RESUMEN
Traumatic brain injury (TBI) can result in excitation: inhibition imbalance, as well as a range of chronic neurological deficits. However, how TBI affects different interneurons, and how this relates to behavioral abnormalities, remains poorly understood. This study examined the effects of a mixed diffuse-focal model of TBI, the lateral fluid percussion injury (LFPI), on interneurons, 8 weeks post-TBI in rats. Brains were labeled with antibodies against calbindin, parvalbumin, calretinin, neuropeptide Y, and somatostatin, and the number of interneurons were assessed in the cortex and hippocampus following LFPI. LFPI caused a reduction in the numbers of interneurons mediating both perisomatic and dendritic inhibition in the somatosensory cortex. In hippocampus, there were heterogenous changes in the number of interneurons while motor cortex, showed no obvious loss in any of the subsets of interneurons after TBI. In parallel to the investigations of changes in the number of interneurons, we also investigated the long-term behavioral consequences of LFPI. Behaviorally, rats given an LFPI displayed transient reduction in performance in motor tasks and were significantly impaired in reversal learning in the water maze task post-TBI. We also report here progressive neurodegeneration in cortex and hippocampus indicated by Fluoro-Jade C in the different brain areas examined after injury. Our findings suggest differential vulnerability of inhibitory neurons to LFPI in the different brain areas examined after injury. These data will aid in evaluation of new treatments for TBI and help target specific neuronal subtypes as a function of injury time and type.
Asunto(s)
Lesiones Traumáticas del Encéfalo/patología , Encéfalo/patología , Interneuronas/patología , Animales , Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Masculino , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
Changes in inhibition following traumatic brain injury (TBI) appear to be one of the major factors that contribute to excitation:inhibition imbalance. Neuron pathology, interneurons in particular evolves from minutes to weeks post injury and follows a complex time course. Previously, we showed that in the long-term in diffuse TBI (dTBI), there was select reduction of specific dendrite-targeting neurons in sensory cortex and hippocampus while in motor cortex there was up-regulation of specific dendrite-targeting neurons. We now investigated the time course of dTBI effects on interneurons in neocortex and hippocampus. Brains were labeled with antibodies against calbindin (CB), parvalbumin (PV), calretinin (CR) neuropeptide Y (NPY), and somatostatin (SOM) at 24â¯h and 2â¯weeks post dTBI. We found time-dependent, brain area-specific changes in inhibition at 24â¯h and 2â¯weeks. At 24â¯h post-injury, reduction of dendrite-targeting inhibitory neurons occurred in sensory cortex and hippocampus. At 2â¯weeks, we found compensatory changes in the somatosensory cortex and CA2/3 of hippocampus affected at 24â¯h, with affected interneuronal populations returning to sham levels. However, DG of hippocampus now showed reduction of dendrite-targeting inhibitory neurons. Finally, with respect to motor cortex, there was an upregulation of dendrite-targeting interneurons in the supragranular layers at 24â¯h returning to normal levels by 2â¯weeks. Overall, our findings reconfirm that dendritic inhibition is particularly susceptible to brain trauma, but also show that there are complex brain-area-specific changes in inhibitory neuronal numbers and in compensatory changes, rather than a simple monotonic progression of changes post-dTBI.
Asunto(s)
Traumatismos Difusos del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/fisiopatología , Corteza Cerebral/fisiopatología , Hipocampo/fisiopatología , Neuronas/fisiología , Animales , Traumatismos Difusos del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hipocampo/patología , Masculino , Inhibición Neural/fisiología , Neuronas/patología , Distribución Aleatoria , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Traumatic brain injury (TBI), caused by direct blows to the head or inertial forces during relative head-brain movement, can result in long-lasting cognitive and motor deficits which can be particularly consequential when they occur in young people with a long life ahead. Much is known of the molecular and anatomical changes produced in TBI but much less is known of the consequences of these changes to neuronal functionality, especially in the cortex. Given that much of our interior and exterior lives are dependent on responsiveness to information from and about the world around us, we have hypothesized that a significant contributor to the cognitive and motor deficits seen after TBI could be changes in sensory processing. To explore this hypothesis, and to develop a model test system of the changes in neuronal functionality caused by TBI, we have examined neuronal encoding of simple and complex sensory input in the rat's exploratory and discriminative tactile system, the large face macrovibrissae, which feeds to the so-called "barrel cortex" of somatosensory cortex. In this review we describe the short-term and long-term changes in the barrel cortex encoding of whisker motion modeling naturalistic whisker movement undertaken by rats engaged in a variety of tasks. We demonstrate that the most common form of TBI results in persistent neuronal hyperexcitation specifically in the upper cortical layers, likely due to changes in inhibition. We describe the types of cortical inhibitory neurons and their roles and how selective effects on some of these could produce the particular forms of neuronal encoding changes described in TBI, and then generalize to compare the effects on inhibition seen in other forms of brain injury. From these findings we make specific predictions as to how non-invasive extra-cranial electrophysiology can be used to provide the high-precision information needed to monitor and understand the temporal evolution of changes in neuronal functionality in humans suffering TBI. Such detailed understanding of the specific changes in an individual patient's cortex can allow for treatment to be tailored to the neuronal changes in that particular patient's brain in TBI, a precision that is currently unavailable with any technique.
RESUMEN
Long-term diffuse traumatic brain injury (dTBI) causes neuronal hyperexcitation in supragranular layers in sensory cortex, likely through reduced inhibition. Other forms of TBI affect inhibitory interneurons in subcortical areas but it is unknown if this occurs in cortex, or in any brain area in dTBI. We investigated dTBI effects on inhibitory neurons and astrocytes in somatosensory and motor cortex, and hippocampus, 8 weeks post-TBI. Brains were labeled with antibodies against calbindin (CB), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY), and somatostatin (SOM) and glial fibrillary acidic protein (GFAP), a marker for astrogliosis during neurodegeneration. Despite persistent behavioral deficits in rotarod performance up to the time of brain extraction (TBI = 73.13 ± 5.23% mean ± SEM, Sham = 92.29 ± 5.56%, P < 0.01), motor cortex showed only a significant increase, in NPY neurons in supragranular layers (mean cells/mm2 ± SEM, Sham = 16 ± 0.971, TBI = 25 ± 1.51, P = 0.001). In somatosensory cortex, only CR+ neurons showed changes, being decreased in supragranular (TBI = 19 ± 1.18, Sham = 25 ± 1.10, P < 0.01) and increased in infragranular (TBI = 28 ± 1.35, Sham = 24 ± 1.07, P < 0.05) layers. Heterogeneous changes were seen in hippocampal staining: CB+ decreased in dentate gyrus (TBI = 2 ± 0.382, Sham = 4 ± 0.383, P < 0.01), PV+ increased in CA1 (TBI = 39 ± 1.26, Sham = 33 ± 1.69, P < 0.05) and CA2/3 (TBI = 26 ± 2.10, Sham = 20 ± 1.49, P < 0.05), and CR+ decreased in CA1 (TBI = 10 ± 1.02, Sham = 14 ± 1.14, P < 0.05). Astrogliosis significantly increased in corpus callosum (TBI = 6.7 ± 0.69, Sham = 2.5 ± 0.38; P = 0.007). While dTBI effects on inhibitory neurons appear region- and type-specific, a common feature in all cases of decrease was that changes occurred in dendrite targeting interneurons involved in neuronal integration. J. Comp. Neurol. 524:3530-3560, 2016. © 2016 Wiley Periodicals, Inc.