RESUMEN

The hippocampus is vulnerable to traumatic brain injury (TBI), and hippocampal damage is associated with cognitive deficits that are often the hallmark of TBI. Recent studies have found that TBI induces enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus, and this cellular response is related to innate cognitive recovery. However, cellular mechanisms of the role of DG neurogenesis in post-TBI recovery remain unclear. This study investigated changes in long-term potentiation (LTP) within the DG in relation to TBI-induced neurogenesis. Adult male rats received a moderate TBI or sham injury and were sacrificed for brain slice recordings at 30 or 60 days post-injury. Recordings were taken from the medial perforant path input to DG granule cells in the presence or absence of the GABAergic antagonist picrotoxin, reflecting activity of either all DG granule cells or predominately newborn granule cells, respectively. Measurements of LTP observed in the total granule cell population (with picrotoxin) showed a prolonged impairment which worsened between 30 and 60 days post-TBI. Under conditions which predominantly reflected the LTP elicited in newly born granule cells (no picrotoxin), a strikingly different pattern of post-TBI changes was observed, with a time-dependent cycle of functional impairment and recovery. At 30 days after injury this cell population showed little or no LTP, but by 60 days the capacity for LTP of the newly born granule cells was no different from that of sham controls. The time-frame of LTP improvements in the newborn cell population, comparable to that of behavioral recovery reported previously, suggests the unique functional properties of newborn granule cells enable them to contribute to restorative change following brain injury.

Asunto(s)

Lesiones Traumáticas del Encéfalo/patología , Hipocampo/patología , Plasticidad Neuronal , Sinapsis/patología , Animales , Atrofia , Conducta Animal , Lesiones Traumáticas del Encéfalo/psicología , Gránulos Citoplasmáticos/patología , Fenómenos Electrofisiológicos , Antagonistas del GABA/farmacología , Potenciación a Largo Plazo , Masculino , Picrotoxina/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función

RESUMEN

The interaction between extracellular matrix (ECM) and regulatory matrix metalloproteinases (MMPs) is important in establishing and maintaining synaptic connectivity. By using fluid percussion traumatic brain injury (TBI) and combined TBI and bilateral entorhinal cortical lesion (TBI + BEC), we previously demonstrated that hippocampal stromelysin-1 (MMP-3) expression and activity increased during synaptic plasticity. We now report a temporal analysis of MMP-3 protein and mRNA response to TBI during both degenerative (2 day) and regenerative (7, 15 day) phases of reactive synaptogenesis. MMP-3 expression during successful synaptic reorganization (following unilateral entorhinal cortical lesion; UEC) was compared with MMP-3 expression when normal synaptogenesis fails (after combined TBI + BEC insult). Increased expression of MMP-3 protein and message was observed in both models at 2 days postinjury, and immuohistochemical (IHC) colocalization suggested that reactive astrocytes contribute to that increase. By 7 days postinjury, model differences in MMP-3 were observed. UEC MMP-3 mRNA was equivalent to control, and MMP-3 protein was reduced within the deafferented region. In contrast, enzyme mRNA remained elevated in the maladaptive TBI + BEC model, accompanied by persistent cellular labeling of MMP-3 protein. At 15 days survival, MMP-3 mRNA was normalized in each model, but enzyme protein remained higher than paired controls. When TBI + BEC recovery was enhanced by the N-methyl-D-aspartate antagonist MK-801, 7-day MMP-3 mRNA was significantly reduced. Similarly, MMP inhibition with FN-439 reduced the persistent spatial learning deficits associated with TBI + BEC insult. These results suggest that MMP-3 might differentially affect the sequential phases of reactive synaptogenesis and exhibit an altered pattern when recovery is perturbed.

Asunto(s)

Adaptación Fisiológica/fisiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Expresión Génica/fisiología , Metaloproteinasa 3 de la Matriz/metabolismo , Plasticidad Neuronal/fisiología , Análisis de Varianza , Animales , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/fisiopatología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/uso terapéutico , Corteza Entorrinal/lesiones , Corteza Entorrinal/patología , Corteza Entorrinal/fisiopatología , Lateralidad Funcional , Regulación de la Expresión Génica/fisiología , Ácidos Hidroxámicos/uso terapéutico , Inmunohistoquímica/métodos , Masculino , Metaloproteinasa 3 de la Matriz/genética , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Microscopía Electrónica de Transmisión , Fármacos Neuroprotectores/uso terapéutico , Oligopéptidos/uso terapéutico , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sinapsis/metabolismo , Sinapsis/patología , Sinapsis/ultraestructura

RESUMEN

The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.

Asunto(s)

Lesiones Encefálicas/enzimología , Hipocampo/enzimología , Hipocampo/lesiones , Metaloproteinasa 3 de la Matriz/metabolismo , Plasticidad Neuronal/fisiología , Terminales Presinápticos/enzimología , Regulación hacia Arriba/fisiología , Animales , Astrocitos/enzimología , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Desnervación/efectos adversos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Corteza Entorrinal/lesiones , Corteza Entorrinal/fisiopatología , Regulación Enzimológica de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/enzimología , Gliosis/etiología , Gliosis/fisiopatología , Hipocampo/patología , Inmunohistoquímica , Masculino , Metaloproteinasa 3 de la Matriz/genética , Vías Nerviosas/lesiones , Vías Nerviosas/fisiopatología , Fármacos Neuroprotectores/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley

RESUMEN

Traumatic brain injury (TBI) is documented to have detrimental effects on CNS metabolism, including alterations in glucose utilization and the depression of mitochondrial oxidative phosphorylation. Studies on mitochondrial metabolism have also provided evidence for reduced activity of the cytochrome oxidase complex of the electron transport chain (complex IV) after TBI and an immediate (lhr) reduction in mitochondrial state 3 respiratory rate, which can persist for up to 14 days postinjury. Using differential display methods to screen for differences in gene expression, we have found that cytochrome c oxidase II (COII), a mitochondrial encoded subunit of complex IV, is upregulated following TBI. Since COII carries a binding site for cytochrome c in the respiratory chain, and since it is required for the passage of chain electrons to molecular oxygen, driving the production of ATP, we hypothesized that metabolic dysfunction resulting from TBI alters COII gene expression directly, perhaps influencing the synaptic plasticity that occurs during postinjury recovery processes. To test this hypothesis, we documented COII mRNA expression and complex IV (cytochrome c oxidase) functional activity at 7 days postinjury, focusing on the long-term postinjury period most closely associated with synaptic reorganization. Both central fluid percussion TBI and combined TBI and bilateral entorhinal cortical lesion were examined. At 7 days survival, differential display, RT-PCR, and Northern blot analysis of hippocampal RNA from both TBI and combined insult models showed a significant induction of COII mRNA. This long-term elevation in COII gene expression was supported by increases in COII immunobinding. By contrast, cytochrome oxidase histochemical activity within tissue sections from injured brains suggested a reduction of complex IV activity within the TBI cases, but not within animals subjected to the combined insult. These differences in cytochrome c oxidase activity were supported by in vitro assay of complex IV using cerebral cortical and hippocampal tissues. Our present results support the hypothesis that COII is selectively vulnerable to TBI and that COII differences may indicate the degree of metabolic dysfunction induced by different pathologies. Taken together, such data will better define the role of metabolic function in long-term recovery after TBI.

Asunto(s)

Lesiones Encefálicas/genética , Lesiones Encefálicas/metabolismo , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Regulación Enzimológica de la Expresión Génica/genética , Mitocondrias/enzimología , Animales , Northern Blotting , Clonación Molecular , Metabolismo Energético/fisiología , Corteza Entorrinal/patología , Inmunohistoquímica , Masculino , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/fisiología , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Hippocampal afferents terminate in well-defined laminae, with a morphological segregation of input which has facilitated the interpretation of structural and functional synaptic reorganization observed after deafferentiation. Historically, most studies have induced hippocampal plasticity using single deafferentiation paradigms, however recent evidence indicates that sequential lesions or models based on combined injuries alter the pattern of dendritic structural reorganization and axonal sprouting. A better understanding of the interaction between deafferentiation-induced structural remodeling and other pathological mechanisms, which commonly coexist in central nervous system trauma, will require the use of combined injury paradigms where such plasticity can be systematically manipulated. In the context of traumatic brain injury, we have developed an injury model that combines the excessive neuroexcitation of concussive brain insult with the targeted hippocampal deafferentation of entorhinal cortical lesion. This review discusses the role of such an approach in defining posttraumatic hippocampal vulnerability, out- lining the effects of combined pathology on hippocampal circuitry, and considers the greater clinical relevance inherent in the combined injury approach. Experimental evidence obtained with the combined concussive plus deafferentation model is presented, detailing the interaction of injury components and highlighting structural, behavioral and electrophysiological evidence for maladaptive hippocampal plasticity. Subsequent studies utilizing pharmacological methods to manipulate this maladaptive plasticity are described, first targeting glutamate, acetylcholine and dopamine receptor pathways, and then applying select drugs to explore how various molecular mechanisms underlying combined neuroexcitation and deafferentation pathology might affect regenerative plasticity. Evidence implicating postinjury neurotransmitter modulation of exeitatory/inhibitory homeostasis, metalloproteinase regulation of extracellular matrix, and mitochondrial metabolic vulnerability is presented. Finally, the effect of age on outcome after combined neuroexcitation plus deafferentation insult is considered, as well as how future studies in such combined injury models will better define the full range of postinjury hippocampal plasticity possible after brain trauma.

Asunto(s)

Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Hipocampo/patología , Hipocampo/fisiopatología , Plasticidad Neuronal/fisiología , Animales

RESUMEN

The rat model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry. Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl in both injury models. After TBI + BEC, l-deprenyl also increased AChE in the dentate molecular layer relative to untreated injured cases. These results suggest that dopaminergic/noradrenergic enhancement facilitates cognitive recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic plasticity in the injured hippocampus.

Asunto(s)

Lesiones Encefálicas/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Selegilina/farmacología , Acetilcolinesterasa/metabolismo , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Axones/patología , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Cognición/efectos de los fármacos , Cognición/fisiología , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Dopamina beta-Hidroxilasa/metabolismo , Corteza Entorrinal/lesiones , Corteza Entorrinal/patología , Corteza Entorrinal/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Vías Nerviosas/lesiones , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Plasticidad Neuronal/fisiología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Factores de Tiempo

RESUMEN

Pathological processes affecting presynaptic terminals may contribute to morbidity following traumatic brain injury (TBI). Posttraumatic widespread neuronal depolarization and elevated extracellular potassium and glutamate are predicted to alter the transduction of action potentials in terminals into reliable synaptic transmission and postsynaptic excitation. Evoked responses to orthodromic single- and paired-pulse stimulation were examined in the CA1 dendritic region of hippocampal slices removed from adult rats following fluid percussion TBI. The mean duration of the extracellularly recorded presynaptic volley (PV) increased from 1.08 msec in controls to 1.54 msec in slices prepared at 1 hr postinjury. There was a time-dependent recovery of this injury effect, and PV durations at 2 and 7 days postinjury were not different from controls. In slices removed at 1 hr postinjury, the initial slopes of field excitatory postsynaptic potentials (fEPSPs) were reduced to 36% of control values, and input/output plots revealed posttraumatic deficits in the transfer of excitation from pre- to postsynaptic elements. Manipulating potassium currents with 1.0 mM tetraethylammonium or elevating potassium ion concentration to 7.5 mM altered evoked responses but did not replicate the injury effects to PV duration. Paired-pulse facilitation of fEPSP slopes was significantly elevated at all postinjury survivals: 1 hr, 2 days, and 7 days. These results suggest two pathological processes with differing time courses: 1) a transient impairment of presynaptic terminal functioning affecting PV durations and the transduction of afferent activity in the terminals to reliable synaptic excitation and 2) a more protracted deficit to the plasticity mechanisms underlying paired-pulse facilitation.

Asunto(s)

Lesiones Encefálicas/fisiopatología , Receptores Presinapticos/fisiología , Animales , Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Estimulación Eléctrica , Electrodos Implantados , Electrofisiología , Potenciales Evocados/fisiología , Activación del Canal Iónico/fisiología , Masculino , Plasticidad Neuronal/fisiología , Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Presinapticos/metabolismo , Sistemas de Mensajero Secundario/efectos de los fármacos

RESUMEN

The combination of central fluid percussion traumatic brain injury (TBI) followed 24 h later by a bilateral entorhinal cortical deafferentation (BEC) produces profound cognitive morbidity. We recently showed that MK-801 given prior to TBI in this insult improved spatial memory for up to 15 days. In the present study we examine whether MK-801 treatment of the BEC component in the combined insult model affects cognitive recovery. Two strategies for drug treatment were tested. Fifteen minutes prior to the BEC lesion in the combined insult, rats were given i.p. doses of either 3 mg/kg (acute group) or 1 mg/kg (chronic group) MK-801. The acute group received no further injections, whereas the chronic group received 1 mg/kg MK-801 i.p. twice a day for 2 days post-BEC lesion. Two additional groups of animals received BEC lesion alone and either acute or chronic MK-801 treatment identical with the combined insult cases. Each group was then assessed for spatial memory deficits with the Morris water maze at days 11-15 and 60-64 postinjury. Both acute and chronic MK-801 treatment in the combined insult group significantly reduced spatial memory deficits at 15 days postinjury relative to untreated injured cases (P < .01). This reduction appeared more robust at 15 days and persisted for up to 64 days in the chronically treated group (P < .05). By contrast, neither acute nor chronic MK-801 treatment affected memory performance with the BEC insult alone. Immunocytochemical localization of parvalbumin showed that chronic administration of MK-801 in the combined insult cases attenuated the injury-induced dendritic atrophy of inhibitory neurons in the dentate gyrus and area CA1. Synaptophysin immunobinding revealed that chronic MK-801 treatment of the BEC component of the combined insult normalized the distribution of presynaptic terminals within the dentate gyrus. These results suggest that cognitive deficits produced by head trauma involving both neuroexcitation and deafferentation can be attenuated with chronic application of glutamatergic antagonists during the period of deafferentation injury and that this attenuation is correlated with axo-dendritic integrity.

Asunto(s)

Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Cognición/fisiología , Maleato de Dizocilpina/farmacología , Corteza Entorrinal/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Vías Aferentes/fisiopatología , Animales , Axones/ultraestructura , Cognición/efectos de los fármacos , Dendritas/ultraestructura , Desnervación , Inmunohistoquímica , Masculino , Parvalbúminas/metabolismo , Ratas , Ratas Sprague-Dawley , Sinaptofisina/metabolismo

RESUMEN

We have used an animal model of traumatic brain injury (TBI) that incorporates both the neurotransmitter toxicity of fluid percussion TBI and deafferentation of bilateral entorhinal cortical (BEC) lesion to explore whether administration of muscarinic cholinergic or N-methyl-D-aspartate glutamatergic antagonists prior to injury ameliorates cognitive morbidity. Fifteen minutes prior to moderate central fluid percussion TBI, rats were given intraperitoneal injections of either scopolamine (1.0 mg/kg) or MK-801 (0.3 mg/kg) and 24 hr later underwent BEC lesion. Body weight was followed for 5 days postinjury, as was beam balance and beam walk performance to assure motor recovery prior to spatial memory testing. Each group was assessed for spatial memory deficits with the Morris water maze at short term (days 11-15) and long-term (60-64 days) postinjury intervals and then compared with untreated combined insult and sham-injured controls. Results showed that each drug significantly elevated body weight relative to untreated injured cases. Both scopolamine and MK-801 reduced beam balance deficits, whereas neither drug had a significant effect on beam walk deficits. Interestingly, short-term cognitive deficits assessed on days 11-15 were differentially affected by the two drugs: MK-801 pretreatment enhanced the recovery of spatial memory performance, whereas scopolamine pretreatment did not. Long-term (days 60-64) deficits in spatial memory were not altered by pretreatment with either drug. Our results suggest that, unlike fluid percussion TBI alone, behavioral impairment may require more select intervention when deafferentation is part of the head trauma pathology.

Asunto(s)

Lesiones Encefálicas/fisiopatología , Corteza Entorrinal/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas Muscarínicos/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Escopolamina/farmacología

RESUMEN

Changes in inhibitory neuronal functioning may contribute to morbidity following traumatic brain injury (TBI). Evoked responses to orthodromic paired-pulse stimulation were examined in the hippocampus and dentate gyrus at 2 and 15 days following lateral fluid percussion TBI in adult rats. The relative strength of inhibition was estimated by measuring evoked paired pulses in three afferent systems: the CA3 commissural input to the CA1 region of the hippocampus; the entorhinal cortical input to the ipsilateral CA1 area (temporoammonic system); and the entorhinal input to the ipsilateral dentate gyrus (perforant path). In addition to quantitative electrophysiological estimates of inhibitory efficacy, levels of gamma-aminobutyric acid (GABA) were qualitatively examined with immunohistochemical techniques. Effects of TBI on paired-pulse responses were pathway-specific, and dependent on time postinjury. At 2 days following TBI, inhibition of population spikes was significantly reduced in the CA3 commissural input to CA1, which contrasted with injury-induced increases in inhibition in the dentate gyrus seen at both 2 and 15 days postinjury. Low-level stimulation, subthreshold for population spikes, also revealed changes in paired-pulse facilitation of field extracellular postsynaptic potentials (fEPSPs), which depended on fiber pathway and time postinjury. Significant injury-induced electrophysiological changes were almost entirely confined to the hemisphere ipsilateral to injury. Intensity of GABA immunobinding exhibited a regional association with electrophysiological indices of inhibition, with the most pronounced increases in GABA levels and inhibition found in the dentate gyrus. TBI-induced effects showed a regional pattern within the hippocampus which corresponds closely to inhibitory changes reported to follow ischemia and kindling. This degree of similarity in outcome following dissimilar injuries may indicate common mechanisms in the nervous system response to injury.

Asunto(s)

Lesiones Encefálicas/fisiopatología , Giro Dentado/fisiopatología , Hipocampo/fisiopatología , Neuronas/fisiología , Animales , Giro Dentado/fisiología , Estimulación Eléctrica , Potenciales Evocados , Lateralidad Funcional , Hipocampo/fisiología , Masculino , Plasticidad Neuronal , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica , Factores de Tiempo , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

Among the pathological processes initiated by traumatic brain injury are excessive neuroexcitation and target cell deafferentation. The current study examines the contribution of these injury components, separately as well as their combined effect, on postinjury alterations in the capacity for long-term potentiation and the immunolocalization of N-methyl-D-aspartate receptors and GABA. Adult rats underwent central fluid percussion traumatic brain injury, electrolytic bilateral entorhinal cortex lesions, or a combined injury of both procedures separated by 24 h. At two or 15 days postinjury, the capacity for long-term potentiation of the Schaffer collateral-commissural input to CA1 was measured in acute electrophysiological recordings. Entorhinal cortical lesions resulted in time-dependent increases in the effectiveness of tetanic stimulation to elevate population postsynaptic potentials and population spike amplitudes. These lesions also resulted in a marked intensification in the density of N-methyl-D-aspartate receptors in the CA1 stratum lacunosum-moleculare. All injury conditions that included fluid percussion as a component (alone or in combined injuries) produced a persistent impairment in long-term potentiation of the evoked population postsynaptic potentials. Thus, in combined injuries, the presence of concussion-induced neuroexcitation attenuated deafferentation-induced response increases. Both N-methyl-D-aspartate receptor and GABA immunobinding following combined injuries were also reduced relative to those observed following entorhinal lesions alone. The present results suggest that a process of receptor plasticity, possibly involving reactive synaptogenesis, may contribute to postdeafferentation enhancements of long-term potentiation, and that a traumatic brain insult will attenuate these enhancements. This interaction of different injury components suggests that recovery of function following brain injury may be enhanced by pharmacological reduction of neuroexcitation during postinjury intervals of reactive receptor plasticity.

Asunto(s)

Lesiones Encefálicas/fisiopatología , Corteza Entorrinal/fisiopatología , Potenciación a Largo Plazo/fisiología , Animales , Lesiones Encefálicas/patología , Estimulación Eléctrica , Electrodos Implantados , Electrofisiología , Corteza Entorrinal/patología , Potenciales Evocados/fisiología , Inmunohistoquímica , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiología , Ácido gamma-Aminobutírico/metabolismo

RESUMEN

The effects of traumatic brain injury (TBI) on hippocampal long-term potentiation (LTP) and cellular excitability were assessed at postinjury days 2, 7, and 15. TBI was induced using a well-characterized central fluid-percussion model. LTP of the Schaffer collateral/commissural system was assessed in vivo in urethane-anesthetized rats. Significant LTP of the population excitatory postsynaptic potential (EPSP) slope was found only in controls, and no recovery to control levels was observed for any postinjury time point. Four measurement parameters reflecting pyramidal cell discharges (population spike) indicated that TBI significantly increased cellular excitability at postinjury day 2: (1) pretetanus baseline recording showed that TBI reduced population spike threshold and latency; (2) tetanic stimulation (400 Hz) increased population spike amplitudes to a greater degree in injured animals than in control animals; (3) tetanus-induced population spike latency shifts were greater in injured cases; and (4) tetanic stimulation elevated EPSP to spike ratios (E-S potentiation) to a greater degree in injured animals. These parameters returned to control levels, as measured on postinjury days 7 and 15. These results suggest that TBI-induced excitability changes persist at least through 2 days postinjury and involve a differential impairment of mechanisms subserving LTP of synaptic efficacy and mechanisms related to action potential generation.

Asunto(s)

Lesiones Encefálicas/fisiopatología , Hipocampo/fisiopatología , Potenciación a Largo Plazo , Transducción de Señal/fisiología , Potenciales de Acción/fisiología , Animales , Estimulación Eléctrica , Potenciales Evocados/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiología , Tetania/fisiopatología

RESUMEN

The present study evaluates how the activity of neurons in the dentate gyrus of adult rats is affected by removal of the projection from the ipsilateral entorhinal cortex (EC) and by the reinnervation which follows this injury. We evaluated the average firing rate and characterized interstimulus interval (ISI) parameters for single units in the granule cell layer of the dentate gyrus in two ways: (I) by recording the activity of single neurons prior to and at 15 min and 2, 4, 6, and 8 h. following a unilateral EC lesion; and (II) by calculating average rates for samples of neurons at 2, 4, 6, 8, and 14 days postlesion. Of a sample of 31 neurons whose activity was recorded before and after an EC lesion, 27 (87%) showed decreased activity, and 4 (13%) showed increased activity. The average prelesion firing rate for all cells was 6.5 spikes/s, and the average rate decreased to 2.5 spikes/s at 15 min postlesion. The average firing rate remained depressed for the 8-h recording session, although it was not possible to maintain the recordings for all cells. Evaluations of ISI histograms revealed three general types: (a) a skewed distribution with a single peak; (b) a bimodal distribution with an early peak at intervals of a few ms and a later peak at approximately the same interval as the distributions with single peaks; (c) cells with low firing rates and more or less rectangular distributions. Cells producing each type of ISI histogram exhibited decreases in firing after EC lesions. However, the 4 neurons that exhibited increases in firing had relatively low firing rates prior to the lesion. There were no significant changes in the coefficient of variation or skewness of the ISI histograms following the lesions. The statistical dependency of successive ISIs as revealed by serial correlograms was relatively low in the prelesion sample, and showed no consistent change following the lesion. Comparison of the average firing rates of different samples of neurons at 2-14 days postlesion revealed that the average activity of neurons in the granule cell layer remained depressed at 2 and 4 days postlesion. However, the activity recovered to a level comparable to the prelesion control by 8 days postlesion. The time course of recovery of unit activity was comparable to the time course of sprouting as revealed by previous electrophysiological studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Asunto(s)

Conducta Animal/fisiología , Desnervación , Hipocampo/fisiología , Regeneración Nerviosa , Neuronas/fisiología , Animales , Electrofisiología , Masculino , Ratas , Ratas Endogámicas , Factores de Tiempo

RESUMEN

Previous studies have demonstrated that polyribosomes are selectively positioned beneath postsynaptic sites on CNS neurons. In spine-bearing neurons, these polyribosomes are selectively localized at the base of the spines, and occasionally within spine heads. The present study evaluates whether there are relationships between the polyribosomes and other organelles of the postsynaptic cytoplasm, including membranous cisterns and spine apparatuses. Dendritic spines from the dentate gyrus and hippocampus of the rat were analyzed at the electron-microscopic level in 2 ways. First, relatively thick sections were prepared for electron microscopy, and spines were photographed in stereo using a goniometer stage. Second, conventional serial thin sections were taken, and spines were reconstructed. From the stereo photographs and serial reconstructions, we determined the proportion of polyribosomes that was associated with membranous cisterns. We also counted the number of ribosomes per cluster to determine whether there were differences between polyribosomes in different intradendritic locations, or between free polyribosomes and polyribosomes on cisternal membranes. From the serially reconstructed spines we determined the incidence of polyribosomes, membranous cisterns, and spine apparatuses, and evaluated the relationships between these organelles. We found that in both the dentate gyrus and hippocampus, about 50% of the polyribosomes that were present beneath the base of spines were associated with membranous cisterns. Polyribosomes that were present in the head of the spine were rarely associated with a cistern, however. The overall incidence of polyribosomes was similar in spines with spine apparatuses and spines without a spine apparatus.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Sistema Nervioso Central/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Neuronas/metabolismo , Organoides/metabolismo , Polirribosomas/metabolismo , Sinapsis/metabolismo , Animales , Sistema Nervioso Central/citología , Sistema Nervioso Central/ultraestructura , Citoplasma/metabolismo , Dendritas/metabolismo , Masculino , Microscopía Electrónica , Neuronas/ultraestructura , Ratas , Ratas Endogámicas

RESUMEN

Adult male rats were implanted with chronically indwelling recording electrodes in the dentate hilus of one hemisphere and bipolar stimulating electrodes in the contralateral entorhinal cortex (EC). Daily measurements were then made of the amplitude of responses, evoked through the crossed temporodentate (CTD) pathway, while the rats were unanesthetized and unrestrained. The implanted rats were also trained to alternate turns in a T-maze, with the use of a rewarded-alternation procedure. After reaching criterion performance in the alternation task, each rat was given a lesion of the EC ipsilateral to the recording electrode (n = 14) or a sham lesion (n = 5). Mean amplitudes of the evoked responses increased over Postlesion Days 4-11, probably due to reactive synaptogenesis in the CTD system, reaching a level that was significantly elevated above prelesion levels by Postlesion Day 6. Rats given EC lesions exhibited a transient impairment in alternation performance, with the mean alternation score significantly below prelesion levels on Postlesion Days 2-6. Although 2 EC-lesioned rats did not show a behavioral deficit, the electrophysiological increases and behavioral recovery were correlated in the remaining 12 cases (Pearson r = .73). These results are consistent with the interpretation that sprouting by the CTD system contributes to recovery of T-maze alternation performance following unilateral EC lesions.

Asunto(s)

Aprendizaje Discriminativo/fisiología , Hipocampo/fisiología , Regeneración Nerviosa , Orientación/fisiología , Animales , Potenciales Evocados , Masculino , Ratas , Ratas Endogámicas , Sinapsis/fisiología

RESUMEN

The present study analyzes how the capacity for LTP emerges during lesion-induced sprouting of the crossed temporo-dentate (CTD) pathway of the rat. Adult rats received unilateral entorhinal lesions and were allowed to survive for intervals from 6 to 40 days. The CTD pathway was then studied using conventional acute neurophysiological procedures. Extracellular field potentials were used to measure the synaptic efficacy of the CTD pathway before and after 400 Hz conditioning stimulation (the typical regimen for inducing LTP in the temporo-dentate system). The normal CTD pathway does not exhibit LTP, as noted in previous studies. LTP was first observed in animals recorded at 8-10 days post-lesion, although the increases in synaptic efficacy were not statistically significant until days 12-16 post-lesion. Electron microscopic analyses of the spine and synapse population of the dentate molecular layer at 8 days post-lesion reveal that spines on the postsynaptic cells are structurally immature when the capacity for the LTP first appears. These results are discussed as they relate to the postulated role of the CTD in behavioral recovery following entorhinal cortical lesions, and the potential cellular mechanisms of LTP.

Asunto(s)

Dendritas/ultraestructura , Hipocampo/fisiología , Sistema Límbico/fisiología , Animales , Hipocampo/ultraestructura , Masculino , Potenciales de la Membrana , Regeneración Nerviosa , Vías Nerviosas/fisiología , Ratas , Ratas Endogámicas , Sinapsis/ultraestructura

RESUMEN

The present study had two primary aims. The first was to determine the extent of the visual field of the deprived eye of a monocularly deprived cat using visual perimetry techniques, since recent reports have been contrary to previous research. The second aim was to determine whether enucleation of the experienced eye of a monocularly deprived cat was associated with any increase in the extent of the visual field of the deprived eye compared to forced usage (reverse-suture). The results indicate that the extent of the visual field using the deprived eye is limited to the ipsilateral monocular visual field. Further, enucleation of the experienced eye leads to a rapid expansion of the visual field of the deprived eye to include the entire ipsilateral hemifield which does not occur following reverse-suture. Possible reasons for the conflicting reports in the literature are discussed.

Asunto(s)

Dominancia Cerebral/fisiología , Retina/fisiología , Privación Sensorial/fisiología , Campos Visuales , Animales , Gatos , Orientación/fisiología , Pruebas del Campo Visual , Percepción Visual/fisiología