Nucleus accumbens dopamine release reflects the selective nature of pair bonds.

In monogamous species, prosocial behaviors directed toward partners are dramatically different from those directed toward unknown individuals and potential threats. Dopamine release in the nucleus accumbens has a well-established role in social reward and motivation, but how this mechanism may be engaged to drive the highly divergent social behaviors directed at a partner or unfamiliar conspecific remains unknown. Using monogamous prairie voles, we first employed receptor pharmacology in partner preference and social operant tasks to show that dopamine is critical for the appetitive drive for social interaction but not for low-effort, unconditioned consummatory behaviors. We then leveraged the subsecond temporal resolution of the fluorescent biosensor, GRABDA, to ask whether differential dopamine release might distinguish between partner and novel social access and interaction. We found that partner seeking, anticipation, and interaction resulted in more accumbal dopamine release than the same events directed toward a novel vole. Further, partner-associated dopamine release decreased after prolonged partner separation. Our results are consistent with a model in which dopamine signaling plays a prominent role in the appetitive aspects of social interactions. Within this framework, differences in partner- and novel-associated dopamine release reflect the selective nature of pair bonds and may drive the partner- and novel-directed social behaviors that reinforce and cement bonds over time. This provides a potential mechanism by which highly conserved reward systems can enable selective, species-appropriate social behaviors.

Potentiation of cholinergic and corticofugal inputs to the lateral amygdala in threat learning.

The amygdala, cholinergic basal forebrain, and higher-order auditory cortex (HO-AC) regulate brain-wide plasticity underlying auditory threat learning. Here, we perform multi-regional extracellular recordings and optical measurements of acetylcholine (ACh) release to characterize the development of discriminative plasticity within and between these brain regions as mice acquire and recall auditory threat memories. Spiking responses are potentiated for sounds paired with shock (CS+) in the lateral amygdala (LA) and optogenetically identified corticoamygdalar projection neurons, although not in neighboring HO-AC units. Spike- or optogenetically triggered local field potentials reveal enhanced corticofugal-but not corticopetal-functional coupling between HO-AC and LA during threat memory recall that is correlated with pupil-indexed memory strength. We also note robust sound-evoked ACh release that rapidly potentiates for the CS+ in LA but habituates across sessions in HO-AC. These findings highlight a distributed and cooperative plasticity in LA inputs as mice learn to reappraise neutral stimuli as possible threats.

Potentiated cholinergic and corticofugal inputs support reorganized sensory processing in the basolateral amygdala during auditory threat acquisition and retrieval.

Reappraising neutral stimuli as environmental threats reflects rapid and discriminative changes in sensory processing within the basolateral amygdala (BLA). To understand how BLA inputs are also reorganized during discriminative threat learning, we performed multi-regional measurements of acetylcholine (ACh) release, single unit spiking, and functional coupling in the mouse BLA and higher-order auditory cortex (HO-AC). During threat memory recall, sounds paired with shock (CS+) elicited relatively higher firing rates in BLA units and optogenetically targeted corticoamygdalar (CAmy) units, though not in neighboring HO-AC units. Functional coupling was potentiated for descending CAmy projections prior to and during CS+ threat memory recall but ascending amygdalocortical coupling was unchanged. During threat acquisition, sound-evoked ACh release was selectively enhanced for the CS+ in BLA but not HO-AC. These findings suggest that phasic cholinergic inputs facilitate discriminative plasticity in the BLA during threat acquisition that is subsequently reinforced through potentiated auditory corticofugal inputs during memory recall.

Neural signatures of auditory hypersensitivity following acoustic trauma.

Neurons in sensory cortex exhibit a remarkable capacity to maintain stable firing rates despite large fluctuations in afferent activity levels. However, sudden peripheral deafferentation in adulthood can trigger an excessive, non-homeostatic cortical compensatory response that may underlie perceptual disorders including sensory hypersensitivity, phantom limb pain, and tinnitus. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic two-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of spatially diffuse hyperactivity, hyper-correlation, and auditory hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles also displayed hypersensitive decoding of spared mid-frequency tones that mirrored behavioral hypersensitivity, suggesting that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may be an underlying source of auditory hypersensitivity. Excess cortical response gain after acoustic trauma was expressed heterogeneously among individual PyrNs, yet 40% of this variability could be accounted for by each cell's baseline response properties prior to acoustic trauma. PyrNs with initially high spontaneous activity and gradual monotonic intensity growth functions were more likely to exhibit non-homeostatic excess gain after acoustic trauma. This suggests that while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where indicators of reduced inhibition can presage pathological hyperactivity following sensorineural hearing loss.

A functional topography within the cholinergic basal forebrain for encoding sensory cues and behavioral reinforcement outcomes.

Basal forebrain cholinergic neurons (BFCNs) project throughout the cortex to regulate arousal, stimulus salience, plasticity, and learning. Although often treated as a monolithic structure, the basal forebrain features distinct connectivity along its rostrocaudal axis that could impart regional differences in BFCN processing. Here, we performed simultaneous bulk calcium imaging from rostral and caudal BFCNs over a 1-month period of variable reinforcement learning in mice. BFCNs in both regions showed equivalently weak responses to unconditioned visual stimuli and anticipated rewards. Rostral BFCNs in the horizontal limb of the diagonal band were more responsive to reward omission, more accurately classified behavioral outcomes, and more closely tracked fluctuations in pupil-indexed global brain state. Caudal tail BFCNs in globus pallidus and substantia innominata were more responsive to unconditioned auditory stimuli, orofacial movements, aversive reinforcement, and showed robust associative plasticity for punishment-predicting cues. These results identify a functional topography that diversifies cholinergic modulatory signals broadcast to downstream brain regions.

Behavioral Approaches to Study Top-Down Influences on Active Listening.

The massive network of descending corticofugal projections has been long-recognized by anatomists, but their functional contributions to sound processing and auditory-guided behaviors remain a mystery. Most efforts to characterize the auditory corticofugal system have been inductive; wherein function is inferred from a few studies employing a wide range of methods to manipulate varying limbs of the descending system in a variety of species and preparations. An alternative approach, which we focus on here, is to first establish auditory-guided behaviors that reflect the contribution of top-down influences on auditory perception. To this end, we postulate that auditory corticofugal systems may contribute to active listening behaviors in which the timing of bottom-up sound cues can be predicted from top-down signals arising from cross-modal cues, temporal integration, or self-initiated movements. Here, we describe a behavioral framework for investigating how auditory perceptual performance is enhanced when subjects can anticipate the timing of upcoming target sounds. Our first paradigm, studied both in human subjects and mice, reports species-specific differences in visually cued expectation of sound onset in a signal-in-noise detection task. A second paradigm performed in mice reveals the benefits of temporal regularity as a perceptual grouping cue when detecting repeating target tones in complex background noise. A final behavioral approach demonstrates significant improvements in frequency discrimination threshold and perceptual sensitivity when auditory targets are presented at a predictable temporal interval following motor self-initiation of the trial. Collectively, these three behavioral approaches identify paradigms to study top-down influences on sound perception that are amenable to head-fixed preparations in genetically tractable animals, where it is possible to monitor and manipulate particular nodes of the descending auditory pathway with unparalleled precision.

Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis.

The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

Visual Memories Bypass Normalization.

How distinct are visual memory representations from visual perception? Although evidence suggests that briefly remembered stimuli are represented within early visual cortices, the degree to which these memory traces resemble true visual representations remains something of a mystery. Here, we tested whether both visual memory and perception succumb to a seemingly ubiquitous neural computation: normalization. Observers were asked to remember the contrast of visual stimuli, which were pitted against each other to promote normalization either in perception or in visual memory. Our results revealed robust normalization between visual representations in perception, yet no signature of normalization occurring between working memory stores-neither between representations in memory nor between memory representations and visual inputs. These results provide unique insight into the nature of visual memory representations, illustrating that visual memory representations follow a different set of computational rules, bypassing normalization, a canonical visual computation.

Effects of emulsifying conditions on creaming effect, mechanical properties and microstructure of processed cheese using a rapid visco-analyzer.

The creaming effects, mechanical properties and microstructures of processed cheeses were investigated under different emulsifying conditions using a rapid visco-analyzer, and the changes in protein network related to the creaming effect and the occurrence of yielding points were discussed. The higher stirring speed affected the fat globules to be smaller, and gave the processed cheese more firmness at fixed stirring time. The longer stirring time caused the protein network to become fine-stranded. A fine-stranded structure promoted the creaming effect, and hence the formation of yielding point in the mechanical properties. The emulsifying salts had active effects on the creaming effect and mechanical properties at longer stirring time. The fine-stranded structures were shown in the cases of a binary mixture of polyphosphate and disodium phosphate (PDSP), polyphosphate (PP), and trisodium citrate (TSC). Monophosphate (MP) showed the lowest ability to alter the protein network, but was assisted at the higher stirring speed.

Effects of pre-cooked cheeses of different emulsifying conditions on mechanical properties and microstructure of processed cheese.

The effect of pre-cooked cheeses of different emulsifying conditions on the viscosities, mechanical properties, fat globules, and microstructure of processed cheese was investigated, and changes in protein network relating to the creaming effect and the occurrence of yielding point were discussed. The addition of pre-cooked cheeses with a short stirring time had no obvious impact on the fat globules and protein network. The random network brought low viscosities and a gradual increase in the fracture stress/strain curve. The addition of pre-cooked cheeses with the long stirring time caused protein network to become fine-stranded. The fine-stranded network caused creaming effect, and brought yielding points in the mechanical properties. The pre-cooked cheese with the small fat globules also caused fat globules to become smaller, and give the processed cheese more firmness. This study provides a potential solution to control the functional properties of processed cheese by using a variety of pre-cooked cheeses.

Skeletal Muscle Involvement in Antisynthetase Syndrome.

Importance: Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients' serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies. Objective: To elucidate the clinical features of myositis in patients with antisynthetase syndrome. Design, Setting, and Participants: In this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016. Exposures: Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped. Main Outcomes and Measures: The main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied. Results: Of 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1-the anti-OJ antibody-was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis. Conclusions and Relevance: Although clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.

Sarcoplasmic MxA expression: A valuable marker of dermatomyositis.

OBJECTIVE: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). METHODS: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti-tRNA-synthetase antibody-associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. RESULTS: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population. CONCLUSIONS: Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that immunohistochemistry-detected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.

Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies.

OBJECTIVE: Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. METHODS: We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. RESULTS: We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. CONCLUSION: Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy.

OBJECTIVE: To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). METHODS: We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively. RESULTS: Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups. CONCLUSIONS: Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti-HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics.

Inflammatory myopathy with anti-signal recognition particle antibodies: case series of 100 patients.

BACKGROUND: Anti-signal recognition particle (SRP) antibodies are used as serological markers of necrotizing myopathy, which is characterized by many necrotic and regenerative muscle fibers without or with minimal inflammatory cell infiltration. The clinical spectrum associated with anti-SRP antibodies seems to be broad. OBJECTIVE: To describe the clinical characteristics, autoantibodies status, and neurological outcome associated with anti-SRP antibody. METHODS: We studied clinical and laboratory findings of 100 patients with inflammatory myopathy and anti-SRP antibodies. Anti-SRP antibodies in serum were detected by the presence of 7S RNA using RNA immunoprecipitation. In addition, enzyme-linked immunosorbent assays (ELISAs) using a 54-kD protein of SRP (SRP54) and 3-hydroxyl-3-methylglutatyl-coenzyme A reductase (HMGCR) were also conducted. RESULTS: The mean onset age of the 61 female and 39 male patients was 51 years (range 4-82 years); duration ≥ 12 months before diagnosis was seen in 23 cases. All patients presented limbs weakness; 63 had severe weakness, 70 neck weakness, 41 dysphagia, and 66 muscle atrophy. Extramuscular symptoms and associated disorders were infrequent. Creatine kinase levels were mostly more than 1000 IU/L. Histological diagnosis showed 84 patients had necrotizing myopathy, and apparent cell infiltration was observed in 16 patients. Anti-SRP54 antibodies were undetectable in 18 serum samples with autoantibodies to 7S RNA. Anti-HMGCR antibodies were positive in 3 patients without the statin treatment, however, were negative in 5 patients with statin-exposure at disease onset. All but 3 patients were treated by corticosteroids and 62 (77 %) of these 81 patients required additional immunotherapy. After 2-years treatment, 22 (27 %) of these 81 patients had poor neurological outcomes with modified Rankin scale scores of 3-5. Multivariate analysis revealed that pediatric disease onset was associated with the poor outcomes. CONCLUSION: Anti-SRP antibodies are associated with different clinical courses and histological presentations.

Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan.

Statins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG. We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies. We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients' serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy. Anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.

[A research of letter color visibility in package insert information using simulator].

Package insert of pharmaceutical drug is one of the most prioritized information for pharmacists to secure safety of patients. However, the color of character, size, font and so on are various company by company product to product from a viewpoint of visibility. It may be cause a serious accident in case visibility is unclear, although it is the most important information. Moreover, package insert with high visibility is required for color vision defectives from a viewpoint of a universal design. Then, the authors selected the package insert which has the boxed warning in the ethical pharmaceutical currently stored mostly in the present health insurance pharmacy and quantified the red color using the color meter. We advocate the state of a suitable package insert from a viewpoint of a universal design, whether the red color is high visible or not for color vision defectives using simulator.