Neuronal Adhesion and Synapse Organization After TBI
Neuronal Adhesion and Synapse Organization After TBI
It is critical to understand the need for and basis of experimental injury that models the human condition in order to target potential therapeutics for TBI. The element of TBI in humans that greatly hinders the development of effective therapeutic targets is the enormous heterogeneity of injuries on a macroscopic scale. Animal models of mild, moderate and severe TBI can provide the basis to further understand the cellular and molecular mechanisms of brain injury. The animal models, which are used to replicate human TBI, control for type and severity of injury, age and sex of animals, recovery period and homogeneity of genetic background. While the findings from one animal model cannot be applicable for all types of injuries, animal models will continue to be the cornerstone for discovery and testing of therapeutic targets in humans. Selection of the proper animal model is critically dependent on the type of molecular or pathophysiological question asked. The authors limit this review to the use of rodents as animal models for human brain injury as studies in rats and mice allow for the mechanistic analysis of recovery processes that is the focus of this survey. When making comparisons among studies, differences in pathology and behavioral tests among strains of mice and rats, after TBI, should be considered.
While cellular processes are similar in the rodent and human brain, there are some striking differences that should be noted. First, the rodent brain is not gyrencephalic, with sulci and gyri, like the human brain. Instead, its cortex is smooth, or lissencephalic. Second, regional brain proportions and positions, connectivity between brain areas and percentages of gray and white matter are markedly different in the rodent versus the human brain. While the physiologic relevance of these differences with respect to human brain injury is not known, the reproducibility of currently used injury models and the generation of data that correlate with many aspects of the human condition support the continued use of rodents in modeling TBI.
The relevance of different TBI models can be determined by drawing parallels between findings in the human disease process and in different animal experimental models. TBI models are designed to mimic human physiological and pathological conditions with brain injury. A complete discussion of each of the models of TBI is beyond the scope of this article, and the authors refer the reader to three excellent papers for in-depth review. Briefly, the most commonly used methods of TBI in experiments reviewed here are direct impact models using penetrating injury with direct contact to the brain or nonpenetrating head injury where the skull remains intact. There are also models of indirect injury, such as blast wave (explosion) injury. Of note, in all these studies the animals are anesthetized to ensure the ethical use of animals in research.
The most commonly used model of direct TBI is fluid percussion injury (FPI) method through a craniotomy. The FPI model causes injury by a piston striking a reservoir of fluid to the surface of intact dura, creating a fluid pressure pulse. Using FPI models in rodents, animals develop: brain edema; intracranial hemorrhage; neuronal loss; and expansion of injury to other brain regions, including the hippocampus, by 1-week postinjury. Apart from neuronal loss, axons of the remaining neurons are swollen. Synaptophysin, a presynaptic vesicle marker, accumulates at synapse terminals, although the overall level of synaptophysin does not change, indicating changes in the cellular trafficking of synaptic proteins. In addition, there is significant spine density loss in the cortex and the dentate gyrus of the hippocampus 24 h after FPI, which provides histological evidence for synaptic dysfunction after TBI. After FPI, animals develop lasting impairments in learning and memory as in humans with brain injury.
The controlled cortical impact (CCI) model causes injury by a direct impact from a piston to the surface of the intact dura through a craniotomy. An advantage of CCI over FPI is greater control over injury parameters. The histopathology that develops with FPI also develops post-CCI, including significant loss of dendritic spines. Furthermore, because of the fine control over the severity of injury, there is a measurable graded change in pathology and cognitive functions that directly correlates with the degree of CCI.
Nonpenetrating injury models mimic closed head injuries. Blast injury models are employed as military personnel are exposed to injury sustained with detonations. With blast injury models, anesthetized animals are typically placed in a compression-driven shock tube. Weight-drop models mimic concussions and a focal blunt head injury is delivered by a weight dropped from a standard height onto the anesthetized animal's intact skull. Both models cause CNS pathophysiology and behavior changes in animals that resemble those found in humans.
Much of the cellular and molecular studies on elevated intracranial pressure, hemorrhage and neuronal tissue injury (as seen in TBI) are derived from experimental work from models of cerebral ischemia after stroke. The initial mechanisms of injury for the two types of complex disease processes of stroke and TBI are very different, but there are striking similarities with respect to subsequent pathophysiology.
Stroke, most frequently caused by a therothrombotic disease of arteries, results in severe and acute decreases in blood flow to brain tissue. Ischemic injury to neurons ensues because they do not store alternative energy sources; metabolic imbalance quickly follows. With metabolic stress, there is failure of membrane ionic pumps and cellular swelling results. Cellular/axonal swelling is detrimental, causing increases in intracranial pressure and further decreases in cerebral blood flow. Focal brain ischemia, which occurs in ischemic stroke in humans, can be modeled by occlusion of the middle cerebral artery (MCAO) in rodents. The cellular pathology and physiology that result from this model of cerebral ischemia include: elevated intracranial pressure; neuronal loss; axonal swelling; accumulation of synaptophysin at synapse terminals; and importantly, a marked loss of synaptic spines directly related to the severity of ischemic injury. In this review, we will include studies on models of cerebral ischemia and cell adhesion molecules because of the similarities between injury caused by ischemia and trauma on the cellular level.
Models of Injury
Rodent Models of Injury & Relevance to the Human Condition
It is critical to understand the need for and basis of experimental injury that models the human condition in order to target potential therapeutics for TBI. The element of TBI in humans that greatly hinders the development of effective therapeutic targets is the enormous heterogeneity of injuries on a macroscopic scale. Animal models of mild, moderate and severe TBI can provide the basis to further understand the cellular and molecular mechanisms of brain injury. The animal models, which are used to replicate human TBI, control for type and severity of injury, age and sex of animals, recovery period and homogeneity of genetic background. While the findings from one animal model cannot be applicable for all types of injuries, animal models will continue to be the cornerstone for discovery and testing of therapeutic targets in humans. Selection of the proper animal model is critically dependent on the type of molecular or pathophysiological question asked. The authors limit this review to the use of rodents as animal models for human brain injury as studies in rats and mice allow for the mechanistic analysis of recovery processes that is the focus of this survey. When making comparisons among studies, differences in pathology and behavioral tests among strains of mice and rats, after TBI, should be considered.
While cellular processes are similar in the rodent and human brain, there are some striking differences that should be noted. First, the rodent brain is not gyrencephalic, with sulci and gyri, like the human brain. Instead, its cortex is smooth, or lissencephalic. Second, regional brain proportions and positions, connectivity between brain areas and percentages of gray and white matter are markedly different in the rodent versus the human brain. While the physiologic relevance of these differences with respect to human brain injury is not known, the reproducibility of currently used injury models and the generation of data that correlate with many aspects of the human condition support the continued use of rodents in modeling TBI.
Performing & Assessing Brain Injury in Rodents
The relevance of different TBI models can be determined by drawing parallels between findings in the human disease process and in different animal experimental models. TBI models are designed to mimic human physiological and pathological conditions with brain injury. A complete discussion of each of the models of TBI is beyond the scope of this article, and the authors refer the reader to three excellent papers for in-depth review. Briefly, the most commonly used methods of TBI in experiments reviewed here are direct impact models using penetrating injury with direct contact to the brain or nonpenetrating head injury where the skull remains intact. There are also models of indirect injury, such as blast wave (explosion) injury. Of note, in all these studies the animals are anesthetized to ensure the ethical use of animals in research.
The most commonly used model of direct TBI is fluid percussion injury (FPI) method through a craniotomy. The FPI model causes injury by a piston striking a reservoir of fluid to the surface of intact dura, creating a fluid pressure pulse. Using FPI models in rodents, animals develop: brain edema; intracranial hemorrhage; neuronal loss; and expansion of injury to other brain regions, including the hippocampus, by 1-week postinjury. Apart from neuronal loss, axons of the remaining neurons are swollen. Synaptophysin, a presynaptic vesicle marker, accumulates at synapse terminals, although the overall level of synaptophysin does not change, indicating changes in the cellular trafficking of synaptic proteins. In addition, there is significant spine density loss in the cortex and the dentate gyrus of the hippocampus 24 h after FPI, which provides histological evidence for synaptic dysfunction after TBI. After FPI, animals develop lasting impairments in learning and memory as in humans with brain injury.
The controlled cortical impact (CCI) model causes injury by a direct impact from a piston to the surface of the intact dura through a craniotomy. An advantage of CCI over FPI is greater control over injury parameters. The histopathology that develops with FPI also develops post-CCI, including significant loss of dendritic spines. Furthermore, because of the fine control over the severity of injury, there is a measurable graded change in pathology and cognitive functions that directly correlates with the degree of CCI.
Nonpenetrating injury models mimic closed head injuries. Blast injury models are employed as military personnel are exposed to injury sustained with detonations. With blast injury models, anesthetized animals are typically placed in a compression-driven shock tube. Weight-drop models mimic concussions and a focal blunt head injury is delivered by a weight dropped from a standard height onto the anesthetized animal's intact skull. Both models cause CNS pathophysiology and behavior changes in animals that resemble those found in humans.
Different Types of Brain Injury: Similarities Between Models of Ischemic Stroke & Trauma
Much of the cellular and molecular studies on elevated intracranial pressure, hemorrhage and neuronal tissue injury (as seen in TBI) are derived from experimental work from models of cerebral ischemia after stroke. The initial mechanisms of injury for the two types of complex disease processes of stroke and TBI are very different, but there are striking similarities with respect to subsequent pathophysiology.
Stroke, most frequently caused by a therothrombotic disease of arteries, results in severe and acute decreases in blood flow to brain tissue. Ischemic injury to neurons ensues because they do not store alternative energy sources; metabolic imbalance quickly follows. With metabolic stress, there is failure of membrane ionic pumps and cellular swelling results. Cellular/axonal swelling is detrimental, causing increases in intracranial pressure and further decreases in cerebral blood flow. Focal brain ischemia, which occurs in ischemic stroke in humans, can be modeled by occlusion of the middle cerebral artery (MCAO) in rodents. The cellular pathology and physiology that result from this model of cerebral ischemia include: elevated intracranial pressure; neuronal loss; axonal swelling; accumulation of synaptophysin at synapse terminals; and importantly, a marked loss of synaptic spines directly related to the severity of ischemic injury. In this review, we will include studies on models of cerebral ischemia and cell adhesion molecules because of the similarities between injury caused by ischemia and trauma on the cellular level.
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