Traumatic brain injury (TBI) is a major public health concern. Even when brain trauma is mild many individuals suffer from neuropsychological impairments such as memory loss, learning deficits, long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI and were designed to produce a relatively homogeneous type of injury, with age, gender, genetic background and the injury parameters all well controlled. Animal models may not be able to fully recapitulate all aspects of secondary injury development observed in human TBI, however, these models are essential for studying the biomechanical, cellular and molecular aspects of human TBI that cannot be addressed in the clinical setting, as well as for developing novel treatments. Animal studies have shown that TBI-induced wide range of effects may result from structural damage and functional deficits within the hippocampus. Functional plasticity of synaptic networks in the hippocampus has been implicated in the development of posttraumatic epilepsy after TBI. Within the hippocampus Dentate Gyrus (DG) acts as “gatekeeper” and “filter” of aberrant or excessive input information. DG function is directly determined by a delicate balance between neuronal excitation and inhibition and TBI can cause changes of this state of equilibrium. Moreover, TBI can affect adult hippocampal neurogenesis (AHN). AHN is the process of generating new neurons in the dentate gyrus (DG) from neural stem cells (NSCs) that integrate into the hippocampal circuitry by establishing synapses with existing neurons. AHN has been shown to participate in space navigation-related memory formation, learning, fear conditioning, anxiety, stress and pattern separation. NSCs are radial astrocytes like cells with radial glia properties. NSCs remain quiescent and are activated progressively to divide asymmetrically giving rise to neuronal precursors. Once they finish their round of divisions they differentiate into astrocytes losing their stem cell capabilities and because the activation of NSCs is coupled with their exhaustion, the population of NSCs declines over time. This decline of NSCs population and neurogenesis, that naturally occurs with aging, might also be accelerated due to neuronal hyperexcitation and excitotoxicity. We hypothesized, that TBI-induced hyperexcitation of existing granule cells (GCs) within DG can induce long-term changes in both NSCs and newborn neurons and those alterations can further contribute to hippocampal dysfunction.
The main goal of Newron-TBI was set to bring light to the long standing debate on how TBI affects DG circuitry and AHN. We aimed to investigate the short and long term effects of controlled cortical impact (CCI) as a model of TBI on NSCs and the neurogenic niche. We aimed to understand what particular changes TBI induces at the cellular, molecular and electrophysiological level in existing GCs, NSCs and newborn neurons.
