CBS Seminar: Samuel Barnes- Age-related dysregulation of micro-circuit homeostasis

Bio: Barnes graduated from Oxford University in 2006 and was awarded an M.R.C. Capacity Building Ph.D. studentship at King’s College London (KCL), to investigate the functional signatures of synaptic connection loss in the cortex. He then completed a post-doc investigating homeostatic plasticity in mouse visual cortex at University College London (UCL). In October 2015, he won the internationally competitive Safra Fellowship, an award which supports early career researchers as they tr¬ansition to independence. In April 2018, he was awarded a UK Dementia Research Institute (UK DRI) Fellowship and became a lecturer in the Division of Brain Sciences at Imperial College London (ICL). In September 2022 he was promoted to Senior Lecturer in Neural Plasticity and in April 2023 successfully underwent UK DRI renewal, providing long-term funding support until 2028. In March 2024, he was appointed Interim Deputy Director of the UK DRI Centre at Imperial. 

His group focuses on homeostatic plasticity mechanisms that regulate neural firing-rate activity within a stable dynamic range, preventing prolonged periods of hyper- or hypo-activity. The group’s central hypothesis is that homeostatic control is neuroprotective but may fail in ageing and the early stages of neurodegeneration, leading to pathophysiological neural-circuit activity. To test this hypothesis, the Barnes Lab use a combination of electrophysiology, 2-Photon calcium imaging and 1-Photon brain-wide imaging. The group combines these approaches with molecular measures such as transcriptomics and spatial proteomics to probe the mechanisms involved in homeostatic control, as well as behavioural testing to measure the consequences of destabilized neural-circuit activity.

Abstract: One approach to promote healthy neurological ageing is to target disease specific mechanisms involved in age-related neurodegenerative disorders. An alternative, and less well understood possibility, is to boost cellular processes supporting endogenous resilience to negative ageing effects in the brain. To address the latter, we determine molecular mechanisms underpinning homeostasis of neuronal activity across brain regions and life-stages in mice. We do this to inform development of interventions that may promote homeostasis and have positive consequences for age-sensitive cognition. We focus on in-vivo mechanisms guarding against neuronal hyperactivity, as these are poorly understood, and their age-related dysregulation has been linked to cognitive impairments.

Recently, we identified the adult cortical plasticity response to elevated activity driven by sensory overstimulation, and then tested how plasticity changes with age in mice. We used in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduced cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also found that overstimulation disrupted cognition in older but not younger animals. Boosting mGluR5 function protected cognition against overstimulation in older animals. Our work suggests that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.