Memory Performance in a Sample of Very Low Birth Weight Adolescents

Prematurely born participants with very low birth weight (VLBW) are at high risk of brain injury in the perinatal period and of later cognitive impairment. Studies of long-term memory sequelae in VLBW participants are scarce and focus on verbal and visual memory assessed by standard clinical memory tests. There is even less research into everyday memory, and the results obtained are contradictory. This study explores long-term memory deficits in VLBW adolescents using 2 standard clinical memory tests and 1 everyday memory test. Results show impairment only in everyday memory. These memory deficits are not specific; they are related to an impaired general cognitive performance. Unlike birth weight, gestational age is a good predictor of intelligence.     

Memory performance in a sample of very low birth weight adolescents

Prematurely born participants with very low birth weight (VLBW) are at high risk of brain injury in the perinatal period and of later cognitive impairment. Studies of long-term memory sequelae in VLBW participants are scarce and focus on verbal and visual memory assessed by standard clinical memory tests. There is even less research into everyday memory, and the results obtained are contradictory. This study explores long-term memory deficits in VLBW adolescents using 2 standard clinical memory tests and 1 everyday memory test. Results show impairment only in everyday memory. These memory deficits are not specific; they are related to an impaired general cognitive performance. Unlike birth weight, gestational age is a good predictor of intelligence.     

Effect of acetyl-l-carnitine on hyperactivity and spatial memory deficits of rats exposed to neonatal anoxia

The effect of acetyl-l-carnitine (ALC) on behavioral deficits following neonatal anoxia (N₂ 100% for 25 min at 30 h after birth) was studied in the rat. Transient hyperactivity at P20–P45 postnatal days and permanent spatial memory deficits were shown by anoxic rats. A chronic ALC treatment (50 mg/kg per die injected intraperitoneally from P2, after anoxia, to P60) significantly reduced the transient increase in sniffing, rearing and locomotory activity of anoxic rats, but, mostly, ameliorated the spatial memory performances in a maze at P30–P40 and in a water maze at P50–P60. No behavioral changes were seen in ALC-treated animals that received sham-exposure at birth. On the basis of these results, the use of ALC for the treatment of perinatal asphyctic insults in children is suggested.     

神经干细胞移植对HIBD新生大鼠学习记忆的影响

目的：探讨脑内移植胚鼠神经干细胞 (NSCs)对新生大鼠缺氧缺血性脑损伤(HIBD)后学习记忆的影响。 方法： 分离孕龄14 d的Sprague-Dawley（SD）大鼠胚胎前脑皮质，采用无血清悬浮培养的方法获得细胞克隆；7 d龄新生大鼠随机分为假手术组（n=10）、HIBD组（n=11）和移植组（n=13），后两组结扎左侧颈总动脉联合8%氧吸入制作HIBD模型，损伤后3 d利用立体定位仪分别在左侧海马区植入培养基作为对照或BrdU 标记的NSCs，观察植入4 周后大鼠学习记忆功能的恢复情况。计数海马CA1区正常神经元，间接免疫荧光法观察移植细胞在脑内的存活、迁移情况。 结果： 在放射形迷宫测试中，移植组较对照组表现出明显的改善，觅水时间缩短(61.40 s±24.83 s vs 89.32 s±31.52 s)，错误次数（2.65±0.57 vs 3.78±0.41）及重复次数明显减少(0.32±0.43 vs 0.81±0.47)(P<0.05)。BrdU间接免疫荧光显示移植后4周，在脑内可见存活的NSCs在海马内广泛分布；尼氏染色显示移植可明显减少海马CA1区的细胞丢失。 结论： 脑内移植胚鼠NSCs对HIBD新生大鼠的学习记忆恢复有良好的促进作用。     

Seizure induced dentate neurogenesis does not diminish with age in rats

Neurogenesis in the mammalian dentate gyrus occurs throughout life, is believed to be important for the laying down of episodic memory and diminishes significantly with increasing age. Pathological insults such as seizures, hypoxia and traumatic brain injury increase dentate neurogenesis compared to age matched controls. Using unilateral intracerebroventricular kainate we show that although baseline neurogenesis is significantly lower in 3 month old rats compared to 1 month old rats, kainate increases neurogenesis to reach similar levels in both age groups. Additionally, this effect is bilateral after a unilateral intracerebroventricular kainate injection. We conclude that the potential for dentate neurogenesis is maintained despite diminishing baseline levels with increasing age and that injury signals override the age related suppression of neurogenesis.     

Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats

Although a number of studies have demonstrated that magnesium improves acute motor and cognitive outcome after traumatic brain injury, others have failed to show positive effects on cognitive outcome and none have examined persistent functional deficits. The present study shows that severe impact-acceleration induced, diffuse traumatic brain injury in rats produced profound motor and cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous administration of magnesium sulfate (250 micromoles/kg) at 30 min after injury significantly improved rotarod (sensorimotor) and open field (stress/anxiety) performance, and led to a faster rate of recovery in the Barnes maze (learning). We conclude that posttraumatic magnesium administration attenuates long-term motor and cognitive deficits after traumatic brain injury, and that this improvement may include some reduction of post-traumatic stress and anxiety.     

三七总皂苷改善宫内缺氧新生鼠脑损伤及学习记忆功能

目的:制作胎鼠宫内缺氧模型,探讨三七总皂苷对宫内缺氧新生大鼠突触重建及学习记忆功能的影响。方法:孕14 d开始将孕鼠置于动物缺氧培养箱中,制作胎鼠宫内缺氧模型。新生鼠经腹腔分别注入三七总皂苷和生理盐水;正常对照组不治疗。免疫荧光法检测脑微管相关蛋白-2(MAP-2)、胶质纤维酸性蛋白(GFAP)、突触素(SYN)和突触分化诱导基因1(SynDIG1)的表达。Morris水迷宫实验检测各组大鼠的学习记忆功能。结果:Morris水迷宫结果表明,与对照组相比,模型组大鼠学习记忆能力明显下降,经三七总皂苷治疗后学习记忆能力明显改善。缺氧后新生鼠脑MAP-2、SYN和SynDIG1表达明显减少,GFAP表达明显增多;治疗组MAP-2、SYN、SynDIG1表达明显高于模型组,GFAP表达明显低于模型组。结论:三七总皂苷可减轻缺氧缺血后神经元的损伤,减弱GFAP的表达,促进突触的重建,改善宫内缺氧大鼠学习记忆功能。     

Interleukin-1β-induced brain injury and neurobehavioral dysfunctions in juvenile rats can be attenuated by α-phenyl-n-tert-butyl-nitrone

Our previous study showed that perinatal exposure to interleukin-1β (IL-1β), an inflammatory cytokine, induces acute injury to developing white matter in the neonatal rat brain, and α-phenyl-n-tert-butyl-nitrone (PBN), a free radical scavenger and antioxidant, protects against IL-1β-induced acute brain injury. The objective of the present study was to further examine whether perinatal exposure to IL-1β resulted in persistent brain damage and neurological disabilities, and whether PBN offers lasting protection. Intracerebral injection of IL-1β (1 μg/kg) was performed in postnatal day 5 (P5) Sprague-Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after IL-1β injection. Perinatal IL-1β exposure significantly affected neurobehavioral functions in juvenile rats. Although some neurobehavioral deficits such as performance in negative geotaxis, cliff avoidance, beam walking, and locomotion were spontaneously reversible, sustained deficits such as poor performance in the vibrissa-elicited forelimb-placing test, the pole test, the passive avoidance task, and the elevated plus-maze task were still observable at P21. Perinatal IL-1β exposure resulted in persistent brain damage including enlargement of ventricles, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, axonal and dendritic injury, and loss of hippocampal CA1 neurons and tyrosine hydroxylase positive neurons in the substantia nigra and ventral tegmental areas of the rat brain. Treatments with PBN provided lasting protection against the IL-1β-induced brain injury and improved the associated neurological dysfunctions in juvenile rats, suggesting that prompt treatments for brain injury induced by perinatal infection/inflammation might have important long-term consequences.     

复方脑肽节苷脂可改善宫内缺氧新生模型小鼠脑损伤并促进突触再生

背景:目前有关复方脑肽节苷脂的研究大多集中在临床一些颅脑损伤和新生儿缺血缺氧性脑病的疗效观察和分析,但其参与神经功能恢复的分子机制少有报道。目的:探讨复方脑肽节苷脂在宫内缺氧新生鼠脑损伤中的保护作用及机制。方法:15只昆明小鼠随机分为对照组、缺氧组和治疗组。于孕14 d开始,缺氧组和治疗组孕鼠置于体积分数10%氧培养箱中,制作胎鼠宫内缺氧模型。孕鼠分娩后,新生鼠经腹腔分别注入复方脑肽节苷脂和PBS,治疗后观察各组小鼠发育情况;对照组不缺氧,不治疗。用免疫荧光和Western blot检测脑胶质纤维酸性蛋白、神经蛋白聚糖、突触分化诱导基因1蛋白和胶原蛋白Ⅳ的表达;小鼠跳台实验测试动物记忆功能。实验方案经漯河医学高等专科学校动物实验伦理委员会批准。结果与结论:①与对照组相比,缺氧组胶质纤维酸性蛋白和神经蛋白聚糖阳性细胞表达显著增加,而突触分化诱导基因1蛋白和胶原蛋白Ⅳ的表达显著减少;②治疗组突触分化诱导基因1蛋白和胶原蛋白Ⅳ表达均较缺氧组显著增加,而胶质纤维酸性蛋白和神经蛋白聚糖的表达较缺氧组显著减少;③与对照组相比,缺氧组大鼠学习记忆能力明显下降,经复方脑肽节苷脂注射液治疗后学习记忆能力明显改善;④结果说明,复方脑肽节苷脂可减轻缺氧后脑损伤,改善学习记忆能力,具体机制可能与抑制星形胶质细胞活化、下调神经蛋白聚糖和上调胶原蛋白Ⅳ表达,减轻脑血管损伤,促进突触的重建有关。     

Perinatal asphyxia results in changes in presynaptic bouton number in striatum and cerebral cortex-a stereological and behavioral analysis

Deficits in cognitive function have been related to quantitative changes in synaptic population, particularly in the cerebral cortex. Here, we used an established model of perinatal asphyxia that induces morphological changes, i.e. neuron loss in the cerebral cortex and striatum, as well as behavioural deficits. We hypothesized that perinatal asphyxia may lead to a neurodegenerative process resulting in cognitive impairment and altered presynaptic bouton numbers in adult rats. We studied cognitive performance at 18 months and presynaptic bouton numbers at 22 months following perinatal asphyxia. Data of the spatial Morris water escape task did not reveal clear memory or learning deficits in aged asphyctic rats compared to aged control rats. However, a memory impairment in aged rats versus young rats was observed, which was more pronounced in asphyctic rats. We found an increase in presynaptic bouton density in the parietal cortex, whereas no changes were found in striatum and frontal cortex in asphyctic rats. An increase of striatal volume was observed in asphyctic rats, leading to an increase in presynaptic bouton numbers in this area. These findings stress the issue that volume measurements have to be taken into account when determining presynaptic bouton density. Furthermore, perinatal asphyxia led to region-specific changes in presynaptic bouton numbers and it worsened the age-related cognitive impairment. These results suggest that perinatal asphyxia induced neuronal loss, which is compensated for by an increase in presynaptic bouton numbers.     

Perinatal asphyxia results in changes in presynaptic bouton number in striatum and cerebral cortex — a stereological and behavioral analysis

Deficits in cognitive function have been related to quantitative changes in synaptic population, particularly in the cerebral cortex. Here, we used an established model of perinatal asphyxia that induces morphological changes, i.e. neuron loss in the cerebral cortex and striatum, as well as behavioural deficits. We hypothesized that perinatal asphyxia may lead to a neurodegenerative process resulting in cognitive impairment and altered presynaptic bouton numbers in adult rats. We studied cognitive performance at 18 months and presynaptic bouton numbers at 22 months following perinatal asphyxia. Data of the spatial Morris water escape task did not reveal clear memory or learning deficits in aged asphyctic rats compared to aged control rats. However, a memory impairment in aged rats versus young rats was observed, which was more pronounced in asphyctic rats. We found an increase in presynaptic bouton density in the parietal cortex, whereas no changes were found in striatum and frontal cortex in asphyctic rats. An increase of striatal volume was observed in asphyctic rats, leading to an increase in presynaptic bouton numbers in this area. These findings stress the issue that volume measurements have to be taken into account when determining presynaptic bouton density. Furthermore, perinatal asphyxia led to region-specific changes in presynaptic bouton numbers and it worsened the age-related cognitive impairment. These results suggest that perinatal asphyxia induced neuronal loss, which is compensated for by an increase in presynaptic bouton numbers.     

Acute perinatal asphyxia impairs non-spatial memory and alters motor coordination in adult male rats

A large body of clinical evidence suggests a possible association between perinatal asphyxia and the onset of early, as well as long-term, neurological and psychiatric disorders including cognitive deficits. The present study investigated cognitive and motor function modifications in a well characterized and clinically relevant experimental rat model of human perinatal asphyxia. The results reported here show that adult rats exposed to a single (20 min) asphyctic episode at delivery displayed: (a) a deficit in non-spatial memory, assessed in a novel object recognition task; (b) an impaired motor coordination, measured by the rotarod test. On the other hand, gross motor activity and spatial memory, evaluated in both the Y maze and the Barnes maze, were not affected by perinatal asphyxia. The results of this study provide further insights into the long-term effects of perinatal asphyxia on neurobehavioural functions.     

Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.     

Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats

Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD), are caused by different mechanisms but may share a common pathway to neuronal injury as a result of the overstimulation of glutamate receptors. It has been suggested that this pathway can be involved in generation of cognitive deficits associated with normal aging. Previous studies performed in our laboratory have demonstrated that aged rats presented recognition memory deficits. The aim of the present study was to evaluate the effect of memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, on age-induced recognition memory deficits. Additionally, parameters of oxidative damage in cerebral regions related to memory formation were evaluated. In order to do that, male Wistar rats (24 months old) received daily injections of saline solution or memantine (20 mg/kg i.p.) during 21 days. The animals were submitted to a novel object recognition task 1 week after the last injection. Memantine-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that memantine is able to reverse age-induced recognition memory deficits. We also demonstrated that memantine reduced the oxidative damage to proteins in cortex and hippocampus, two important brain regions involved in memory formation. Thus, the present findings suggest that, at least in part, age-induced cognitive deficits are related to oxidative damage promoted by NMDA receptor overactivation.     

Gap junctional intercellular communication in hypoxia-ischemia-induced neuronal injury

Brain hypoxia-ischemia is a relatively common and serious problem in neonates and in adults. Its consequences include long-term histological and behavioral changes and reduction in seizure threshold. Gap junction intercellular communication is pivotal in the spread of hypoxia-ischemia related injury and in mediating its long-term effects. This review provides a comprehensive and critical review of hypoxia-ischemia and hypoxia in the brain and the potential role of gap junctions in the spread of the neuronal injury induced by these insults. It also presents the effects of hypoxia-ischemia and of hypoxia on the state of gap junctions in vitro and in vivo. Understanding the mechanisms involved in gap junction-mediated neuronal injury due to hypoxia will lead to the development of novel therapeutic strategies.     

Assessment of cognitive function following magnesium therapy in the traumatically injured brain.

Many studies have examined the preclinical efficacy of Mg2+ therapy in models of traumatic brain injury. However, more of these studies have examined sensorimotor and motor performance than cognitive performance following injury. The present paper reviews the use of Mg2+ therapy to facilitate cognitive recovery in several models of cortical injury in the rodent. The first study examined the ability of daily injections of MgCl2 (1 or 2 mmol) to impair acquisition of a reference memory task in the Morris Water Maze. Additional studies examined the ability of MgCl2 to improve cognitive function following bilateral anterior medial cortex ablations, bilateral frontal cortex contusions, and unilateral frontal contusions. The results from these studies indicate that MgCl2 therapy is biologically active and readily crosses the blood-brain barrier because daily injections of MgCl2 impaired learning of a reference memory task in intact rats. Mg2+ therapy for brain injury revealed that administration of post-injury MgCl2 effectively improved recovery of cognitive deficits following injury. These results suggest that Mg2+ therapy is effective in facilitating cognitive recovery of function following brain injury; however, there are task and dose-dependent aspects to this recovery.     

Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound

Aging is characterized by a progressive decline of cognitive performance, which has been partially attributed to structural and functional alterations of hippocampus. Importantly, aging is the major risk factor for the development of neurodegenerative diseases, especially Alzheimer's disease. An important therapeutic approach to counteract the age-associated memory dysfunctions is to maintain an appropriate microenvironment for successful neurogenesis and synaptic plasticity. In this study, we show that chronic oral administration of peptide 021 (P021), a small peptidergic neurotrophic compound derived from the ciliary neurotrophic factor, significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats. Treatment with P021 inhibited the deficit in neurogenesis in the aged rats and increased the expression of brain derived neurotrophic factor. Furthermore, P021 restored synaptic deficits both in the cortex and the hippocampus. In vivo magnetic resonance spectroscopy revealed age-dependent alterations in hippocampal content of several metabolites. Remarkably, P021 was effective in significantly reducing myoinositol (INS) concentration, which was increased in aged compared with young rats. These findings suggest that stimulating endogenous neuroprotective mechanisms is a potential therapeutic approach to cognitive aging, Alzheimer's disease, and associated neurodegenerative disorders and P021 is a promising compound for this purpose.     

c-Fos, N-methyl-d-aspartate receptor 2C, GABA-A-alpha1 immonoreactivity, seizure latency and neuronal injury following single or recurrent neonatal seizures in hippocampus of Wistar rat

To evaluate the long-term effects of single or recurrent prolonged neonatal seizures on seizure threshold and neuronal activity in the brain, a novel "twist" seizure was induced by coupling early-life flurothyl-induced seizures with later exposure to pentylenetetrazol. The authors assigned six neonatal rats for each group: the single-seizure group (SS), the recurrent-seizure group (RS) and the control group. At postnatal day 46, seizure threshold was examined using pentylenetetrazol, and then the brain slices were evaluated with thionine staining, in situ end labeling and immunohistochemical studies. The Results showed that the rats in SS and RS groups all had reduced latencies to develop generalized tonic seizures induced by PTZ compared with controls (P<0.01). Morphologic changes, cell loss and apoptotic cells were observed only in those of RS group. Significant fos and NR2C-immunoreactive positive cells were seen in hippocampus of rats in both SS and RS groups compared with controls (P<0.01). A significant decrease in the number of GABA-A-alpha1 immunoreactive positive neurons was detected in hippocampus in rats of SS and RS groups compared with the controls (P<0.01). We conclude that neonatal rats subjected to prolonged seizures have pronounced long-term effects on seizure threshold and neuronal neurophysiological activity in the brain. Obvious neuronal injury, however, was only seen in rat with recurrent-seizures. Subtle brain damage might occur in rats experiencing single prolonged neonatal seizures.     

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.     

Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging

Homer1c has been shown to play a role in learning and memory. Overexpression of Homer1c in the hippocampus can improve memory in normal rats and can also rescue spatial learning deficits in Homer1 knockout mice. In a previous study, we found that Homer1c mRNA is upregulated after a spatial learning paradigm in aged rats that successfully learn the task, when compared to aged rats that are learning-impaired (AI). This study was designed to validate the role of Homer1c in successful cognitive aging. In this article, we report that gene delivery of Homer1c into the hippocampus of aged learning-impaired rats significantly improves individual performance on an object location memory task. The learning ability of these rats on the Morris Water Maze was also superior to that of AI control rats. In summary, using 2 independent spatial memory tasks, we demonstrate that Homer1c is sufficient to improve the spatial learning deficits in a rodent model of cognitive aging. These results point to Homer1c as a potential therapeutic target for improving age-related cognitive impairment.