Between 1.5 – 3.8 million people experience a traumatic brain injury each year in the United States and at least 75% of these injuries are a mild TBI (concussive injuries without loss of consciousness). TBI remains a growing health concern, as it’s a leading cause of long-term neurological disability in the world, induces accelerated cognitive aging, and is the strongest environmental risk factor for the development of dementia. Even mild TBI (concussive injury) is associated with a >2-fold increase in the risk of dementia diagnosis. The pathophysiology of TBI is very complex, resulting in chronic behavioral and cognitive impairments that affect the quality of life of millions of individuals. Little is known about the cellular mechanisms responsible for the development of cognitive deficits after injury, thus with no identified targetable mechanisms, there are no treatments to prevent or mitigate deficits resulting from TBI. This dissertation investigates mechanisms contributing to TBI-induced cognitive decline and broadens the scope of TBI research to understand the effect biological sex, aging, and therapeutic whole-brain irradiation.In Chapter 2, I investigated the effect of concussive injury and ISR inhibition on cortical spine dynamics and density and short-term memory function. Concussive injury induced aberrant changes in spine dynamics and density and short-term memory dysfunction. Targeting the ISR using the small-molecule inhibitor ISRIB reversed the maladaptive changes in cortical spine dynamics and the short-term memory dysfunction. Importantly these restorative effects were maintained weeks after treatment ended. In Chapter 3, we investigated the effect of mild repetitive traumatic brain injury, ISR inhibition, and biological sex on cognitive and behavioral function and neuronal function. Mild repetitive injury resulted in increased risk-taking behavior only in male mice and this behavior phenotype was associated with increased activation of the ISR and cell-specific synaptic alterations in type A layer V pyramidal neurons of the medial prefrontal cortex. Importantly, brief pharmacological inhibition of the ISR with ISRIB reversed injury-induced risk-taking behavior and the associated cell-specific deficits in synaptic function. In Chapter 4, we investigated the role of the ISR in healthy age-related cognitive decline. Temporary treatment with ISRIB leads to improvement in spatial, working, and episodic memory. At a cellular level the cognitive enhancement was paralleled by i) improved intrinsic neuron excitability, ii) increased dendritic spine density, iii) reversal of age-induced changes in IFN and T cell responses in the hippocampus and blood, and iv) reversal of ISR activation. In Chapter 5, we investigated the effect whole-brain therapeutic irradiation and concussive injury on the functional role of brain engrafted macrophages. Replacement of microglia with monocyte derived brain engrafted macrophages (BEMs) prevented loss of synapses and consequent memory deficits. Importantly, BEMs replacing microglia were also protective against a second injury to the brain. These chapters collectively add to our understanding of the pathophysiology of TBI with the aim that we are closer to providing effective treatment for a major health crisis in the future.