Faculty Bibliography

INTRODUCTION:Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI. METHODS:26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. RESULTS:A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). CONCLUSION:This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Coordinated motor behaviors depend on feedback communication between peripheral sensory systems and central circuits in the brain and spinal cord. Relay of muscle- and tendon-derived sensory information to the CNS is facilitated by functionally and anatomically diverse groups of spinocerebellar tract neurons (SCTNs), but the molecular logic by which SCTN diversity and connectivity is achieved is poorly understood. We used single-cell RNA sequencing and genetic manipulations to define the mechanisms governing the molecular profile and organization of SCTN subtypes. We found that SCTNs relaying proprioceptive sensory information from limb and axial muscles are generated through segmentally restricted actions of specific Hox genes. Loss of Hox function disrupts SCTN-subtype-specific transcriptional programs, leading to defects in the connections between proprioceptive sensory neurons, SCTNs, and the cerebellum. These results indicate that Hox-dependent genetic programs play essential roles in the assembly of neural circuits necessary for communication between the brain and spinal cord.

Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3⁺-PrP^Sc-reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3⁺-astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrP^Sc deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3⁺-PrP^Sc-reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases.

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1^+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1^+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1^+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRAB_NE) sensors with a 230% peak ΔF/F₀ response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRAB_NE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRAB_NE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.

Wind is a major navigational cue for insects, but how wind direction is decoded by central neurons in the insect brain is unknown. Here we find that walking flies combine signals from both antennae to orient to wind during olfactory search behavior. Movements of single antennae are ambiguous with respect to wind direction, but the difference between left and right antennal displacements yields a linear code for wind direction in azimuth. Second-order mechanosensory neurons share the ambiguous responses of a single antenna and receive input primarily from the ipsilateral antenna. Finally, we identify novel "wedge projection neurons" that integrate signals across the two antennae and receive input from at least three classes of second-order neurons to produce a more linear representation of wind direction. This study establishes how a feature of the sensory environment-wind direction-is decoded by neurons that compare information across two sensors.

Performance on cognitive tasks during learning is used to measure knowledge, yet it remains controversial since such testing is susceptible to contextual factors. To what extent does performance during learning depend on the testing context, rather than underlying knowledge? We trained mice, rats and ferrets on a range of tasks to examine how testing context impacts the acquisition of knowledge versus its expression. We interleaved reinforced trials with probe trials in which we omitted reinforcement. Across tasks, each animal species performed remarkably better in probe trials during learning and inter-animal variability was strikingly reduced. Reinforcement feedback is thus critical for learning-related behavioral improvements but, paradoxically masks the expression of underlying knowledge. We capture these results with a network model in which learning occurs during reinforced trials while context modulates only the read-out parameters. Probing learning by omitting reinforcement thus uncovers latent knowledge and identifies context- not "smartness"- as the major source of individual variability.

Young adult-born granule cells (abGCs) in the dentate gyrus (DG) have a profound impact on cognition and mood. However, it remains unclear how abGCs distinctively contribute to local DG information processing. We found that the actions of abGCs in the DG depend on the origin of incoming afferents. In response to lateral entorhinal cortex (LEC) inputs, abGCs exert monosynaptic inhibition of mature granule cells (mGCs) through group II metabotropic glutamate receptors. By contrast, in response to medial entorhinal cortex (MEC) inputs, abGCs directly excite mGCs through N-methyl-d-aspartate receptors. Thus, a critical function of abGCs may be to regulate the relative synaptic strengths of LEC-driven contextual information versus MEC-driven spatial information to shape distinct neural representations in the DG.

The demands on a sensory system depend not only on the statistics of its inputs but also on the task. In olfactory navigation, for example, the task is to find the plume source; allocation of sensory resources may therefore be driven by aspects of the plume that are informative about source location, rather than concentration per se. Here we explore the implications of this idea for encoding odor concentration.To formalize the notion that sensory resources are limited, we considered coding strategies that partitioned the odor concentration range into a set of discriminable intervals. We developed a dynamic programming algorithm that, given the distribution of odor concentrations at several locations, determines the partitioning that conveys the most information about location. We applied this analysis to planar laser-induced fluorescence measurements of spatiotemporal odor fields with realistic advection speeds (5 to 20 cm/sec), with or without a nearby boundary or obstacle. Across all environments, the optimal coding strategy allocated more resources (i.e., more and finer discriminable intervals) to the upper end of the concentration range than would be expected from histogram equalization, the optimal strategy if the goal were to reconstruct the plume, rather than to navigate. Finally, we show that ligand binding, as captured by the Hill equation, transforms odorant concentration into response levels in a way that approximates information maximization for navigation. This behavior occurs when the Hill dissociation constant is near the mean odor concentration, an adaptive set-point that has been observed in the olfactory system of flies.SIGNIFICANCE STATEMENTThe first step of olfactory processing is receptor binding, and the resulting relationship between odorant concentration and the bound receptor fraction is a saturating one. While this Hill nonlinearity can be viewed as a distortion that is imposed by the biophysics of receptor binding, here we show that it also plays an important information-processing role in olfactory navigation. Specifically, by combining a novel dynamic-programming algorithm with physical measurements of turbulent plumes, we determine the optimal strategy for encoding odor concentration when the goal is to determine location. This strategy is distinct from histogram equalization, the strategy that maximizes information about plume concentration, and is closely approximated by the Hill nonlinearity when the binding constant is near the ambient mean.

Complex mechanisms are required to form neuromuscular synapses, direct their subsequent maturation, and maintain the synapse throughout life. Transcriptional and post-translational pathways play important roles in synaptic differentiation and direct the accumulation of the neurotransmitter receptors, acetylcholine receptors (AChRs), to the postsynaptic membrane, ensuring for reliable synaptic transmission. Rapsyn, an intracellular peripheral membrane protein that binds AChRs, is essential for synaptic differentiation, but how Rapsyn acts is poorly understood. We screened for proteins that coisolate with AChRs in a Rapsyn-dependent manner and show that microtubule actin cross linking factor 1 (MACF1), a scaffolding protein with binding sites for microtubules (MT) and actin, is concentrated at neuromuscular synapses, where it binds Rapsyn and serves as a synaptic organizer for MT-associated proteins, EB1 and MAP1b, and the actin-associated protein, Vinculin. MACF1 plays an important role in maintaining synaptic differentiation and efficient synaptic transmission in mice, and variants in MACF1 are associated with congenital myasthenia in humans.