Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: A systems, network and cellular evaluation
Section snippets
Generation of TBI animals
Adult male C57BL/6J mice (5–7 weeks, 20–25 g; Jackson Laboratory, Bar Harbor, ME, USA) were used in all experiments. All experimental procedures and protocols for animal studies were approved by the University of Pennsylvania and the Children’s Hospital of Philadelphia Institutional for Animal Care and Use Committees in accordance with international guidelines on the ethical use of animals. Experiments were designed to minimize the number of animals required and those used were cared for,
Injury-Induced retrograde amnesia
Since retrograde amnesia is a feature of human TBI, the present study tested FPI retrograde amnesia in the mouse using contextual fear response. Brain-injured mice were hypothesized to be incapable of recalling the association between a trained context and the aversive stimulus that was conditioned prior to brain injury. Injured mice (n=17) demonstrated a 38% decrease in fear-associated freezing in the trained context as compared with sham (n=18) during the total 5 min testing period 1 week
Discussion
A hippocampal-dependent cognitive deficit in contextual fear-associated memory was observed 1 week following mouse FPI. These deficits were observed concordantly with a 30–40% neuronal loss throughout the hippocampus and functional alterations that are present in the surviving 60–70% of the hippocampal neurons ipsilateral to the injury. In brain-injured animals, observed alterations include: (1) hippocampal-dependent reductions in fear-associated freezing in the context associated with the foot
Conclusions
We have utilized a systems approach to explore hippocampal changes that may contribute to the cognitive deficits that follow brain injury at the systems, network and cellular levels. The extent to which hippocampal neuron loss, shifts in excitability and synaptic alterations contribute to the observed cognitive deficit remains to be determined. The changes in hippocampal circuit function after FPI may be due to a combination of the reduction of number of viable neurons throughout the
Acknowledgments
We thank Patrick Williams, Krishna Reddy and Dr. Harun Evcimen for technical support; and Drs. Ted Abel and Matt Lattal for guidance and insightful discussions regarding behavioral paradigms. We are grateful to Dr. Karl-Anton Dorph-Petersen for assistance with stereological analysis and Dr. Greg Carlson for constructive suggestions on the manuscript. This work was supported by the Sharpe Foundation, the Groff Foundation (M.S.G.) and NIH/NINDS NS45975 (A.S.C.).
References (87)
- et al.
Hippocampally dependent and independent chronic spatial navigational deficits following parasagittal fluid percussion brain injury in the rat
Brain Res
(1997) - et al.
Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice
Neurobiol Aging
(1998) - et al.
The EPSP-spike (E-S) component of long-term potentiation in the rat hippocampal slice is modulated by GABAergic but not cholinergic mechanisms
Neurosci Lett
(1989) - et al.
Brain injury-induced enhanced limbic epileptogenesisanatomical and physiological parallels to an animal model of temporal lobe epilepsy
Epilepsy Res
(1996) - et al.
Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury
Brain Res
(1998) - et al.
Is the HM story only a “remote memory”? Some facts about hippocampus and memory in humans
Behav Brain Res
(2001) Contextual learning and cue association in fear conditioning in micea strain comparison and a lesion study
Behav Brain Res
(1998)- et al.
Delayed recovery of intellectual function after minor head injury
Lancet
(1974) - et al.
Mild traumatic lesion of the right parietal cortex in the ratcharacterisation of a conditioned freezing deficit and its reversal by dizocilpine
Behav Brain Res
(1998) - et al.
Field potential evidence for long-term potentiation of feed-forward inhibition in the rat dentate gyrus
Brain Res
(1987)
Lactate accumulation following fluid percussion injurythe role of ionic fluxes induced by excitatory amino acids
Brain Res
Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats
Brain Res
Analysis of the kinetics of synaptic inhibition points to a reduction in GABA release in area CA1 of the genetically epileptic mouse, El
Epilepsy Res
Short-term recognition memory in relation to severity of head injury
Cortex
Neuropsychiatric sequelae of head injuries
Psychiatr Clin North Am
Mifepristone protects CA1 hippocampal neurons following traumatic brain injury in rat
Neuroscience
Traumatic brain injury in the ratcharacterization of a lateral fluid-percussion model
Neuroscience
Contributions of the entorhinal cortex, amygdala and hippocampus to human memory
Neuropsychologia
Positive and negative modulation of the GABA(A) receptor and outcome after traumatic brain injury in rats
Brain Res
Learning impairments and motor dysfunctions in adult Lhx5-deficient mice displaying hippocampal disorganization
Physiol Behav
Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats
Neuroscience
The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus
Brain Res
Chronic failure in the maintenance of long-term potentiation following fluid percussion injury in the rat
Brain Res
Persistent memory dysfunction is associated with bilateral hippocampal damage following experimental brain injury
Neurosci Lett
Tonic inhibition originates from synapses close to the soma
Neuron
Stereological methods for estimating the total number of neurons and synapsesissues of precision and bias
Trends Neurosci
Diffuse axonal injury in head injurydefinition, diagnosis and grading
Histopathology
Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys
J Neurosci
Temporally graded retrograde amnesia of contextual fear after hippocampal damage in ratswithin-subjects examination
J Neurosci
Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex
J Neurosci
Neuronal cell loss in the CA3 subfield of the hippocampus following cortical contusion utilizing the optical disector method for cell counting
J Neurotrauma
Memory deficits characterized by patterns of lesions to the hippocampus and parahippocampal cortex
Ann NY Acad Sci
Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model
Science
Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse
Acta Neuropathol (Berl)
Adaptation of the fluid percussion injury model to the mouse
J Neurotrauma
Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus
Hippocampus
Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors
J Neurophysiol
Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons
J Neurophysiol
Dentate granule cell GABA(A) receptors in epileptic hippocampusenhanced synaptic efficacy and altered pharmacology
Eur J Neurosci
Impaired K(+) homeostasis and altered electrophysiologic properties of post-traumatic hippocampal glia
J Neurosci
A fluid percussion model of experimental brain injury in the rat
J Neurosurg
Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy
Proc Natl Acad Sci USA
Interneurons of the hippocampus
Hippocampus
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These authors contributed equally to this study.