Thalamic microglia drive cognitive impairment after cortical injuries

ABSTRACT Traumatic brain injury (TBI) increases the risks for cognitive impairment and dementia, such as Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Multiple human imaging studies of the brains after traumatic brain injury reported the signs of prominent microglial activation in the thalamus that highly correlates with cognitive impairment. Nevertheless, the role of thalamic microglia in cognitive impairment after TBI remains unclear. We have recently discovered a unique role of thalamic microglia in cortical injury-induced recognition memory deficits in mice. Our preliminary studies demonstrated that local depletion of thalamic microglia, not hippocampal microglia, counteracted recognition memory deficits. Thalamic microglial depletion also improved thalamic neuronal survival and restored c-Fos expression in multiple recognition memory-related brain regions, including the medial prefrontal cortex (mPFC), hippocampus (HPC), and perirhinal cortex (PRh). Local activation of thalamic neurons restored recognition memory deficits, highlighting a primary role of thalamic neuropathology in the behavioral phenotype. Our single-cell RNA sequencing (scRNA-seq) data revealed the development of microglial subtypes in the thalamus, including the one with high phagocytic capability. Consistent with the molecular findings, the thalamic microglia in the injured brains engulfed neurons and inhibition of phagocytosis attenuated recognition memory deficits in the injured mice. These data suggest that thalamic microglia may promote recognition memory deficits by damaging neurons and synapses. Thus, in the proposed study, we will test our hypothesis that excessive microglial phagocytosis in the thalamus after cortical injuries damages neurons and synapses, causing cognitive impairment. We will use a well-established cortical controlled impact (CCI) model in mice. In Aim 1, we will elucidate cortical injury-induced microglial changes and their effects on neurons in the thalamus. In Aim 2, we will demonstrate that removal of thalamic microglia has an immediate restorative effect and a long-term ameliorative effect on recognition memory in the injured mice. In Aim 3, we will evaluate the effects of microglial phagocytosis inhibition on thalamic neuronal pathology and cognitive impairment after cortical injuries. Together, this study will assess the role of thalamic microglia phagocytosis in cognitive impairment after cortical injuries. The findings will provide a novel mechanistic insight into the critical thalamic pathology underlying TBI-induced long-term neurological deficits.