Mapping the primate lateral geniculate nucleus: A review of experiments and methods

Mapping neuronal responses in the lateral geniculate nucleus (LGN) is key to understanding how visual information is processed in the brain. This paper focuses on our current knowledge of the dynamics the receptive field (RF) as broken down into the classical receptive field (CRF) and the extra-classical receptive field (ECRF) in primate LGN. CRFs in the LGN are known to be similar to those in the retinal ganglion cell layer in terms of both spatial and temporal characteristics, leading to the standard interpretation of the LGN as a relay center from retina to primary visual cortex. ECRFs have generally been found to be large and inhibitory, with some differences in magnitude between the magno-, parvo-, and koniocellular pathways. The specific contributions of the retina, thalamus, and visual cortex to LGN ECRF properties are presently unknown. Some reports suggest a retinal origin for extra-classical suppression based on latency arguments and other reports have suggested a thalamic origin for extra-classical suppression. This issue is complicated by the use of anesthetized animals, where cortical activity is likely to be altered. Thus further study of LGN ECRFs is warranted to reconcile these discrepancies. Producing descriptions of RF properties of LGN neurons could be enhanced by employing preferred naturalistic stimuli. Although there has been significant work in cats with natural scene stimuli and noise that statistically imitates natural scenes, we highlight a need for similar data from primates. Obtaining these data may be aided by recent advancements in experimental and analytical techniques that permit the efficient study of nonlinear RF characteristics in addition to traditional linear factors. In light of the reviewed topics, we conclude by suggesting experiments to more clearly elucidate the spatial and temporal structure of ECRFs of primate LGN neurons

Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Funder: Charles H. Hood Child Health FoundationFunder: Wellcome Trust ISSFFunder: CRUK Cambridge CentreFunder: AstraZeneca PhD studentshipFunder: Suh Kyungbae FoundationFunder: University of Cambridge Joint Research Grants SchemeFunder: Isaac Newton TrustThe autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neuronal material. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. Activation of non-canonical NF-κB signalling is also observed in cerebellar microglia of individuals with Ataxia-telangiectasia. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia-telangiectasia

ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia

Summary: While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T