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1.
Sci Transl Med ; 11(507)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462510

RESUMO

Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic adenovirus 26 (Ad26)-based HIV-1 vaccine candidate. To investigate the basis of this protection, we performed whole transcriptomics profiling by RNA sequencing (RNA-seq) in sorted lymphocytes from peripheral blood samples taken during these studies at different time points after vaccination but before challenge. We observed a transcriptional signature in B cells that associated with protection from acquisition of simian immunodeficiency virus (SIV) or the simian-human immunodeficiency virus (SHIV) in both studies. Strong antibody responses were elicited, and genes from the signature for which expression was enriched specifically associated with higher magnitude of functional antibody responses. The same gene expression signature also associated with protection in RV144 in the only human HIV vaccine trial to date that has shown efficacy and in two additional NHP studies that evaluated similar canarypox-based vaccine regimens. A composite gene expression score derived from the gene signature was one of the top-ranked correlates of protection in the NHP vaccine studies. This study aims to bridge preclinical and clinical data with the identification of a gene signature in B cells that is associated with protection from SIV and HIV infection by providing a new approach for evaluating future vaccine candidates.

2.
Hum Brain Mapp ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361075

RESUMO

The cerebellum is involved in a wide range of behaviours. A key organisational principle from animal studies is that somatotopically corresponding sensory input and motor output reside in the same cerebellar cortical areas. However, compelling evidence for a similar arrangement in humans and whether it extends to cognitive functions is lacking. To address this, we applied cerebellar optimised whole-brain functional MRI in 20 healthy subjects. To assess spatial overlap within the sensorimotor and cognitive domains, we recorded activity to a sensory stimulus (vibrotactile) and a motor task; the Sternberg verbal working memory (VWM) task; and a verb generation paradigm. Consistent with animal data, sensory and motor activity overlapped with a somatotopic arrangement in ipsilateral areas of the anterior and posterior cerebellum. During the maintenance phase of the Sternberg task, a positive linear relationship between VWM load and activity was observed in right Lobule VI, extending into Crus I bilaterally. Articulatory movement gave rise to bilateral activity in medial Lobule VI. A conjunction of two independent language tasks localised activity during verb generation in right Lobule VI-Crus I, which overlapped with activity during VWM. These results demonstrate spatial compartmentalisation of sensorimotor and cognitive function in the human cerebellum, with each area involved in more than one aspect of a given behaviour, consistent with an integrative function. Sensorimotor localisation was uniform across individuals, but the representation of cognitive tasks was more variable, highlighting the importance of individual scans for mapping higher order functions within the cerebellum.

3.
Nature ; 563(7733): E33, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30315222

RESUMO

In this Brief Communications Arising Comment, the first three authors (Osuna, Lim and Kublin) should have been listed as equally contributing authors; this has been corrected online.

4.
PLoS Pathog ; 14(9): e1007257, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30180214

RESUMO

HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To better understand viral immune evasion targeting HLA-C, we have characterized HLA-C downregulation by a range of primary HIV-1 viruses. 128 replication competent viral isolates from 19 individuals with effective anti-retroviral therapy, show that a substantial minority of individuals harbor latent reservoir virus which strongly downregulates HLA-C. Untreated infections display no change in HLA-C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. Vpu molecules cloned from plasma of 195 treatment naïve individuals in chronic infection demonstrate that downregulation of HLA-C adapts to host HLA genotype. HLA-C alleles differ in the pressure they exert for downregulation, and individuals with higher levels of HLA-C expression favor greater viral downregulation of HLA-C. Studies of primary and mutant molecules identify 5 residues in the transmembrane region of Vpu, and 4 residues in the transmembrane domain of HLA-C, which determine interactions between Vpu and HLA. The observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA-C alleles differ in likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA-C expression is favored in the absence of these responses. Finding that latent reservoir viruses can downregulate HLA-C could have implications for HIV-1 cure therapy approaches in some individuals.

5.
Cerebellum ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30259343

RESUMO

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30198299

RESUMO

Much has been learnt from the functions of host restriction factors during acute and chronic HIV-1 infection, but far less is known about their role in HIV-1-infected individuals in which viral load is stably suppressed with antiretroviral therapy (ART). In this study transcriptional expression of 42 host restriction factors was determined for memory CD4+ T cells sorted from 10 uninfected and 21 HIV-1-infected individuals, treated with suppressive ART and for which the viral reservoir was quantified. No significant associations were observed between restriction factor expression and HIV-1 reservoir size, quantified by measurement of HIV-1 Gag DNA using droplet digital polymerase chain reaction, and by measurement of replication-competent inducible virus using quantitative viral outgrowth assays. Expression of eight of the restriction factors differed significantly, and with a false discovery rate of <10%, between ART-suppressed and uninfected individuals. APOBEC3G, ISG15, LGALS3BP, RNASEL, and MX2 were upregulated in the ART-suppressed individuals, likely because of increased levels of immune activation observed in virally suppressed compared with uninfected individuals. In contrast CDKN1A, TRIM11, and BRD4 were expressed at lower levels in ART-suppressed than uninfected individuals. This suggests perturbation of the CD4+ memory T cell compartment, in which a viral reservoir persists in HIV-1-infected individuals with effective ART. Modulation of restriction factor expression, or overrepresentation of cell subsets that intrinsically express these restriction factors at lower levels could result in the distinct expression of restriction factors observed in treated infected individuals.

8.
J Virol ; 92(23)2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30209173

RESUMO

Efforts to cure human immunodeficiency virus (HIV) infection are obstructed by reservoirs of latently infected CD4+ T cells that can reestablish viremia. HIV-specific broadly neutralizing antibodies (bNAbs), defined by unusually wide neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, thus targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4+ T cells has not been determined. Thus, the extent to which neutralization breadths and potencies can be used to infer the corresponding parameters of infected cell binding is currently unknown. We assessed the breadths and potencies of bNAbs against 36 viruses reactivated from peripheral blood CD4+ T cells from antiretroviral (ARV)-treated HIV-infected individuals by using paired neutralization and infected cell binding assays. Single-antibody breadths ranged from 0 to 64% for neutralization (80% inhibitory concentration [IC80] of ≤10 µg/ml) and from 0 to 89% for binding, with two-antibody combinations (results for antibody combinations are theoretical/predicted) reaching levels of 0 to 83% and 50 to 100%, respectively. Infected cell binding correlated with virus neutralization for 10 of 14 antibodies (e.g., for 3BNC117, r = 0.82 and P < 0.0001). Heterogeneity was observed, however, with a lack of significant correlation for 2G12, CAP256.VRC26.25, 2F5, and 4E10. Our results provide guidance on the selection of bNAbs for interventional cure studies, both by providing a direct assessment of intra- and interindividual variabilities in neutralization and infected cell binding in a novel cohort and by defining the relationships between these parameters for a panel of bNAbs.IMPORTANCE Although antiretroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their ability to both prevent the infection of new cells (neutralization) and direct the killing of infected cells. We isolated 36 HIV strains from individuals whose virus was suppressed by medication and tested 14 different antibodies for neutralization of these viruses and for binding to cells infected with the same viruses (critical for engaging natural killer cells). For both neutralization and infected cell binding, we observed variation both between individuals and amongst different viruses within an individual. For most antibodies, neutralization activity correlated with infected cell binding. These data provide guidance on the selection of antibodies for clinical trials.

9.
Handb Clin Neurol ; 154: 45-58, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903451

RESUMO

In this chapter, we compare current understanding of the anatomy and functional compartmentation of the human cerebellum with detailed knowledge in nonhuman species. The anatomy of the cerebellum is highly conserved across mammals and comparison of functional data suggests that similar principles of organization also hold true for somatotopy. In particular, there is a dual representation of the limbs in the cerebellar cortex in rat, ferret, cat, monkey, and human. In animals, a key organizing principle of the cerebellum is its division into a series of longitudinally oriented olivocorticonuclear modules that are narrow in the mediolateral axis but extend across multiple cerebellar lobules in the rostrocaudal plane. This contrasts with existing understanding of the human cerebellum that suggests that functional compartmentation is organized mainly at the level of different lobes and lobules. However, advances in spatial resolution of imaging techniques mean we are now able to start to examine whether a longitudinal modular organization is also present within the human cerebellum. This has implications for the diagnosis and future treatment of clinical disorders that involve the cerebellum, since it is possible that variations in symptomatology may relate to this finer grain localization.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/anatomia & histologia , Vias Neurais/anatomia & histologia , Animais , Doenças Cerebelares/fisiopatologia , Humanos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia
10.
Cerebellum ; 2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29876802

RESUMO

The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form.

11.
Cerebellum ; 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29931663

RESUMO

In the original version of this paper, the Title should have been written with "A Consensus paper" to read "Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper".

12.
Cerebellum Ataxias ; 5: 8, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29610671

RESUMO

The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders.

13.
14.
J Physiol ; 595(15): 5341-5357, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28516455

RESUMO

KEY POINTS: Cerebellar Purkinje cells (PCs) generate two types of action potentials, simple and complex spikes. Although they are generated by distinct mechanisms, interactions between the two spike types exist. Zebrin staining produces alternating positive and negative stripes of PCs across most of the cerebellar cortex. Thus, here we compared simple spike-complex spike interactions both within and across zebrin populations. Simple spike activity undergoes a complex modulation preceding and following a complex spike. The amplitudes of the pre- and post-complex spike modulation phases were correlated across PCs. On average, the modulation was larger for PCs in zebrin positive regions. Correlations between aspects of the complex spike waveform and simple spike activity were found, some of which varied between zebrin positive and negative PCs. The implications of the results are discussed with regard to hypotheses that complex spikes are triggered by rises in simple spike activity for either motor learning or homeostatic functions. ABSTRACT: Purkinje cells (PCs) generate two types of action potentials, called simple and complex spikes (SSs and CSs). We first investigated the CS-associated modulation of SS activity and its relationship to the zebrin status of the PC. The modulation pattern consisted of a pre-CS rise in SS activity, and then, following the CS, a pause, a rebound, and finally a late inhibition of SS activity for both zebrin positive (Z+) and negative (Z-) cells, though the amplitudes of the phases were larger in Z+ cells. Moreover, the amplitudes of the pre-CS rise with the late inhibitory phase of the modulation were correlated across PCs. In contrast, correlations between modulation phases across CSs of individual PCs were generally weak. Next, the relationship between CS spikelets and SS activity was investigated. The number of spikelets/CS correlated with the average SS firing rate only for Z+ cells. In contrast, correlations across CSs between spikelet numbers and the amplitudes of the SS modulation phases were generally weak. Division of spikelets into likely axonally propagated and non-propagated groups (based on their interspikelet interval) showed that the correlation of spikelet number with SS firing rate primarily reflected a relationship with non-propagated spikelets. In sum, the results show both zebrin-related and non-zebrin-related physiological heterogeneity in SS-CS interactions among PCs, which suggests that the cerebellar cortex is more functionally diverse than is assumed by standard theories of cerebellar function.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Células de Purkinje/fisiologia , Potenciais de Ação , Animais , Feminino , Masculino , Ratos Sprague-Dawley , Ratos Wistar
15.
J Physiol ; 595(13): 4151-4158, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28294351

RESUMO

The ability to interact with challenging environments requires coordination of sensory and motor systems that underpin appropriate survival behaviours. All animals, including humans, use active and passive coping strategies to react to escapable or inescapable threats, respectively. Across species the neural pathways involved in survival behaviours are highly conserved and there is a consensus that knowledge of such pathways is a fundamental step towards understanding the neural circuits underpinning emotion in humans and treating anxiety or other prevalent emotional disorders. The midbrain periaqueductal grey (PAG) lies at the heart of the defence-arousal system and its integrity is paramount to the expression of survival behaviours. To date, studies of 'top down control' components of defence behaviours have focused largely on the sensory and autonomic consequences of PAG activation. In this context, effects on motor activity have received comparatively little attention, despite overwhelming evidence of a pivotal role for the PAG in coordinating motor responses essential to survival (e.g. such as freezing in response to fear). In this article we provide an overview of top down control of sensory functions from the PAG, including selective control of different modalities of sensory, including proprioceptive, information forwarded to a major supsraspinal motor control centre, the cerebellum. Next, evidence from our own and other laboratories of PAG control of motor outflow is also discussed. Finally, the integration of sensorimotor functions by the PAG is considered, as part of coordinated defence behaviours that prepare an animal to be ready and able to react to danger.


Assuntos
Retroalimentação Fisiológica , Substância Cinzenta Periaquedutal/fisiologia , Tratos Piramidais/fisiologia , Animais , Humanos
16.
J Physiol ; 595(1): 283-299, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27265808

RESUMO

KEY POINTS: Purkinje cells are the sole output of the cerebellar cortex and fire two distinct types of action potential: simple spikes and complex spikes. Previous studies have mainly considered complex spikes as unitary events, even though the waveform is composed of varying numbers of spikelets. The extent to which differences in spikelet number affect simple spike activity (and vice versa) remains unclear. We found that complex spikes with greater numbers of spikelets are preceded by higher simple spike firing rates but, following the complex spike, simple spikes are reduced in a manner that is graded with spikelet number. This dynamic interaction has important implications for cerebellar information processing, and suggests that complex spike spikelet number may maintain Purkinje cells within their operational range. ABSTRACT: Purkinje cells are central to cerebellar function because they form the sole output of the cerebellar cortex. They exhibit two distinct types of action potential: simple spikes and complex spikes. It is widely accepted that interaction between these two types of impulse is central to cerebellar cortical information processing. Previous investigations of the interactions between simple spikes and complex spikes have mainly considered complex spikes as unitary events. However, complex spikes are composed of an initial large spike followed by a number of secondary components, termed spikelets. The number of spikelets within individual complex spikes is highly variable and the extent to which differences in complex spike spikelet number affects simple spike activity (and vice versa) remains poorly understood. In anaesthetized adult rats, we have found that Purkinje cells recorded from the posterior lobe vermis and hemisphere have high simple spike firing frequencies that precede complex spikes with greater numbers of spikelets. This finding was also evident in a small sample of Purkinje cells recorded from the posterior lobe hemisphere in awake cats. In addition, complex spikes with a greater number of spikelets were associated with a subsequent reduction in simple spike firing rate. We therefore suggest that one important function of spikelets is the modulation of Purkinje cell simple spike firing frequency, which has implications for controlling cerebellar cortical output and motor learning.


Assuntos
Células de Purkinje/fisiologia , Potenciais de Ação , Animais , Gatos , Feminino , Masculino , Ratos Sprague-Dawley , Ratos Wistar
17.
Ann Neurol ; 81(2): 212-226, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28009062

RESUMO

OBJECTIVES: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. METHODS: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum. RESULTS: Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G-CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. INTERPRETATION: These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212-226.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ataxia de Friedreich/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Proteínas de Ligação ao Ferro/metabolismo , Condução Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nervos Periféricos/efeitos dos fármacos , Fator de Células-Tronco/farmacologia , Animais , Modelos Animais de Doenças , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/fisiopatologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/administração & dosagem , Fator de Células-Tronco/administração & dosagem
18.
Cerebellum ; 16(1): 230-252, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27193702

RESUMO

For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less suitable for one or the other of these functions, and why having multiple functions makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest that it has the potential to act in both the motor learning and motor control functions of the cerebellum.


Assuntos
Cerebelo/fisiologia , Aprendizagem/fisiologia , Atividade Motora/fisiologia , Núcleo Olivar/fisiologia , Animais , Consenso , Humanos , Vias Neurais/fisiologia
19.
J Neurosci ; 36(50): 12707-12719, 2016 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-27974618

RESUMO

The dorsal and ventral periaqueductal gray (dPAG and vPAG, respectively) are embedded in distinct survival networks that coordinate, respectively, innate and conditioned fear-evoked freezing. However, the information encoded by the PAG during these survival behaviors is poorly understood. Recordings in the dPAG and vPAG in rats revealed differences in neuronal activity associated with the two behaviors. During innate fear, neuronal responses were significantly greater in the dPAG compared with the vPAG. After associative fear conditioning and during early extinction (EE), when freezing was maximal, a field potential was evoked in the PAG by the auditory fear conditioned stimulus (CS). With repeated presentations of the unreinforced CS, animals displayed progressively less freezing accompanied by a reduction in event-related field potential amplitude. During EE, the majority of dPAG and vPAG units increased their firing frequency, but spike-triggered averaging showed that only ventral activity during the presentation of the CS was significantly coupled to EMG-related freezing behavior. This PAG-EMG coupling was only present for the onset of freezing activity during the CS in EE. During late extinction, a subpopulation of units in the dPAG and vPAG continued to show CS-evoked responses; that is, they were extinction resistant. Overall, these findings support roles for the dPAG in innate and conditioned fear and for the vPAG in initiating but not maintaining the drive to muscles to generate conditioned freezing. The existence of extinction-susceptible and extinction-resistant cells also suggests that the PAG plays a role in encoding fear memories. SIGNIFICANCE STATEMENT: The periaqueductal gray (PAG) orchestrates survival behaviors, with the dorsal (dPAG) and ventral (vPAG) PAG concerned respectively with innate and learnt fear responses. We recorded neural activity from dPAG and vPAG in rats during the expression of innate fear and extinction of learned freezing. Cells in dPAG responded more robustly during innate fear, but dPAG and vPAG both encoded the time of the conditioned stimulus during early extinction and displayed extinction sensitive and resistant characteristics. Only vPAG discharge was correlated with muscle activity, but this was limited to the onset of conditioned freezing. The data suggest that the roles of dPAG and vPAG in fear behavior are more complex than previously thought, including a potential role in fear memory.


Assuntos
Medo/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Estimulação Acústica , Animais , Condicionamento (Psicologia)/fisiologia , Eletromiografia , Potenciais Evocados/fisiologia , Extinção Psicológica/fisiologia , Masculino , Ratos , Ratos Wistar
20.
J Neurosci ; 36(30): 7841-51, 2016 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-27466330

RESUMO

UNLABELLED: Pathways arising from the periphery that target the inferior olive [spino-olivocerebellar pathways (SOCPs)] are a vital source of information to the cerebellum and are modulated (gated) during active movements. This limits their ability to forward signals to climbing fibers in the cerebellar cortex. We tested the hypothesis that the temporal pattern of gating is related to the predictability of a sensory signal. Low-intensity electrical stimulation of the ipsilateral hindlimb in awake rats evoked field potentials in the C1 zone in the copula pyramidis of the cerebellar cortex. Responses had an onset latency of 12.5 ± 0.3 ms and were either short or long duration (8.7 ± 0.1 vs 31.2 ± 0.3 ms, respectively). Both types of response were shown to be mainly climbing fiber in origin and therefore evoked by transmission in hindlimb SOCPs. Changes in response size (area of field, millivolts per millisecond) were used to monitor differences in transmission during rest and three phases of rearing: phase 1, rearing up; phase 2, upright; and phase 3, rearing down. Responses evoked during phase 2 were similar in size to rest but were smaller during phases 1 and 3, i.e., transmission was reduced during active movement when self-generated (predictable) sensory signals from the hindlimbs are likely to occur. To test whether the pattern of gating was related to the predictability of the sensory signal, some animals received the hindlimb stimulation only during phase 2. Over ∼10 d, the responses became progressively smaller in size, consistent with gating-out transmission of predictable sensory signals relayed via SOCPs. SIGNIFICANCE STATEMENT: A major route for peripheral information to gain access to the cerebellum is via ascending climbing fiber pathways. During active movements, gating of transmission in these pathways controls when climbing fiber signals can modify cerebellar activity. We investigated this phenomenon in rats during their exploratory behavior of rearing. During rearing up and down, transmission was reduced at a time when self-generated, behaviorally irrelevant (predictable) signals occur. However, during the upright phase of rearing, transmission was increased when behaviorally relevant (unpredictable) signals may occur. When the peripheral stimulation was delivered only during the upright phase, so its occurrence became predictable over time, transmission was reduced. Therefore, the results indicate that the gating is related to the level of predictability of a sensory signal.


Assuntos
Vias Aferentes/fisiologia , Cerebelo/fisiologia , Comportamento Exploratório/fisiologia , Vias Neurais/fisiologia , Núcleo Olivar/fisiologia , Sensação/fisiologia , Animais , Retroalimentação Fisiológica/fisiologia , Masculino , Inibição Neural/fisiologia , Neurônios Aferentes/fisiologia , Ratos , Ratos Wistar
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