A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli.

Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.

Inhibitory top-down projections from zona incerta mediate neocortical memory.

Top-down projections convey a family of signals encoding previous experiences and current aims to the sensory neocortex, where they converge with external bottom-up information to enable perception and memory. Whereas top-down control has been attributed to excitatory pathways, the existence, connectivity, and information content of inhibitory top-down projections remain elusive. Here, we combine synaptic two-photon calcium imaging, circuit mapping, cortex-dependent learning, and chemogenetics in mice to identify GABAergic afferents from the subthalamic zona incerta as a major source of top-down input to the neocortex. Incertocortical transmission undergoes robust plasticity during learning that improves information transfer and mediates behavioral memory. Unlike excitatory pathways, incertocortical afferents form a disinhibitory circuit that encodes learned top-down relevance in a bidirectional manner where the rapid appearance of negative responses serves as the main driver of changes in stimulus representation. Our results therefore reveal the distinctive contribution of long-range (dis)inhibitory afferents to the computational flexibility of neocortical circuits.

Probing top-down information in neocortical layer 1.

Accurate perception of the environment is a constructive process that requires integration of external bottom-up sensory signals with internally generated top-down information. Decades of work have elucidated how sensory neocortex processes physical stimulus features. By contrast, examining how top-down information is encoded and integrated with bottom-up signals has been challenging using traditional neuroscience methods. Recent technological advances in functional imaging of brain-wide afferents in behaving mice have enabled the direct measurement of top-down information. Here, we review the emerging literature on encoding of these internally generated signals by different projection systems enriched in neocortical layer 1 during defined brain functions, including memory, attention, and predictive coding. Moreover, we identify gaps in current knowledge and highlight future directions for this rapidly advancing field.

A thalamocortical top-down circuit for associative memory.

The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and computational modeling, we find that the higher-order thalamus is required for associative learning and transmits memory-related information that closely correlates with acquired behavioral relevance. In turn, these signals are tightly and dynamically controlled by local presynaptic inhibition. Our results not only identify the higher-order thalamus as a highly plastic source of cortical top-down information but also reveal a level of computational flexibility in layer 1 that goes far beyond hard-wired connectivity.

Ascl1 Balances Neuronal versus Ependymal Fate in the Spinal Cord Central Canal.

Generation of neuronal types at the right time, location, and number is essential for building a functional nervous system. Significant progress has been reached in understanding the mechanisms that govern neuronal diversity. Cerebrospinal fluid-contacting neurons (CSF-cNs), an intriguing spinal cord central canal population, are produced during advanced developmental stages, simultaneous with glial and ependymal cells. It is unknown how CSF-cNs are specified after the neurogenesis-to-gliogenesis switch. Here, we identify delayed Ascl1 expression in mouse spinal progenitors during the gliogenic phase as key in CSF-cN differentiation. With fate mappings and time-controlled deletions, we demonstrate that CSF-cNs derive from Ascl1-expressing cells and that Ascl1 triggers late neurogenesis in the amniote spinal cord. Ascl1 abrogation transforms prospective CSF-cN progenitors into ependymocytes. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and nonneuronal composition of the spinal central canal.

Disinhibition Goes Spatial.

Memorizing significant locations in the environment is a fundamental capacity of the brain. In this issue, Turi et al. (2019) present multidisciplinary evidence for a critical involvement of disinhibitory interneurons in hippocampal CA1 in this process.

Learning-Related Plasticity in Dendrite-Targeting Layer 1 Interneurons.

A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons (INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition. VIDEO ABSTRACT.

Unique processing during a period of high excitation/inhibition balance in adult-born neurons.

The adult dentate gyrus generates new granule cells (GCs) that develop over several weeks and integrate into the preexisting network. Although adult hippocampal neurogenesis has been implicated in learning and memory, the specific role of new GCs remains unclear. We examined whether immature adult-born neurons contribute to information encoding. By combining calcium imaging and electrophysiology in acute slices, we found that weak afferent activity recruits few mature GCs while activating a substantial proportion of the immature neurons. These different activation thresholds are dictated by an enhanced excitation/inhibition balance transiently expressed in immature GCs. Immature GCs exhibit low input specificity that switches with time toward a highly specific responsiveness. Therefore, activity patterns entering the dentate gyrus can undergo differential decoding by a heterogeneous population of GCs originated at different times.

[Dupuytren's disease simulated by epithelioid sarcoma with atypical perineural invasion of the median nerve. Case report]. / Malattia di Dupuytren simulata da un sarcoma epitelioide con atipica invasione perineurale del nervo mediano. Caso clinico.

Epithelioid sarcoma is an infrequent tumour, especially in upper limb, which nerve spread is not common. We describe the case of a 27 years old caucasian male with initial diagnosis of Dupuytren's disease. He underwent palmar fascia surgery, but the surgical treatment was followed by recurrence of the deformity in retraction of 4th and 5th finger of the left hand. When he presented himself at our attention, the patient underwent surgical biopsy and new histological examination was made with diagnosis of epithelioid sarcoma. We highlight essentially two aspects of this case: the diagnostic delay of tumour caused by simulation of the Dupuytren's disease and the atypical perineural spread along the median nerve.

The pillar pain in the carpal tunnel's surgery. Neurogenic inflammation? A new therapeutic approach with local anaesthetic.

AIM: After the surgical decompression of the transverse carpal ligament as treatment of the tunnel carpal syndrome, pillar pain manifestation is possible. This is a painful and temporary invaliding syndrome with unknown aetiology. Aim of the study is to demonstrate that pillar pain is based on autonomic irritation that disappears with simple infiltration of local anaesthetic (LA), or rather by neuromodulation. METHODS: Eighty-four patients were enrolled for this study and underwent an open release technique surgery. They were then asked for regular postoperative follow-ups. RESULTS: Thirty-two out of 84 patients (38%) developed pillar pain. Accordingly, injection of LA as pain treatment has since been studied and results compared with the conventional protocol for this painful syndrome. CONCLUSION: Even if the number of the patients considered is not great, there is evidence of a decrement of pillar pain by means of LA injections. Excellent functional outcomes and satisfaction were achieved using LA infiltrations for pillar pain after carpal tunnel decompression. The minimally invasive technique offers a quick, easy, effective, and inexpensive method useful to minimize and cure in a few days the pillar pain.

[Tenosynovial giant cell tumour of the hand and wrist: early diagnosis and surgical treatment]. / Tumore a cellule giganti tenosinoviale della mano e del polso: diagnosi precoce e trattamento chirurgico.

Fourty two patients with tenosynovial giant cell tumour, treated with radical excision, underwent detailed follow-up to evaluate the outcomes and to find early the possible recurrence of disease. Radical excision is the only way to have a complete recovery from disease and total recovery of function. Early diagnosis of recurrence is possible by careful clinical examination, ultrasonography and, in selected cases, magnetic resonance imaging.

[Surgical treatment of painful amputation neuromas with hyaluronic acid gel. Preliminary study of six patients]. / Trattamento chirurgico dei neuromi d'amputazione dolorosi con gel di acido ialuronico. Lavoro preliminare su 6 casi.

Amputation neuroma is the consequence of a traumatic event that interrupt the anatomic structure of a nerve. After the lesion, the nerve begin an plerosis attempt. This condition determines hyposensitivity on its innervation area and a painful syndrome. The pattern's resolution is possible with the neuroma's tissue exeresis and the sinking of proximal stump into closer tissue. This operation reduces or eliminates axonal nerve's flux. The hyaluronic acid (Hyaloglide 0.8-1 ml) use is based on the necessity of proximal stump preservation from mechanical and thermic stimuli that are responsible of typical neuroma's symptoms. In this study we used hyaluronic acid on six painful amputation neuroma patterns on sensitive nerves of upper and lower extremities.

[Double compression of the ulnar nerve at the elbow and at the wrist (double-crush syndrome). Case report and review of the literature]. / Doppia compressione del nervo ulnare alla doccia epitrocleo-olecranica ed al polso (double-crush syndrome). Descrizione di un caso e revisione della letteratura.

Double compression of a peripheral nerve is not rare in medical practice. This article describes an ulnar neuropathy along the elbow and the wrist segments with electro-diagnostic examination (EDX). The proximal compression was an ulnar entrapment at the olecranon-epitrochlear semi-canal; the distal one was after the canal of Guyon, due to an arthro-synovial cyst arising from the pisohamatum joint. There aren't analogous clinical reports in the literature.

Transmyocardial laser revascularization. Early clinical experience.

OBJECTIVE: To analyze the initial clinical experience of transmyocardial laser revascularization (TMLR) in patients with severe diffuse coronary artery disease. METHODS: Between February, 1998 and February, 1999, 20 patients were submitted to TMLR at the Heart Institute (InCor), University of São Paulo Medical School, Brazil, isolated or in association with conventional coronary artery bypass graft (CABG). All patients had severe diffuse coronary artery disease, with angina functional class III/IV (Canadian Cardiovascular Society score) unresponsive to medical therapy. Fourteen patients were submitted to TMLR as the sole therapy, whereas 6 underwent concomitant CABG. Fifty per cent of the patients had either been previously submitted to a CABG or to a percutaneous transluminal coronary angioplasty (PTCA). Mean age was 60 years, ranging from 45 to 74 years. RESULTS: All patients had three-vessel disease, with normal or mildly impaired left ventricular global function. Follow-up ranged from 1 to 13 months (mean 6.6 months), with no postoperative short or long term mortality. There was significant symptom improvement after the procedure, with 85% of the patients free of angina, and the remaining 15% of the patients showing improvement in functional class, as well as in exercise tolerance. CONCLUSION: This novel technique can be considered a low risk alternative for a highly selected group of patients not suitable for conventional revascularization procedures.

Inspeçäo sanitária e industrial de produtos de origem animal no Brasil / Sanitary and industrial inspection of animal products in Brazil

O artigo descreve a origem e a evoluçäo dos serviços de Inspeçäo Sanitária e Industrial de produtos de origem animal no Brasil, narrando o desenvolvimento da legislaçäo concernente destacando a participaçäo dos Médicos-Veterinários na gênese de sua estrutura. Expöe, ainda, a responsabilidade do SIPA e seus índices de atuaçäo, em que participam aproximadamente 900 Médicos-Veterinários

New projections in the development of a vaccination model using two microorganisms and its application in leishmaniasis and leprosy

Conventional vaccination is oriented toward the prevention of disease in individuals capable of developing normal immune responses. A new model of vaccination employing two microorganisms has been described for the correction of variable degrees of antigen-specifit deficiency in the development of effective cell-mediated immunity in two diseases, leprosy and cutaneous leishmaniasis, both of which are characterized by a spectrum of clinical manifestations. A schematic representation of the immunologic defect in the severe and progressive forms of these diseases and a possible mechanism for its correction using this vaccine model are presented. Immunotherapeutic and immunoprophylactic applications of the model are described, with particular reference to recent experience in the immunotherapy of localized cutaneous leishmaniasis. The efficacy, virtual absence of secondary effects, ease of administration and low cost of this therapeutic modality indicate that it offers an important option or field use in endemic of leishmaniasis

Hormonal influences upon the in vitro glucose uptake in the thymus of adrenalectomized rats.

The experiments carried out on male albino Wistar rats weighing 100 g show that following adrenalectomy the in vitro glucose uptake in the thymus may be influenced by a series of hormones. The inhibitory action of hydrocortisone upon this phenomenon is intensified, while desoxycorticosterone acetate brings the glucose uptake back to the level found in the normal rat's thymus. Insulin stimulates markedly the glucose consumption in the thymus, while in the glands of adrenalectomized rats it reduces the inhibitory effect of both hydrocortisone and desoxycorticosterone acetate.