembles of neurons in the robust nucleus of the arcopallium (RA) control the acoustic structure of specific song parts, but not the timing nor the order of song elements. Subunits of an ivermectin-gated chloride channel were expressed in a subset of RA neurons, and ligand administration consistently suppressed neuronal excitability. Suppression of activity in a group of RA neurons caused the birds to sing songs with degraded elements, although the order of song elements was unaffected. Furthermore some syllables disappeared in the middle or at the end of song motifs. Thus, our data suggest that generation of specific song parts is controlled by a subset of RA neurons, whereas elements order coordination and timing of whole songs are controlled by a higher premotor area.

Bidirectional plasticity in fast-spiking GABA circuits by visual experience.

Experience-dependent plasticity in the brain requires balanced excitation-inhibition. How individual circuit elements contribute to plasticity outcome in complex neocortical networks remains unknown. Here we report an intracellular analysis of ocular dominance plasticity-the loss of acuity and cortical responsiveness for an eye deprived of vision in early life. Unlike the typical progressive loss of pyramidal-cell bias, direct recording from fast-spiking cells in vivo reveals a counterintuitive initial shift towards the occluded eye followed by a late preference for the open eye, consistent with a spike-timing-dependent plasticity rule for these inhibitory neurons. Intracellular pharmacology confirms a dynamic switch of GABA (gamma-aminobutyric acid) impact to pyramidal cells following deprivation in juvenile mice only. Together these results suggest that the bidirectional recruitment of an initially binocular GABA circuit may contribute to experience-dependent plasticity in the developing visual cortex.

A Retrospective Examination of the Efficacy of Paravertebral Block for Patients Requiring Intraoperative High-Dose Unfractionated Heparin Administration During Thoracoabdominal Aortic Aneurysm Repair.

OBJECTIVE: Postoperative respiratory complications are serious and frequently observed among patients who undergo thoracoabdominal aortic aneurysm (TAAA) repair. Paravertebral block (PVB) can provide effective analgesia for relief of postoperative thoracotomy pain and may reduce respiratory complications. However, the impact of PVB on postoperative pain and respiratory function in patients who undergo TAAA repair requiring intraoperative high-dose heparin administration is unknown. This study examined the efficacy of PVB on postoperative pain and respiratory function after TAAA repairs. DESIGN: Retrospective, observational cohort study. SETTING: Single center in Japan. PARTICIPANTS: Fifty-eight consecutive patients who underwent TAAA repair from March 2013 to October 2014. INTERVENTIONS: Application of thoracic PVB. MEASUREMENT AND MAIN RESULTS: A total of 56 patients were analyzed. Two patients were excluded because 1 patient was dead within 24 hours after surgery and 1 patient was 9 years old. Patients with PVB were defined as group P (n = 17), and patients without PVB as group C (n = 39). There was no significant difference in baseline characteristics between the 2 groups. Both postoperative pain at rest and postoperative pain while coughing were assessed using a numeric rating scale (NRS); the incidence of reintubation and noninvasive positive-pressure ventilation (NPPV) also were compared between the 2 groups. The NRS score of postoperative pain at rest was significantly lower in group P (group P: Median 2, interquartile range 1 to 3; group C: Median 6, interquartile range 5 to 7; p = 0.000), and the NRS score of postoperative pain while coughing was significantly lower in group P (group P: Median 5, interquartile range 3.5 to 6.5; group C: Median 8, interquartile range 7 to 10; p = 0.000). Reintubation rate was significantly lower in group P (group P: 0%, group C: 23%, p = 0.045); the incidences of NPPV (group P: 12%, group C: 46%, p = 0.016) and postoperative pneumonia were significantly lower in group P (group P: 0%, group C: 28%, p = 0.024). CONCLUSIONS: PVB significantly reduced postoperative pain at rest and while coughing and significantly reduced the reintubation rate, the rate of NPPV use, and postoperative pneumonia without complications. PVB could be a safe and an effective analgesic method that reduces postoperative respiratory exacerbation in patients who undergo TAAA repair.

Transient sensorimotor projections in the developmental song learning period.

Memory recall and guidance are essential for motor skill acquisition. Like humans learning to speak, male zebra finches learn to sing by first memorizing and then matching their vocalization to the tutor's song (TS) during specific developmental periods. Yet, the neuroanatomical substrate supporting auditory-memory-guided sensorimotor learning has remained elusive. Here, using a whole-brain connectome analysis with activity-dependent viral expression, we identified a transient projection into the motor region, HVC, from neuronal ensembles responding to TS in the auditory forebrain, the caudomedial nidopallium (NCM), in juveniles. Virally induced cell death of the juvenile, but not adult, TS-responsive NCM neurons impaired song learning. Moreover, isolation, which delays closure of the sensory, but not the motor, learning period, did not affect the decrease of projections into the HVC from the NCM TS-responsive neurons after the song learning period. Taken together, our results suggest that dynamic axonal pruning may regulate timely auditory-memory-guided vocal learning during development.

Effects of early versus late rehabilitative training on manual dexterity after corticospinal tract lesion in macaque monkeys.

Dexterous hand movements can be restored with motor rehabilitative training after a lesion of the lateral corticospinal tract (l-CST) in macaque monkeys. To maximize effectiveness, the optimal time to commence such rehabilitative training must be determined. We conducted behavioral analyses and compared the recovery of dexterous hand movements between monkeys in which hand motor training was initiated immediately after the l-CST lesion (early-trained monkeys) and those in which training was initiated 1 mo after the lesion (late-trained monkeys). The performance of dexterous hand movements was evaluated by food retrieval tasks. In early-trained monkeys, performance evaluated by the success rate in a vertical slit task (retrieval of a small piece of food through a narrow vertical slit) recovered to the level of intact monkeys during the first 1-2 mo after the lesion. In late-trained monkeys, the task success rate averaged ∼30% even after 3 mo of rehabilitative training. We also evaluated hand performance with the Klüver board task, in which monkeys retrieved small spherical food pellets from cylindrical wells. Although the success rate of the Klüver board task did not differ between early- and late-trained monkeys, kinematic movement analysis showed that there was a difference between the groups: late-trained monkeys with an improved success rate frequently used alternate movement strategies that were different from those used before the lesion. These results suggest that early rehabilitative training after a spinal cord lesion positively influences subsequent functional recovery.

Successful treatment with spinal cord stimulation for pain due to eosinophilic granulomatosis with polyangiitis: a case report.

BACKGROUND: Although most patients of eosinophilic granulomatosis with polyangiitis (EGPA) experience a reduction in pain within several weeks to months of the initiation of immunotherapies, some suffer from residual neuropathic symptoms for a long time. CASE PRESENTATION: A 28-year-old woman diagnosed with EGPA visited. She had been treated with steroid pulse therapy, intravenous immunoglobulin, and mepolizumab (antiinterleukin-5 agent). Her symptoms other than peripheral neuropathy improved, but posterior lower thigh pain and weakness of the lower legs worsened. At the initial visit, she used crutches and complained of numb pain in both posterior lower thighs, especially the left one. She also presented with left foot drop and reported a decreased tactile sensation on the lateral sides of both lower thighs. We performed spinal cord stimulation (SCS) at the L1 level on both sides. Her pain remarkably decreased, her tactile sensation improved, her muscle strength increased, and she was able to walk without crutches. CONCLUSIONS: We herein report the first case of lower extremity pain being successfully treated with SCS in an EGPA patient who did not respond well to drug therapy. Because the cause of pain in EGPA is neuropathy induced by vasculitis, there is ample ability for SCS to improve this pain. When pain is neuropathic, whatever the cause, SCS may be worth trying, even for pain from disorders other than EGPA.

Neural circuit for social authentication in song learning.

Social interactions are essential when learning to communicate. In human speech and bird song, infants must acquire accurate vocalization patterns and learn to associate them with live tutors and not mimetic sources. However, the neural mechanism of social reality during vocal learning remains unknown. Here, we characterize a neural circuit for social authentication in support of accurate song learning in the zebra finch. We recorded neural activity in the attention/arousal state control center, the locus coeruleus (LC), of juvenile birds during song learning from a live adult tutor. LC activity increased with real, not artificial, social information during learning that enhanced the precision and robustness of the learned song. During live social song learning, LC activity regulated long-term song-selective neural responsiveness in an auditory memory region, the caudomedial nidopallium (NCM). In accord, optogenetic inhibition of LC presynaptic signaling in the NCM reduced NCM neuronal responsiveness to live tutor singing and impaired song learning. These results demonstrate that the LC-NCM neural circuit integrates sensory evidence of real social interactions, distinct from song acoustic features, to authenticate song learning. The findings suggest a general mechanism for validating social information in brain development.

Genetically identified neurons in avian auditory pallium mirror core principles of their mammalian counterparts.

In vertebrates, advanced cognitive abilities are typically associated with the telencephalic pallium. In mammals, the pallium is a layered mixture of excitatory and inhibitory neuronal populations with distinct molecular, physiological, and network phenotypes. This cortical architecture is proposed to support efficient, high-level information processing. Comparative perspectives across vertebrates provide a lens to understand the common features of pallium that are important for advanced cognition. Studies in songbirds have established strikingly parallel features of neuronal types between mammalian and avian pallium. However, lack of genetic access to defined pallial cell types in non-mammalian vertebrates has hindered progress in resolving connections between molecular and physiological phenotypes. A definitive mapping of the physiology of pallial cells onto their molecular identities in birds is critical for understanding how synaptic and computational properties depend on underlying molecular phenotypes. Using viral tools to target excitatory versus inhibitory neurons in the zebra finch auditory association pallium (calmodulin-dependent kinase alpha [CaMKIIα] and glutamate decarboxylase 1 [GAD1] promoters, respectively), we systematically tested predictions derived from mammalian pallium. We identified two genetically distinct neuronal populations that exhibit profound physiological and computational similarities with mammalian excitatory and inhibitory pallial cells, definitively aligning putative cell types in avian caudal nidopallium with these molecular identities. Specifically, genetically identified CaMKIIα and GAD1 cell types in avian auditory association pallium exhibit distinct intrinsic physiological parameters, distinct auditory coding principles, and inhibitory-dependent pallial synchrony, gamma oscillations, and local suppression. The retention, or convergence, of these molecular and physiological features in both birds and mammals clarifies the characteristics of pallial circuits for advanced cognitive abilities.

Photochemistry of linear-shaped phenylacetylenyl- and (phenylacetylenyl)phenylacetylenyl-substituted aromatic enediynes.

The series of linear-shaped phenylacetylenyl- and (phenylacetylenyl)phenylacetylenyl-substituted aromatic enediynes 1-3 were synthesized as pure trans and cis isomers and their photochemistry explored. With expansion of the π-electron system, the absorption spectra red-shifted and the molar extinction coefficients dramatically increased up to 122000 M(-1) cm(-1) for trans-3. The absorption spectra of cis-2 and cis-3 consisted of two independent absorption bands. The fluorescence quantum yields of the molecules were high, even for the cis isomers (Φ(f) = 0.39-0.61). The fluorescence decay of each of the compounds was analyzed as a single exponential and the wavelength dependence of time constants was not observed, indicating a single emitting state in all cases. All isomers exhibited mutual cis-trans photoisomerization. The quantum yield of both trans-to-cis and cis-to-trans photoisomerization considerably decreased in 2 and 3, presumably due to an increased number of photochemical processes that yield nonreactive excited species and which result in nonradiative deactivation. Three energy minima exist in the excited triplet state, where the energy of planar conformation decreased with the extension of the phenyl acetylenyl chain, resulting in the promotion of nonradiative processes without conformational change.

Early Auditory Experience Modifies Neuronal Firing Properties in the Zebra Finch Auditory Cortex.

Songbirds learn to sing much as humans learn to speak. In zebra finches, one of the premier songbird models, males learn to sing for later courtship through a multistep learning process during the developmental period. They first listen to and memorize the song of a tutor (normally their father) during the sensory learning period. Then, in the subsequent sensory-motor learning phase (with large overlap), they match their vocalizations to the memorized tutor song via auditory feedback and develop their own unique songs, which they maintain throughout their lives. Previous studies have suggested that memories of tutor songs are shaped in the caudomedial nidopallium (NCM) of the brain, which is analogous to the mammalian higher auditory cortex. Isolation during development, which extends the sensory learning period in males, alters song preference in adult females, and NCM inactivation decreases song preference. However, the development of neurophysiological properties of neurons in this area and the effect of isolation on these neurons have not yet been explained. Here, we performed whole-cell patch-clamp recording on NCM neurons from juvenile zebra finches during the sensory learning period, 20, 40, or 60 days post-hatching (DPH) and examined their neurophysiological properties. In contrast to previous reports in adult NCM neurons, the majority of NCM neurons of juvenile zebra finches showed spontaneous firing with or without burst firing patterns, and the percentage of neurons that fired increased in the middle of the sensory learning period (40 DPH) and then decreased at the end (60 DPH) in both males and females. We further found that auditory isolation from tutor songs alters developmental changes in the proportions of firing neurons both in males and females, and also changes those of burst neurons differently between males that sing and females that do not. Taken together, these findings suggest that NCM neurons develop their neurophysiological properties depending on auditory experiences during the sensory song learning period, which underlies memory formation for song learning in males and song discrimination in females.

Neuronal mechanisms regulating the critical period of sensory experience-dependent song learning.

Neuronal circuits are intensively shaped depending on experiences received during developmental critical periods. How neuronal circuits are sculpted can even affect the later development of higher cognitive functions, such as vocal communication skills. Here, we propose songbirds that learn to sing from early auditory experiences as a model for understanding the neuronal mechanisms underlying the development of multistep vocal learning. By applying the principal concepts of neuronal mechanisms for regulating the timing of critical periods, which have been well investigated by using experience-dependent mammalian cortical plasticity, we review our current understanding of the underlying neuronal mechanism of the song-learning critical period.

Social interaction with a tutor modulates responsiveness of specific auditory neurons in juvenile zebra finches.

Behavioral states of animals, such as observing the behavior of a conspecific, modify signal perception and/or sensations that influence state-dependent higher cognitive behavior, such as learning. Recent studies have shown that neuronal responsiveness to sensory signals is modified when animals are engaged in social interactions with others or in locomotor activities. However, how these changes produce state-dependent differences in higher cognitive function is still largely unknown. Zebra finches, which have served as the premier songbird model, learn to sing from early auditory experiences with tutors. They also learn from playback of recorded songs however, learning can be greatly improved when song models are provided through social communication with tutors (Eales, 1989; Chen et al., 2016). Recently we found a subset of neurons in the higher-level auditory cortex of juvenile zebra finches that exhibit highly selective auditory responses to the tutor song after song learning, suggesting an auditory memory trace of the tutor song (Yanagihara and Yazaki-Sugiyama, 2016). Here we show that auditory responses of these selective neurons became greater when juveniles were paired with their tutors, while responses of non-selective neurons did not change. These results suggest that social interaction modulates cortical activity and might function in state-dependent song learning.

Neuronal and microglial localization of secreted phosphoprotein 1 (osteopontin) in intact and damaged motor cortex of macaques.

We previously reported that mRNA encoding secreted phosphoprotein 1 (SPP1), also known as osteopontin, is preferentially expressed in large neurons in layer V of the macaque motor cortex, most of which are presumed to be corticospinal tract neurons. As a first step to elucidating the cellular function of SPP1 in macaque neurons, we examined the localization of SPP1 in the primary motor cortex (M1) of the macaque by using immunohistochemistry. SPP1 immunoreactivity was found to be localized in the cell bodies of neurons, but not outside the cells, indicating that SPP1 was not secreted from these neurons. The results of electron microscope analysis and double-labeling analysis with marker proteins suggested that SPP1 was localized in the mitochondria of neurons. The distributions of SPP1 in the neurons corresponded to those of integrin αV, a putative receptor for SPP1. The distribution of SPP1 was also investigated in macaques whose M1 had been lesioned. We found that SPP1 was secreted by proliferated microglia in the lesioned area. Double-labeling analysis indicated that SPP1 immunoreactivity in the microglia was colocalized with CD44, another putative receptor for SPP1. Success rates in the small-object-retrieval task were positively correlated with SPP1 immunoreactivity in the neurons in the perilesional area. SPP1 has multiple roles in the macaque motor cortex, and it may be a key protein during recovery of hand movement after brain damage.

Auditory experience-dependent cortical circuit shaping for memory formation in bird song learning.

As in human speech acquisition, songbird vocal learning depends on early auditory experience. During development, juvenile songbirds listen to and form auditory memories of adult tutor songs, which they use to shape their own vocalizations in later sensorimotor learning. The higher-level auditory cortex, called the caudomedial nidopallium (NCM), is a potential storage site for tutor song memory, but no direct electrophysiological evidence of tutor song memory has been found. Here, we identify the neuronal substrate for tutor song memory by recording single-neuron activity in the NCM of behaving juvenile zebra finches. After tutor song experience, a small subset of NCM neurons exhibit highly selective auditory responses to the tutor song. Moreover, blockade of GABAergic inhibition, and sleep decrease their selectivity. Taken together, these results suggest that experience-dependent recruitment of GABA-mediated inhibition shapes auditory cortical circuits, leading to sparse representation of tutor song memory in auditory cortical neurons.