Development of Prolonged Focal Cerebral Edema and Regional Cation Changes Following Experimental Brain Injury in the Rat

The present study examined the formation of regional cerebral edema in adult rats subjected to lateral (parasagittal) experimental fluid-percussion brain injury. Animals receiving fluid-percussion brain injury of moderate severity over the left parietal cortex were assayed for brain water content at 6 h, 24 h, and 2, 3, 5, and 7 days post injury. Regional sodium and potassium concentrations were measured in a separate group of animals at 10 min, 1 h, 6 h, and 24 h following fluid-percussion injury. Injured parietal cortex demonstrated significant edema, beginning at 6 h post injury (p less than 0.05) and persisting up to 5 days post injury. In the hippocampus ipsilateral to the site of cortical injury, significant edema occurred as early as 1 h post injury (p less than 0.05), with resolution of water accumulation beginning at 3 days. Sodium concentrations significantly increased in both injured cortex (1 h post injury, p less than 0.05) and injured hippocampus (10 min post injury, p less than 0.05). Potassium concentrations fell significantly 1 h post injury within the injured cortex (p less than 0.05), whereas significant decreases were not observed until 24 h post injury within the injured hippocampus. Cation alterations persisted throughout the 24-h post injury period. These results demonstrate that regional brain edema and cation deregulation occur in rats subjected to lateral fluid-percussion brain injury and that these changes may persist for a prolonged period after brain injury.     

脑外伤时猫大脑皮质和海马N─甲基─D─天冬氨酸受体的变化

本实验采用放射性配基受体结合分析法,测定了猫脑外伤时大脑皮质和海马Ｎ─甲基─Ｄ─天冬氨酸受体（ＮＭＤＡＲ）的变化。并用氨基酸自动分析仪观察了猫大脑皮质兴奋性氨基酸含量变化。结果表明,伤后２和６ｈ两侧大脑皮质和海马ＮＭＤＡＲ的最大结合容量明显降低,伤后２ｈ以海马变化最大,并以伤后６ｈ伤侧大脑皮质中降低最为显著;而大脑皮质兴奋性氨基酸含量伤后５ｍｉｎ即显著升高,然后呈下降趋势,且以伤侧大脑皮质变化为大。提示：脑外伤后ＮＭＤＡＲ的下调与兴奋性氨基酸的大量释放有关,可能在兴奋毒性脑损伤中起重要作用。     

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post‐TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d‐amphetamine‐induced rotational behavior. Adult male Sprague–Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine‐induced rotational behavior was assessed 10 days post‐CCI. Fourteen days post‐CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V_max (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury‐related changes in vesicular monoamine transporter or D₂ receptor expression (DRD₂) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.     

The effects of α-lipoic acid on immature rats with traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality during childhood. TBI enhances formation of reactive oxygen species that cause neuron damage and apoptosis. α-Lipoic acid (LA) is a free radical scavenger and biological antioxidant. We investigated the effects of LA treatment on the parietal and prefrontal cortex, and on the hippocampal regions of the brain in 7-day-old rat pups that had been subjected to contusion injury. Forty-two male rats were divided randomly into a control group, a TBI group and a TBI + LA treated group. LA was administered 30 min after TBI through an intragastric tube once daily for 2 days. Forty-eight hours after TBI, the animals were sacrificed and tissues were examined for apoptosis and density of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and active caspase-3 immunostaining were used to detect apoptosis. Glutathione peroxidase (GPx), superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels also were measured. Histological evaluation showed that LA treatment significantly reduced TBI-induced neuronal death in the hippocampus, prefrontal and parietal cortex; TUNEL- and caspase-3-positive cells also were decreased in the same regions. In addition, LA administration increased GPx and SOD activity in the prefrontal cortex. It appears that LA may be beneficial for TBI in rats.     

Mitochondrial dysfunction early after traumatic brain injury in immature rats

Mitochondria play central roles in acute brain injury; however, little is known about mitochondrial function following traumatic brain injury (TBI) to the immature brain. We hypothesized that TBI would cause mitochondrial dysfunction early (<4 h) after injury. Immature rats underwent controlled cortical impact (CCI) or sham injury to the left cortex, and mitochondria were isolated from both hemispheres at 1 and 4 h after TBI. Rates of phosphorylating (State 3) and resting (State 4) respiration were measured with and without bovine serum albumin. The respiratory control ratio was calculated (State 3/State 4). Rates of mitochondrial H(2)O(2) production, pyruvate dehydrogenase complex enzyme activity, and cytochrome c content were measured. Mitochondrial State 4 rates (ipsilateral/contralateral ratios) were higher after TBI at 1 h, which was reversed with bovine serum albumin. Four hours after TBI, pyruvate dehydrogenase complex activity and cytochrome c content (ipsilateral/contralateral ratios) were lower in TBI mitochondria. These data demonstrate abnormal mitochondrial function early (相似文献   

Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite

Programmed cell death occurs after ischemic, excitotoxic, and traumatic brain injury (TBI). Recently, a caspase-independent pathway involving intranuclear translocation of mitochondrial apoptosis-inducing factor (AIF) has been reported in vitro; but whether this occurs after acute brain injury was unknown. To address this question adult rats were sacrificed at various times after TBI. Western blot analysis on subcellular protein fractions demonstrated intranuclear localization of AIF in ipsilateral cortex and hippocampus at 2-72 h. Immunocytochemical analysis showed AIF labeling in neuronal nuclei with DNA fragmentation in the ipsilateral cortex and hippocampus. Immunoelectronmicroscopy verified intranuclear localization of AIF in hippocampal neurons after TBI, primarily in regions of euchromatin. Large-scale DNA fragmentation ( approximately 50 kbp), a signature event in AIF-mediated cell death, was detected in ipsilateral cortex and hippocampi by 6 h. Neuron-enriched cultures exposed to peroxynitrite also demonstrated intranuclear AIF and large-scale DNA fragmentation concurrent with impaired mitochondrial respiration and cell death, events that are inhibited by treatment with a peroxynitrite decomposition catalyst. Intranuclear localization of AIF and large-scale DNA fragmentation occurs after TBI and in neurons under conditions of oxidative/nitrosative stress, providing the first evidence of this alternative mechanism by which programmed cell death may proceed in neurons after brain injury.     

Dynamic Changes in Brain Activations and Functional Connectivity during Affectively Different Tactile Stimuli

In the present study, we compared brain activations produced by pleasant, neutral and unpleasant touch, to the anterior lateral surface of lower leg of human subjects. It was found that several brain regions, including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII), as well as contralateral middle and posterior insula cortex were commonly activated under the three touch conditions. In addition, pleasant and unpleasant touch conditions shared a few brain regions including the contralateral posterior parietal cortex (PPC) and bilateral premotor cortex (PMC). Unpleasant touch specifically activated a set of pain-related brain regions such as contralateral supplementary motor area (SMA) and dorsal parts of bilateral anterior cingulated cortex, etc. Brain regions specifically activated by pleasant touch comprised bilateral lateral orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), intraparietal cortex and left dorsal lateral prefrontal cortex (DLPFC). Using a novel functional connectivity model based on graph theory, we showed that a series of brain regions related to affectively different touch had significant functional connectivity during the resting state. Furthermore, it was found that such a network can be modulated between affectively different touch conditions.     

创伤性脑损伤对大鼠海马骨架蛋白及学习记忆功能影响

创伤性脑损伤（traumatic brain injury,TBI）是极为常见的外伤性疾病,致死率和致残率很高。存活者伴随的空间认知功能障碍,给患者家庭和社会造成了极大的负担。目前,对TBI造成的空间记忆障碍缺乏系统研究。脑损伤后海马组织与记忆有关的分子以及组成神经元骨架的分子如何变化研究甚少。本研究采用Wistar大鼠为研究对象,并随机将其分为假手术（sham）组和创伤性脑损伤（TBI）组。TBI组再按致伤后时间长短分为6 h、12 h、24 h、72 h、15 d五个亚组。TBI组应用PinPointTM颅脑撞击器撞击而致伤,sham组不撞击。采用Morris水迷宫评价实验动物空间记忆能力;干湿重法测定脑含水量,评估脑水肿与海马水通道蛋白4（aquaporin-4,AQP-4）的相关性;海马神经元特异性核蛋白（neuron specific nuclear protein,NeuN）标记和免疫荧光检测评估TBI致大鼠神经元丢失情况;通过Western印迹检测TBI致海马骨架相关蛋白质和记忆相关蛋白质含量变化。本研究证实,与sham组相比,TBI组大鼠潜伏期明显增加［（61.98±12.82) s vs.(28.32±8.52) s,n=5,P<0.01,day 15］,探索时间明显缩短［（36.98±0.37) s vs. (73.68±5.09) s,n=5,P<0.01,day15］,表明脑创伤损害了动物的空间参考记忆能力和空间工作记忆能力。与sham组相比,TBI组大鼠海马AQP-4在蛋白质水平上的表达和脑含水量持续升高,15 d恢复正常;在12 h［（3.78±0.74),(83.78±0.35)%］和72 h［（3.49±0.85),(82.28±0.63)%］均形成两个波峰,n=5,P均<0.01,表明继发性脑损伤与持续脑水肿和海马AQP-4在蛋白质上的高表达有关。与sham组相比,NeuN标记和免疫荧光检测发现,TBI后24 h 致大鼠海马神经元丢失严重［（198.2±8.002) vs.(297.2±6.866) cells/mm2, n=5,P<0.01］,表明TBI动物的海马功能受损。与sham相比,TBI组海马神经元树突标志物微管结合蛋白2（microtubule associated proein 2,MAP2）和突触前终末特异性标记物突触素（synaptophysin,SYN）在蛋白质水平均伤后逐步降低（n=5,P均<0.01）,72 h［（0.55±0.05) vs.(1.27±0.08), (0.52±0.14) vs.(1.06±0.16), n=5,P均<0.01］降低最明显;TBI组形成神经元纤维缠结主要成分的过度磷酸化tau（ser404）,伤后逐步升高,72 h［（1.25±0.11)vs. (0.33±0.07), n=5,P<0.01］升高最明显。 MAP2、SYN和过度磷酸化的tau（ser404）检测指标的改变,表明脑损伤致神经元受损,神经元生长和损伤修复能力减弱,最终导致神经元骨架破环,TBI损害了动物的海马空间记忆能力。与sham组相比,TBI组大鼠海马环磷酸腺苷反应元件结合蛋白（cAMP response element binding protein,CREB）和磷酸化CREB ser133(phosphorylated CREB Ser133, pCREB Ser133)含量降低明显（n=5,P均<0.05）,表明脑损伤动物海马的存储记忆能力减弱;TBI组大鼠海马一般调控阻遏蛋白激酶2(general control nonderepressible 2 kinase,GCN2)蛋白质升高明显（n=5,P均<0.05）,表明脑损伤动物海马将新信息转化成长期记忆能力下降。本研究提示,创伤性脑损伤可使大鼠海马神经元骨架破坏,进而导致在学习记忆过程中起重要作用的分子蛋白质下调,抑制记忆储存的蛋白质（GCN2）上调,促使学习记忆功能障碍。     

对侧外周神经移位到损伤手臂引起的体感皮层功能动态重组

单侧肢体的外周神经损伤通常导致对侧体感皮层的功能重组. 然而,接受了对侧颈 7 (C7) 外周神经移位手术治疗单侧手臂臂丛全撕脱的病人,在术后早期当其患手被触摸时,只在其健手产生感觉. 在术后晚期,病人才逐渐恢复其患手和健手的正常、独立的功能. 我们在模拟对侧颈 7 (C7) 外周神经移位手术病例的大鼠模型上,用记录体感诱发电位的方法研究了患手和健手的体感代表区. 患手的体感和运动功能由于 C7 神经的再生而逐渐恢复. 术后第 5 个月始, 13 只大鼠患手的体感代表区只出现在其同侧的皮层,同时患手和健手的代表区在该皮层内是高度重叠的 (除掉一个例外),虽然刺激它们产生的体感诱发电位的潜伏期和反应幅度有很大的不同. 结果表明,移位到患手的对侧外周神经能够导致同侧体感皮层动态的功能重组,提示身体另侧感觉输入的介入激发了大脑显著的可塑性.     

创伤性脑损伤对大鼠海马骨架蛋白及学习记忆功能影响

创伤性脑损伤（traumatic brain injury,TBI）是极为常见的外伤性疾病,致死率和致残率很高。存活者伴随的空间认知功能障碍,给患者家庭和社会造成了极大的负担。目前,对TBI造成的空间记忆障碍缺乏系统研究。脑损伤后海马组织与记忆有关的分子以及组成神经元骨架的分子如何变化研究甚少。本研究采用Wistar大鼠为研究对象,并随机将其分为假手术（sham）组和创伤性脑损伤（TBI）组。TBI组再按致伤后时间长短分为6 h、12 h、24 h、72 h、15 d五个亚组。TBI组应用PinPointTM颅脑撞击器撞击而致伤,sham组不撞击。采用Morris水迷宫评价实验动物空间记忆能力;干湿重法测定脑含水量,评估脑水肿与海马水通道蛋白4（aquaporin-4,AQP-4）的相关性;海马神经元特异性核蛋白（neuron specific nuclear protein,NeuN）标记和免疫荧光检测评估TBI致大鼠神经元丢失情况;通过Western印迹检测TBI致海马骨架相关蛋白质和记忆相关蛋白质含量变化。本研究证实,与sham组相比,TBI组大鼠潜伏期明显增加［（61.98±12.82) s vs.(28.32±8.52) s,n=5,P<0.01,day 15］,探索时间明显缩短［（36.98±0.37) s vs. (73.68±5.09) s,n=5,P<0.01,day15］,表明脑创伤损害了动物的空间参考记忆能力和空间工作记忆能力。与sham组相比,TBI组大鼠海马AQP-4在蛋白质水平上的表达和脑含水量持续升高,15 d恢复正常;在12 h［（3.78±0.74),(83.78±0.35)%］和72 h［（3.49±0.85),(82.28±0.63)%］均形成两个波峰,n=5,P均<0.01,表明继发性脑损伤与持续脑水肿和海马AQP-4在蛋白质上的高表达有关。与sham组相比,NeuN标记和免疫荧光检测发现,TBI后24 h 致大鼠海马神经元丢失严重［（198.2±8.002) vs.(297.2±6.866) cells/mm2, n=5,P<0.01］,表明TBI动物的海马功能受损。与sham相比,TBI组海马神经元树突标志物微管结合蛋白2（microtubule associated proein 2,MAP2）和突触前终末特异性标记物突触素（synaptophysin,SYN）在蛋白质水平均伤后逐步降低（n=5,P均<0.01）,72 h［（0.55±0.05) vs.(1.27±0.08), (0.52±0.14) vs.(1.06±0.16), n=5,P均<0.01］降低最明显;TBI组形成神经元纤维缠结主要成分的过度磷酸化tau（ser404）,伤后逐步升高,72 h［（1.25±0.11)vs. (0.33±0.07), n=5,P<0.01］升高最明显。 MAP2、SYN和过度磷酸化的tau（ser404）检测指标的改变,表明脑损伤致神经元受损,神经元生长和损伤修复能力减弱,最终导致神经元骨架破环,TBI损害了动物的海马空间记忆能力。与sham组相比,TBI组大鼠海马环磷酸腺苷反应元件结合蛋白（cAMP response element binding protein,CREB）和磷酸化CREB ser133(phosphorylated CREB Ser133, pCREB Ser133)含量降低明显（n=5,P均<0.05）,表明脑损伤动物海马的存储记忆能力减弱;TBI组大鼠海马一般调控阻遏蛋白激酶2(general control nonderepressible 2 kinase,GCN2)蛋白质升高明显（n=5,P均<0.05）,表明脑损伤动物海马将新信息转化成长期记忆能力下降。本研究提示,创伤性脑损伤可使大鼠海马神经元骨架破坏,进而导致在学习记忆过程中起重要作用的分子蛋白质下调,抑制记忆储存的蛋白质（GCN2）上调,促使学习记忆功能障碍。     

Enhanced Phosphodiestric Breakdown of Phosphatidylinositol Bisphosphate After Experimental Brain Injury

Abstract: Regional levels of lactate and inositol 1,4,5-trisphosphate (IP₃), a cellular second messenger of the excitatory neurotransmitter system, were measured after lateral fluid percussion (FP) brain injury in rats. At 5 min postinjury, tissue lactate concentrations were significantly elevated in the cortices and hippocampi of both the ipsilateral and contralateral hemispheres. By 20 min postinjury, lactate concentrations were elevated only in the cortices and hippocampus of the ipsilateral hemisphere. Whereas the IP₃ concentrations were elevated in the hippocampi of the ipsilateral and contralateral hemisphere and in the cortex of ipsilateral hemisphere at 5 min postinjury, no elevation in these sites was found at 20 min postinjury. Histologic analysis revealed neuronal damage in the cortex and CA3 regions of hippocampus ipsilateral to the injury at 24 h postinjury. The present results suggest activation of the phosphoinositide signal transduction pathway at the onset of injury and of a possible requirement of early persistent metabolic dysfunction (>20 min) such as the lactate accumulation in the delayed neuronal damage.     

Distinct effects on long-term function of injured and contralateral kidneys following unilateral renal ischemia-reperfusion

Salt-sensitive hypertension and chronic kidney disease (CKD) following recovery from acute kidney injury (AKI) may occur secondary to incomplete repair, or by activation of circulating factors stimulated by injury. We created two types of renal injury induced by unilateral ischemia-reperfusion (I/R); in a direct/ipsilateral AKI group, rats were subjected to unilateral I/R and the untouched contralateral kidney was removed by unilateral nephrectomy after 5 wk to isolate effects on the injured kidney. In the remote/contralateral AKI group, the injured kidney was removed after 5 wk to isolate effects on the untouched kidney. When these animals were subsequently challenged with elevated dietary sodium for an additional 4 wk (0.4 to 4%), both remote/contralateral and direct/ipsilateral AKI rats manifested a significant increase in blood pressure relative to sham-operated controls. Similarly, in acute studies, both ipsilateral and contralateral kidneys had impaired pressure natriuresis and hemodynamic responses. Reductions in vascular density were observed following direct/ipsilateral injury, but were not observed in the remote/contralateral kidney. However, both remote/contralateral and direct/ipsilateral kidneys contained interstitial cells, some of which were identified as activated (low CD62L/CD4+) T lymphocytes. In contrast, only the direct/ipsilateral AKI group demonstrated significant CKD following exposure to elevated salt. This was characterized by a significant reduction in creatinine clearance, an increase in albuminuria, and a dramatic expansion of interstitial inflammation. Taken together, these data suggest that the salt-sensitive features of AKI on hypertension and CKD are segregable such that effects on hemodynamics and hypertension occur independent of direct renal damage. However, prior direct injury to the kidney is required to elicit the full manifestation of CKD induced by elevated sodium intake.     

Temporal profile and cell subtype distribution of activated caspase-3 following experimental traumatic brain injury

This study investigated the temporal expression and cell subtype distribution of activated caspase-3 following cortical impact-induced traumatic brain injury in rats. The animals were killed and examined for protein expression of the proteolytically active subunit of caspase-3, p18, at intervals from 6 h to 14 days after injury. In addition, we also investigated the effect of caspase-3 activation on proteolysis of the cytoskeletal protein alpha-spectrin. Increased protein levels of p18 and the caspase-3-specific 120-kDa breakdown product to alpha-spectrin were seen in the cortex ipsilateral to the injury site from 6 to 72 h after the trauma. Immunohistological examinations revealed increased expression of p18 in neurons, astrocytes, and oligodendrocytes from 6 to 72 h following impact injury. In contrast, no evidence of caspase-3 activation was seen in microglia at all time points investigated. Quantitative analysis of caspase-3-positive cells revealed that the number of caspase-3-positive neurons exceeded the number of caspase-3-positive glia cells from 6 to 72 h after injury. Moreover, concurrent assessment of nuclear histopathology using hematoxylin identified p18-immunopositive cells exhibiting apoptotic-like morphological profiles in the cortex ipsilateral to the injury site. In contrast, no evidence of increased p18 expression or alpha-spectrin proteolysis was seen in the ipsilateral hippocampus, contralateral cortex, or hippocampus up to 14 days after the impact. Our results are the first to demonstrate the concurrent expression of activated caspase-3 in different CNS cells after traumatic brain injury in the rat. Our findings also suggest a contributory role of activated caspase-3 in neuronal and glial apoptotic degeneration after experimental TBI in vivo.     

Oxidative stress in head trauma in aging

Oxidative damage is proposed as a key mediator of exacerbated morphological responses and deficits in behavioral recovery in aged subjects with traumatic brain injury (TBI). In the present study, we show exacerbated loss of tissue in middle aged (12 months) and aged (22 months) Fisher-344 rats compared to young animals (3 months) subjected to moderate TBI. Analysis of 4-hydroxynonenal (4-HNE) and acrolein, neurotoxic by-products of lipid peroxidation, shows significant (P < 0.05) age-dependent increases in ipsilateral (IP) hippocampus 1 and 7 days post injury. In IP cortex, 4-HNE was significantly elevated 1 day post injury in all age groups, and both 4-HNE and acrolein were elevated in middle aged and aged animals 7 days post injury. Comparison of antioxidant enzyme activities shows significant (P < 0.05) age-dependent decreases of manganese superoxide dismutase in IP hippocampus and cortex 1 and 7 days post injury. Glutathione reductase activity also showed an age-dependent decrease. Overall, our data show increased levels of oxidative damage, diminished antioxidant capacities, and increased tissue loss in TBI in aging.     

Creatine-Enhanced Diet Alters Levels of Lactate and Free Fatty Acids After Experimental Brain Injury

Free fatty acids (FFA) and lactic acid are markers of secondary cellular injury following traumatic brain injury (TBI). We previously showed that animals fed a creatine (Cr)-enriched diet are afforded neuroprotection following TBI. To further characterize the neuroprotective Cr diet, we studied neurochemical changes in cortex and hippocampus following a moderate injury. Adult rats were fed either a control or Cr-supplemented diet (0.5%, 1%) for 2 weeks before TBI. At 30 min or 6 h after injury, tissue was processed for quantitative analysis of neurochemical changes. Both lactate and FFA were significantly increased in all tissues ipsilateral to the injury. Cr-fed animals had significantly lower levels, although the levels were elevated compared to sham controls. Animals fed a 1% Cr-diet were afforded greater neuroprotection than animals fed a 0.5% Cr diet. These results support the idea that a Cr-enriched diet can provide substantial neuroprotection in part by suppressing secondary brain injury.     

Chronic metabolic sequelae of traumatic brain injury: prolonged suppression of somatosensory activation

Injuries to the brain acutely disrupt normal metabolic function and may deactivate functional circuits. It is unknown whether these metabolic abnormalities improve over time. We used 2-deoxyglucose (2-DG) autoradiographic image-averaging to assess local cerebral glucose utilization (lCMR(Glc)) of the rat brain 2 mo after moderate (1.7-2.1 atm) fluid-percussion traumatic brain injury (FPI). Four animal groups (n = 5 each) were studied: sham-injured rats with and without stimulation of the vibrissae-barrel field ipsilateral to injury; and animals with prior FPI, with or without this stimulation. In sham-injured rats, resting lCMR(Glc) was normal, and vibrissae stimulation produced right-sided metabolic activation of the ventrolateral thalamic and somatosensory-cortical projection areas. In rats with prior injury, lCMR(Glc) contralateral to injury was normal, but lCMR(Glc) of the ipsilateral forebrain was depressed by approximately 38-45% compared with shams. Whisker stimulation in rats with prior trauma failed to induce metabolic activation of either cortex or thalamus. Image-mapping of histological material obtained in the same injury model was undertaken to assess the possible influence of injury-induced regional brain atrophy on computed lCMR(Glc); an effect was found only in the lateral cortex at the trauma epicenter. Our results show that, 2 mo after trauma, resting cerebral metabolic perturbations persist, and the whisker-barrel somatosensory circuit shows no signs of functional recovery.     

Increased Expression of Apolipoprotein D Following Experimental Traumatic Brain Injury

Increasing evidence suggests that apolipoprotein D (apoD) could play a major role in mediating neuronal degeneration and regeneration in the CNS and the PNS. To investigate further the temporal pattern of apoD expression after experimental traumatic brain injury in the rat, male Sprague-Dawley rats were subjected to unilateral cortical impact injury. The animals were killed and examined for apoD mRNA and protein expression and for immunohistological analysis at intervals from 15 min to 14 days after injury. Increased apoD mRNA and protein levels were seen in the cortex and hippocampus ipsilateral to the injury site from 48 h to 14 days after the trauma. Immunohistological investigation demonstrated a differential pattern of apoD expression in the cortex and hippocampus, respectively: Increased apoD immunoreactivity in glial cells was detected from 2 to 3 days after the injury in cortex and hippocampus. In contrast, increased expression of apoD was seen in cortical and hippocampal neurons at later time points following impact injury. Concurrent histopathological examination using hematoxylin and eosin demonstrated dark, shrunken neurons in the cortex ipsilateral to the injury site. In contrast, no evidence of cell death was observed in the hippocampus ipsilateral to the injury site up to 14 days after the trauma. No evidence of increased apoD mRNA or protein expression or neuronal pathology by hematoxylin and eosin staining was detected in the contralateral cortex and hippocampus. Our results reveal induction of apoD expression in the cortex and hippocampus following traumatic brain injury in the rat. Our data also suggest that increased apoD expression may play an important role in cortical neuronal degeneration after brain injury in vivo. However, increased expression of apoD in the hippocampus may not necessarily be indicative of neuronal death.     

Temporal and spatial profile of caspase 8 expression and proteolysis after experimental traumatic brain injury

Recent studies have demonstrated that the downstream caspases, such as caspase 3, act as executors of the apoptotic cascade after traumatic brain injury (TBI) in vivo. However, little is known about the involvement of caspases in the initiation phase of apoptosis, and the interaction between these initiator caspases (e.g. caspase 8) and executor caspases after experimental brain injuries in vitro and in vivo. This study investigated the temporal expression and cell subtype distribution of procaspase 8 and cleaved caspase 8 p20 from 1 h to 14 days after cortical impact-induced TBI in rats. Caspase 8 messenger RNA levels, estimated by semiquantitaive RT-PCR, were elevated from 1 h to 72 h in the traumatized cortex. Western blotting revealed increased immunoreactivity for procaspase 8 and the proteolytically active subunit of caspase 8, p20, in the ipsilateral cortex from 6 to 72 h after injury, with a peak at 24 h after TBI. Similar to our previous studies, immunoreactivity for the p18 fragment of activated caspase 3 also increased in the current study from 6 to 72 h after TBI, but peaked at a later timepoint (48 h) as compared with proteolyzed caspase 8 p20. Immunohistologic examinations revealed increased expression of caspase 8 in neurons, astrocytes and oligodendrocytes. Assessment of DNA damage using TUNEL identified caspase 8- and caspase 3-immunopositive cells with apoptotic-like morphology in the cortex ipsilateral to the injury site, and immunohistochemical investigations of caspase 8 and activated caspase 3 revealed expression of both proteases in cortical layers 2-5 after TBI. Quantitative analysis revealed that the number of caspase 8 positive cells exceeds the number of caspase 3 expressing cells up to 24 h after impact injury. In contrast, no evidence of caspase 8 and caspase 3 activation was seen in the ipsilateral hippocampus, contralateral cortex and hippocampus up to 14 days after the impact. Our results provide the first evidence of caspase 8 activation after experimental TBI and suggest that this may occur in neurons, astrocytes and oligodendrocytes. Our findings also suggest a contributory role of caspase 8 activation to caspase 3 mediated apoptotic cell death after experimental TBI in vivo.     

Increased Amyloid Precursor Protein and Tau Expression Manifests as Key Secondary Cell Death in Chronic Traumatic Brain Injury

In testing the hypothesis of Alzheimer's disease (AD)‐like pathology in late stage traumatic brain injury (TBI), we evaluated AD pathological markers in late stage TBI model. Sprague–Dawley male rats were subjected to moderate controlled cortical impact (CCI) injury, and 6 months later euthanized and brain tissues harvested. Results from H&E staining revealed significant 33% and 10% reduction in the ipsilateral and contralateral hippocampal CA3 interneurons, increased MHCII‐activated inflammatory cells in many gray matter (8–20‐fold increase) and white matter (6–30‐fold increased) regions of both the ipsilateral and contralateral hemispheres, decreased cell cycle regulating protein marker by 1.6‐ and 1‐fold in the SVZ and a 2.3‐ and 1.5‐fold reductions in the ipsilateral and contralateral dentate gyrus, diminution of immature neuronal marker by two‐ and onefold in both the ipsilateral and contralateral SVZ and dentate gyrus, and amplified amyloid precursor protein (APP) distribution volumes in white matter including corpus callosum, fornix, and internal capsule (4–38‐fold increase), as well as in the cortical gray matter, such as the striatum hilus, SVZ, and dentate gyrus (6–40‐fold increase) in TBI animals compared to controls (P's < 0.001). Surrogate AD‐like phenotypic markers revealed a significant accumulation of phosphorylated tau (AT8) and oligomeric tau (T22) within the neuronal cell bodies in ipsilateral and contralateral cortex, and dentate gyrus relative to sham control, further supporting the rampant neurodegenerative pathology in TBI secondary cell death. These findings indicate that AD‐like pathological features may prove to be valuable markers and therapeutic targets for late stage TBI. J. Cell. Physiol. 232: 665–677, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.     

Electrical activity of the rat brain following antenatal hypoxia

EEG and EPs in the visual and parietal neocortical areas and the hippocampus were studied in freely behaving rats at the age of two-three months after antenatal hypoxia. Increase of spectral power in delta and theta bands and its decrease in alpha and beta bands in the background EEG and in responses to a protracted light stimulation were observed in experimental animals in comparison to control ones. The most pronounced changes were observed in the parietal cortex and hippocampus. The character of changes in latencies and the share of individual EP components recorded point to an accelerated excitation reverberation in neuronal networks in response to afferent stimuli and to a prolongation of after-discharges in the parietal cortex and hippocampus testifying to peculiarity of information processing in these brain structures. On the basis of other authors' data, certain parallelism is supposed to exist between the electrophysiological parameters in experimental animals and some groups of children with mental retardation.