On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Amyloid plaques and normal ageing have differential effects on microglial Ca2+ activity in the mouse brain.

In microglia, changes in intracellular calcium concentration ([Ca2+]i) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca2+ activity, microglial Ca2+ signals are much rarer and poorly understood. Here, we studied [Ca2+]i changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+ transients occurred ~ 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+ responses change in Alzheimer's disease (AD) using AppNL-G-F knock-in mice. Proximity to Aß plaques strongly affected microglial Ca2+ activity. Although spontaneous Ca2+ transients were unaffected in microglial processes, they were fivefold more frequent in microglial somata near Aß plaques than in wild-type microglia. Microglia away from Aß plaques in AD mice showed intermediate properties for morphology and Ca2+ responses, partly resembling those of wild-type microglia. By contrast, somatic Ca2+ responses evoked by tissue damage were less intense in microglia near Aß plaques than in wild-type microglia, suggesting different mechanisms underlying spontaneous vs. damage-evoked Ca2+ signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca2+]i. Somatic damage-evoked Ca2+ responses were greatly reduced in microglia from old mice, as in the AD mice. In contrast to AD, however, old age did not alter the occurrence of spontaneous Ca2+ signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca2+ activity in microglia from healthy, aged and AD-like brains.

Modelling homeostatic plasticity in the auditory cortex results in neural signatures of tinnitus.

Tinnitus is a clinical condition where a sound is perceived without an external sound source. Homeostatic plasticity (HSP), serving to increase neural activity as compensation for the reduced input to the auditory pathway after hearing loss, has been proposed as a mechanism underlying tinnitus. In support, animal models of tinnitus show evidence of increased neural activity after hearing loss, including increased spontaneous and sound-driven firing rate, as well as increased neural noise throughout the auditory processing pathway. Bridging these findings to human tinnitus, however, has proven to be challenging. Here we implement hearing loss-induced HSP in a Wilson-Cowan Cortical Model of the auditory cortex to predict how homeostatic principles operating at the microscale translate to the meso- to macroscale accessible through human neuroimaging. We observed HSP-induced response changes in the model that were previously proposed as neural signatures of tinnitus, but that have also been reported as correlates of hearing loss and hyperacusis. As expected, HSP increased spontaneous and sound-driven responsiveness in hearing-loss affected frequency channels of the model. We furthermore observed evidence of increased neural noise and the appearance of spatiotemporal modulations in neural activity, which we discuss in light of recent human neuroimaging findings. Our computational model makes quantitative predictions that require experimental validation, and may thereby serve as the basis of future human studies of hearing loss, tinnitus, and hyperacusis.

Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain.

Central nervous system myelination increases action potential conduction velocity. However, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supported by mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitude in the spatial learning task was found to correlate with action potential conduction velocity in the fimbria-fornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in the adult mouse brain.

Pivotal role of carnosine in the modulation of brain cells activity: Multimodal mechanism of action and therapeutic potential in neurodegenerative disorders.

Carnosine (ß-alanyl-l-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Although discovered more than a hundred years ago and having been extensively studied in the periphery, the role of carnosine in the brain remains mysterious. Carnosinemia, a rare metabolic disorder with increased levels of carnosine in urine and low levels or absence of carnosinase in the blood, is associated with severe neurological symptoms in humans. This review deals with the role of carnosine in the brain in both physiological and pathological conditions, with a focus on preclinical evidence suggesting a high therapeutic potential of carnosine in neurodegenerative disorders. We review carnosine and carnosinemia's discoveries and the extensive research on the role and benefits of carnosine in the periphery. We then turn to carnosine's biochemistry and distribution in the brain. Using an array of recent observations as a foundation, we draw a parallel with the role of carnosine in muscles and speculate on the role of carnosine in promoting the metabolic support of neurons by glial cells. Finally, carnosine has been shown to exert a multimodal activity including inhibition of protein cross-linking and aggregation of amyloid-ß and related proteins, free radical generation, nitric oxide detoxification, and an anti-inflammatory activity. It could thus play an important role in the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease. We discuss the potential of carnosine in this context and speculate on new preclinical research directions.

Harnessing Microglia and Macrophages for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors, with a dismal prognosis. During the course of the disease, microglia and macrophages both infiltrate the tumor microenvironment and contribute considerably in glioma development. Thus, tumor-associated microglia and macrophages have recently emerged as potentially key therapeutic targets. Here, we review the physiology of microglia and their responses in brain cancer. We further discuss current treatment options for GBM using radiotherapy, and novel advances in our knowledge of microglia physiology, with emphasis on the recently discovered pathway that controls the baseline motility of microglia processes. We argue that the latter pathway is an interesting therapeutic avenue to pursue for the treatment of glioblastoma.