Hippocampus

The regenerative decline of organisms during ageing is linked to the reduced proliferative activity, impaired function and exhaustion of tissue-specific stem and progenitor cells. Studies using heterochronic parabiosis, involving the surgical attachment of young and old organisms so that they share a common vascular system, have revealed that the systemic environment has a profound effect on stem cell function. In particular, specific youthful rejuvenating circulatory factors reverse age-related declines in stem cell function, whereas the old milieu contains inhibitory factors that impede stem cell function in young animals. Similarly, the effects of certain dietary interventions, namely calorie restriction, also induce a more youthful cellular and molecular phenotype in ageing stem cells throughout the body. Further to this, there are key molecular pathways involved in translating the availability of nutrients into altered stem cell function, including signalling in the insulin and insulin-like growth factor and mechanistic target of rapamycin (mTOR) pathways. In this review, we discuss the potential role of dietary interventions to promote a more rejuvenating systemic milieu in order to enhance stem cell function and promote healthy ageing.

This article reviews the state-of-the-art research in posttraumatic stress disorder (PTSD) from several perspectives: (1) Sex differences: PTSD is more frequent among women, who tend to have different types of precipitating traumas and higher rates of comorbid panic disorder and agoraphobia than do men. (2) Risk and resilience: The presence of Group C symptoms after exposure to a disaster or act of terrorism may predict the development of PTSD as well as comorbid diagnoses. (3) Impact of trauma in early life: Persistent increases in CRF concentration are associated with early life trauma and PTSD, and may be reversed with paroxetine treatment. (4) Imaging studies: Intriguing findings in treated and untreated depressed patients may serve as a paradigm of failed brain adaptation to chronic emotional stress and anxiety disorders. (5) Neural circuits and memory: Hippocampal volume appears to be selectively decreased and hippocampal function impaired among PTSD patients. (6) Cognitive behavioral approaches: Prolonged exposure therapy, a readily disseminated treatment modality, is effective in modifying the negative cognitions that are frequent among PTSD patients. In the future, it would be useful to assess the validity of the PTSD construct, elucidate genetic and experiential contributing factors (and their complex interrelationships), clarify the mechanisms of action for different treatments used in PTSD, discover ways to predict which treatments (or treatment combinations) will be successful for a given individual, develop an operational definition of remission in PTSD, and explore ways to disseminate effective evidence-based treatments for this condition.

The use of transcranial low-level laser (light) therapy (tLLLT) to treat stroke and traumatic brain injury (TBI) is attracting increasing attention. We previously showed that LLLT using an 810-nm laser 4 h after controlled cortical impact (CCI)-TBI in mice could significantly improve the neurological severity score, decrease lesion volume, and reduce Fluoro-Jade staining for degenerating neurons. We obtained some evidence for neurogenesis in the region of the lesion. We now tested the hypothesis that tLLLT can improve performance on the Morris water maze (MWM, learning, and memory) and increase neurogenesis in the hippocampus and subventricular zone (SVZ) after CCI-TBI in mice. One and (to a greater extent) three daily laser treatments commencing 4-h post-TBI improved neurological performance as measured by wire grip and motion test especially at 3 and 4 weeks post-TBI. Improvements in visible and hidden platform latency and probe tests in MWM were seen at 4 weeks. Caspase-3 express...

Physical activities for a few days can increase brain-derived neurotrophic factor (BDNF) mRNA in rat hippocampus. To investigate the influence of maternal exercise during pregnancy on rat pup hippocampal BDNF mRNA, we studied its expression by a semi-quantitative RT-PCR method after young pregnant rats were exercised on a motor driven treadmill. Pups of exercised mothers had significantly increased hippocampal BDNF

In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.

Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testin...

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Brain-pancreas relative protein (BPRP) is a novel protein that mainly expresses in brain and pancreas. In our previous study, we found that various stressors significantly decreased the expression of BPRP in pancreas in vivo, accompanied by changes in insulin and glucose levels, and that expression of BPRP in pancreas also decreased significantly in diabetic rats induced by Streptozocin (STZ). All these findings suggest that BPRP may be a glucose or insulinsensitive protein. However, how the changes in insulin or glucose levels influence the expression of BPRP in hippocampus requires further study. Here, we investigated the effects of insulin or glucose on the expression of BPRP in primary cultured hippocampal neurons. We supplied hippocampal neurons with glucose, insulin, or supernatant from pancreatic b-cells, which secrete insulin into the supernatant. Our data showed that insulin had beneficial effect on the viability while no significant effect on the expression of BPRP in hippocampal neurons. On the contrary, 40 mM glucose or free glucose culture significantly decreased the expression of BPRP, while had no significant effect on the viability and apoptosis of hippocampal neurons. Further study showed that levels of insulin in the supernatant collected from pancreatic b-cells medium changed over days, and that supernatant increased the viability of hippocampal neurons, while it had no obvious effect on the expression of BPRP in hippocampal neurons. These results suggest that BPRP may be a glucose-sensitive protein.

Shootin1 has been ascribed a role in regulating polarization of primary hippocampal neurons. To better understand the possible role of Shootin1 in the developing brain, we identified a member of the kinesin superfamily, KIF20B, as a novel Shootin1 interacting protein and a potential mediator of Shootin1 interaction with microtubules. KIF20B/Shootin1 binding was mapped to a 57 aa KIF20B sequence, which was used as a dominant-negative fragment. Direct interaction between that peptide (MBD) and Shootin1 was confirmed by surface plasmon resonance-based technology and the affinity was determined in the 10 Ϫ7 M range. The proteins are expressed in the developing brain and formed a complex in vivo based on coimmunoprecipitation experiments and coimmunostaining in primary neurons. In primary hippocampal neurons Kif20b knockdown reduced Shootin1 mobilization to the developing axon, as evidenced by immunostaining and fluorescence recovery after photobleaching analysis, suggesting that Shootin1 is a novel KIF20B cargo. shRNA targeting of Shootin1 reduced PIP3 accumulation in the growth cone, as did Kif20b shRNA. In the developing mouse brain, Kif20b knockdown or expression of the KIF20B minimal binding domain inhibited neuronal migration, and in vivo migration assays suggested that Shootin1/ Kif20b acts in the same genetic pathway. Time-lapse imaging of multipolar cells in the subventricular zone revealed that downregulating levels of either Shootin1 or Kif20b hindered the transition from multipolar to bipolar cells. Collectively, our data demonstrate the importance of the Shootin1/KIF20B interaction to the dynamic process of pyramidal neuronal polarization and migration.

Major depressive disorder is a severe psychiatric condition which forms a substantial burden to patients and society. Despite continuous efforts to unravel its etiology and pathophysiology, many questions remain. The majority of neurobiological research and classical pharmacotherapy regimens have approached this illness as the consequence of a failing monoaminergic neurotransmitter system. In the last decades, involvement of adult hippocampal neurogenesis in the pathogenesis and treatment of depressive disorder has gained an enormous interest. Numerous neurobiological systems and circuits thus appear to underlie this complex multi-factorial disease. One of them is the cholinergic system, which plays a major role in the regulation of various CNS functions, such as arousal, attention, cognition and memory. Cognitive impairments are often observed in depression, next to low mood, anhedonia and other clinical symptoms. Cholinergic dysfunctions may account for the development of cognitive symptoms during the course of depression. Changes in hippocampal neurogenesis, often associated with chronic stress in animal models, may be in part mediated by cholinergic dysfunction, which in turn could underlie the cognitive disturbances observed in depression. Here, we discuss the involvement of the cholinergic system in depressive disorder, with particular focus on its role in associated cognitive impairment. Since such deficits are often modified by cholinergic drugs, application of these neuropharmacological findings may provide a new therapeutic niche while yielding valuable insight into the pathophysiology of this complex illness.

Growing evidence suggests that decreased brainderived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain. V

Protein synthesis-dependent forms of hippocampal long-term potentiation (late LTP) and long-term depression (late LTD) are prominent cellular mechanisms underlying memory formation. Recent data support the hypothesis that neurons store relevant information in dendritic functional compartments during late LTP and late LTD rather than in single synapses. It has been suggested that processes of "synaptic tagging" are restricted to such functional compartments. Here, we show that in addition to apical CA1 dendrites, synaptic tagging also takes place within basal CA1 dendritic compartments after LTP induction. We present data that tagging in the basal dendrites is restricted to these compartments. Plasticity-related proteins, partially nonspecific to the locally induced process, are synthesized in dendritic compartments and then captured by local, process-specific synaptic tags. We support these findings in two ways: (1) late LTP/LTD, locally induced in apical or basal (late LTP) dendrites of hippocampal CA1 neurons, does not spread to the basal or apical compartment, respectively; (2) the specificity of the synaptic plasticity event is achieved by the activation of process-and compartmentspecific synaptic tag molecules. We have identified calcium/calmodulin-dependent protein kinase II as the first LTP-specific and extracellular signal-regulated kinase 1/2 as LTD-specific tag molecules in apical dendritic CA1 compartments, whereas either protein kinase A or protein kinase M mediates LTP-specific tags in basal dendrites.

Salicylate intoxication is a cause of tinnitus in humans and it is often used to produce tinnitus-like perception in animal models. Here we assess whether salicylate induces anxiety-like electrophysiological and behavioural signs. Using microwire electrode arrays, we recorded local field potential in the ventral and, in some experiments dorsal hippocampus, in an open field arena 1 hour after salicylate (300mg/kg) injection. We found that animals treated with salicylate moved dramatically less than saline treated animals. Salicylate-treated animals showed a strong 4-6Hz (type 2) oscillation in the ventral hippocampus (with smaller peaks in dorsal hippocampus electrodes). Coherence in the 4-6Hz-theta band was low in the ventral and dorsal hippocampus when compared to movement-related theta coherence (7-10Hz). Moreover, movement related theta oscillation frequency decreased and its dependency on running speed was abolished. Our results suggest that salicylate-induced theta is mostly re...

öTo elucidate the role of dendritic morphology in signal transfer, the passive propagation of somatic and dendritic potentials was compared in multi-compartment models of three interneuron subpopulations in the CA1 region. Nine calbindin-, 15 calretinin-and 10 parvalbumin-containing cells were modelled incorporating the detailed geometry, the currents of the action potentials in the soma, and the AMPA, N-methyl-D-aspartate and GABA-B receptor-mediated postsynaptic currents in the dendrites. The cable properties show characteristic di¡erences among the subpopulations. The morphotonic length of calbindin and calretinin cell dendrites is larger than of parvalbumin cells. Thus parvalbumin cells are more compact than calbindin or calretinin cells unless the ratio of their axial and membrane resistivities exceeds the ratios of the other two cell types by more than 33%. In calbindin cells, the distal parts of the extremely long dendrites that invade the alveus are virtually isolated from the soma for passively propagating signals. The synaptic potentials evoked at a given morphotonic distance from the soma show larger di¡erences locally on the dendrites than on the soma in all subpopulations. Both the somatic and dendritic amplitude ratios are the smallest in PV cells. In calbindin cells the somatic amplitude of synaptic potentials evoked at the same morphotonic distance from the soma is similar regardless of the number of branchpoints along their path. In calretinin and parvalbumin cells, from dendrites with long primary segments synaptic potentials reach the soma with larger amplitude than from dendrites that are branching close to the soma. The dendrites with the larger impact on somatic membrane potential are usually the dendrites that enter the stratum lacunosum-moleculare. These results indicate that dendritic morphology plays a role in changing the e¡ectiveness of synaptic potentials evoked at di¡erent dendritic locations, and in this way is likely to be an important factor in determining the integrative properties of the di¡erent neuron populations.

SVNCIlRONIZATION of neuronal activity is fundamental in the operation of cortical networks ' . With respect to an ongoing synchronized oscillation, the precise timing of action potentials is an attractive candidate mechanism for information coding'-', Networks of inhibilory interneurons ha,'e been proposed to ha,'e a role in entraining cortica l, synchronized 40-Hz activity·". Here wc demonstrate that individual GABAergic interneurons' can effecti vely phase spontaneous firing and subthreshold oscillations in hippocampa l pyramidal cells at 0 frequencies (4-7 Hz). The efficiency of this entrainment is due to interaction of GA BA Areceptor-mediated hyperl.olarizing synaptic events with intrinsic oscillatory mechanisms tuned to this frequency range in I.yramidal cells. Moreover, this GABAergic mechanism is sufficient to synchronize the firing of pyramidal cells. Thus, owing to the dh'ergence of each GA BAergic interneuron·· ' o, more than a thousand pyramidal cells may share a common temporal reference established by an individ ual interneuron.

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated. R. (1990) Glucocortioicds inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinol-0gy 52, 57-62.

The transcription factor CREB (cyclic AMP response element binding protein) is implicated in diverse brain functions and represents a prospective target in gene therapy for human disorders. However, the transgenic expression and stability of exogenously expressed CREB within the cell remains poorly characterized. Here we found that transient expression of a CREB dominant interfering mutant A-CREB or the inducible cAMP early repressor, ICER, led to the dramatic decrease of exogenously co-expressed CREB in 293 human embryonic kidney cells. Elevation of protein kinase A activity within the cells restored CREB protein levels. A-CREB did not effect the transient expression of a truncated CREB lacking the leucine zipper domain demonstrating a specific effect of heterodimerization on CREB protein stability. Somatic gene transfer into the rat brain using a recombinant adeno-associated virus vector provided robust expression of both transgenic CREB and ICER mRNAs under the control of a constitutive neuron specific enolase (NSE) promoter. In contrast to ICER, the expression of the transgenic CREB mRNA did not result in elevation of CREB protein levels within dentate granule cells of the hippocampus, suggesting its prompt degradation under basal conditions. However, following tetanization of the perforant pathway, which is known to induce CREB phosphorylation, there was a significant increase in the amount of transgenic CREB protein within dentate granule cells. Hence, heterodimerization of unphosphorylated CREB with either A-CREB or ICER triggers CREB protein degradation, whereas phosphorylation prevents CREB from such degradation both in vitro and in vivo.

The neural consequences of early-life exposure to methylphenidate (MPH; Ritalin) are of great interest given the widespread, and sometimes inappropriate, use in children. Here we examine the impact of juvenile MPH exposure on adult hippocampal neurogenesis. Methods: Rats received MPH (2.0 mg/kg, intraperitoneal, twice daily) or saline (SAL) during preadolescence (postnatal days 20 -35). Hippocampal cell proliferation (Experiment 1), neurogenesis (Experiment 2), and stress-induced changes in cell proliferation (Experiment 3) were assessed at several developmental stages including adulthood. Results: Juvenile exposure to MPH did not alter proliferation at any developmental time point relative to control rats; however, exposure to MPH significantly decreased the long-term survival of newborn cells in adult rats, particularly in the temporal hippocampus. Although MPH-treated rats had higher levels of corticosterone after restraint stress, they did not show the expected greater decrease in hippocampal cell proliferation relative to control animals. Conclusions: Early-life exposure to MPH inhibits the survival of adult-generated neurons in the temporal hippocampus and may reduce progenitor sensitivity to corticosterone-induced decreases in proliferation. These findings suggest that decreased adult neurogenesis is an enduring consequence of early-life exposure to MPH and are discussed for their relevance to humans.

One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was c o m b i n e d with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of c a l c i u m -c a l m o d u l i n -d e p e ndent kinase II (CaMKII) resulted in a loss of h i p p o c a m p a l long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit m e m o r y task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit m e m o r y storage, in a manner that is independent of its potential role in development.

Intrahippocampal injections of zinc chloride (5-10 nmol) caused a discrete lesion in the rat hippocampus, involving all neuronal perikarya. In addition to the necrosis, the lesion was also characterized by a decrease in staining of the neuropil, the presence of pyknotic neurons, and occasionally infarction. Pathological changes occurred within 8 h of an injection, and neuronal loss, as judged by the loss of Nissl staining, was complete within 24 h. On the other hand, the loss of acidophilic staining of the neurons was more gradual, as acid fuchsin staining was still present in neurons in the periphery of the damaged area 4 days later. In comparison with an excitotoxic lesion, glial infiltration into the damaged area was minimal, even up to 3 weeks later, suggesting that some glial cell toxicity also occurred.

The actions of 5-HT1A receptors on cell proliferation in the rat neonatal dentate gyrus are unknown. We injected a 5-HT1A receptor agonist (ipsapirone) or antagonist (Way 100635) 1 h before injections of BrdU in neonates of both genders between days 2 -4, a peak time of dentate gyrus granule cell proliferation. The BrdU immunoreactive (IR) nuclei in the granule cell layer and subgranular zone were examined after 2 weeks. The BrdU-IR nuclear staining patterns were classified as being either diffuse (homogenous dark BrdU-staining throughout the nucleus) or punctate (multiple distinct small stained spots within the nucleus). Most BrdU-labeled nuclei with a diffuse pattern were seen in the subgranular zone while the punctate pattern nuclei were seen within the granular cell layer of the dentate gyrus. 5-HT1A antagonist showed no overall change in absolute number or pattern of labeled nuclei compared to control animals. After a 5-HT1A agonist, there was also no differences in the total number of BrdU-IR nuclei (punctate and diffuse pattern). However, in both genders, the proportion of the BrdU-labeled nuclei showing a punctate compared to diffuse pattern increased: 33% in females and 18% in males. In females, the 5-HT1A receptor agonist increased the number of nuclei showing a punctate pattern by 41%, while in males the 5-HT1A receptor agonist decreased the number of nuclei showing a diffuse pattern by 29%. These results indicate gender-specific 5-HT1A receptor action on the state of nuclear DNA in the cells of the dentate gyrus, without increasing the total number of BrdU-labeled nuclei. D

Performance in several memory tasks is known to be unaffected by hippocampal damage sustained before learning, but is severely disrupted if the same damage occurs after learning. Memories for preferred locations, or home bases, in exploratory tasks can be formed by rats with hippocampal damage, but it is unknown if the memory for a home base survives hippocampal damage. To examine this question, for 30 min each day for five consecutive days, rats explored a circular open field containing one local cue. By Day 5 the rats preferentially went directly to that location, spent the majority of their time at that location, made rapid direct trips to that location when returning from an excursion and so demonstrated that the location was a home base. Memory for the cued location was examined after a 24 h or 14-day interval with the cue removed. In Experiments 1 and 2, control rats and rats with prior N-methyl-D-aspartic acid hippocampal lesions demonstrated memory of the home base location by making direct trips to that location. In Experiment 3, rats that had first explored the open field and cue and then received hippocampal lesions showed no memory for the cued location. The absence of anterograde impairment vs. the presence of retrograde impairment for memory of a spatial home base confirms a role for the hippocampus in the retention of spatial memory acquired during exploration. V V C 2009 Wiley-Liss, Inc.

Epilepsy as one of the most common neurological disorders affects more than 50 million people worldwide with a higher prevalence rate in low-income countries. Excessive electrical discharges in neurons following neural cell damage or loss cause recurrent seizures. One of the most common and difficult to treat types of epilepsy is temporal lobe epilepsy (TLE) which results from hippocampal sclerosis. Nowadays, similar to other diseases, epilepsy also is a candidate for treatment with different types of stem cells. Various stem cell types were used for treatment of epilepsy in basic and experimental researches. Two major roles of stem cell therapy in epilepsy are prophylaxis against chronic epilepsy and amelioration cognitive function after the occurrence of TLE. Several animal studies have supported the use of these cells for treating drug-resistant TLE. Although stem cell therapy seems like a promising approach for treatment of epilepsy in the future however, there are some serious ...

Whether high-cholesterol diets (HCD) induce a high incidence of memory deficits in diabetes requires to be established; if so, whether they induce impairments of memory acquired in the pre-diabetic stage as well as in the diabetic stage also needs to be elucidated, and part of the related mechanisms involved in this dysfunction should be determined. The mice were grouped into: normal mice fed normal diets (NN), diabetic mice fed normal diets (DN), normal mice fed HCD (NH), and diabetic mice fed HCD (DH). Animals were subjected to Morris water maze testing: 1) Learning in the pre-diabetic stage and memory retrieval in the diabetic stage; 2) Learning and memory retrieval in the diabetic stage. Following water maze testing, biochemical parameters were estimated in the animals. The results showed that significant impairments of memory retrieval, acquired in the diabetic stage, were observed only in DH group, neither in DN nor NH group in a short term compared with NN group. Biochemical ...

Diabetes mellitus is an endocrine disorder of carbohydrate metabolism resulting primarily from inadequate insulin release (Type 1 insulindependent diabetes mellitus) or insulin insensitivity coupled with inadequate compensatory insulin release (Type 2 non-insulin-dependent diabetes mellitus). Previous studies involving behavioural and electrophysiological analysis indicate that diabetes mellitus induces cognitive impairment and defects of long-term potentiation in the hippocampus. Considered to be an important mechanism of learning and memory in mammals, long-term potentiation is known to require regulation of the glutamate receptor properties. According to many studies, defects of long-term potentiation in the hippocampus of diabetic animals are due to abnormal glutamate receptors. We review here the changes in glutamate receptors that may account for modifications of long-term potentiation in various models of diabetes mellitus. As glutamate receptors are also involved in the appearance of neurodegenerative states, we discuss the possibility that deficits in long-term potentiation during chronic diabetes might arise from dysfunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in early stages of the disease. This review addresses the possible role of hyperglycaemia and insulin in regulating these receptors. D

In this paper, we summarize the data obtained in our laboratory showing the effects of glucocorticoids on human cognitive function in older adults, young adults and children. We first present data obtained in the aged human population which showed that long-term exposure to high endogenous levels of glucocorticoids is associated with both memory impairments and a 14% smaller volume of the hippocampus. We then report on studies showing that in older adults with moderate levels of glucocorticoids, memory performance can be acutely modulated by pharmacological manipulations of glucocorticoids. In young adults, we present data obtained in our laboratory showing that cognitive processing sustained by the frontal lobes is also sensitive to acute increases of glucocorticoids. We also summarize studies showing that just as in older adults, memory performance in young adults can be acutely modulated by pharmacological manipulations of glucocorticoids. We then present a study in which we showed a differential involvement of adrenergic and glucocorticoid hormones for short-and long-term memory of neutral and emotional information. In the last section of the paper, we present data obtained in a population of young children and teenagers from low and high socioeconomic status (SES), where we showed that children from low SES present significantly higher levels of basal cortisol when compared to children from high SES. We then present new data obtained in this population showing that children and teenagers from low and high SES do not process the plausibility of positive and negative attributes in the same way. Children from low SES tended to process positive and negative attributes on a more negative note than children from high SES, and this type of processing was significantly related to basal cortisol at age 10, 12 and 14. Altogether, the results of these studies show that both bottom-up (effects of glucocorticoids on cognitive function), and top-down (effects of cognitive processing on glucocorticoid secretion) effects exist in the human population. Q

Sleep deprivation induces oxidative stress and impairs learning and memory processes. Vitamin E, on the other hand, is a strong antioxidant that has neuroprotective effect on the brain. In this study, we examined the potential protective effect of chronic administration of vitamin E on chronic sleep deprivationinduced cognitive impairment. In addition, possible molecular targets for vitamin E effects on chronic sleep deprivation-induced cognitive impairment were determined. Sleep deprivation was induced in rats using modified multiple platform model. Vitamin E (100 mg/kg) was administered to animals by oral gavage. Behavioral study was conducted to test the spatial learning and memory using the radial arm water maze (RAWM). In addition, the hippocampus was dissected out and antioxidant markers including glutathione (GSH), oxidized glutathione (GSSG) and GSH/GSSG, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) were assessed. The results of this project revealed that chronic sleep deprivation impaired both (short-and long-term) memories (P < 0.05), while vitamin E treatment prevented such effect. Additionally, vitamin E normalized chronic sleep deprivation-induced reduction in the hippocampus GSH/GSSG ratio, and activity of catalase, SOD, and GPx. In conclusion, sleep deprivation induces memory impairment, and treatment with vitamin E prevented this impairment probably through its antioxidant action in the hippocampus.

The precise contribution of visual information to contextual fear-learning and discrimination has remained elusive. To better understand this contribution, we coupled the context pre-exposure facilitation effect (CPFE) fear conditioning paradigm with presentations of distinct visual scenes displayed on 4 LCD screens surrounding a conditioning chamber. Adult male Long-Evans rats received non-reinforced context pre-exposure on Day 1, an immediate 1.5 mA foot shock on Day 2, and a non-reinforced context test on Day 3. Rats were pre-exposed to either digital Context (dCtx) A, dCtx B, a distinct Context C, or no context on Day 1. Context A and B were identical except for the visual image displayed on the LCD monitors. Immediate shock and retention testing occurred in dCtx A. Rats pre-exposed dCtx A showed the CPFE with significantly higher levels of freezing compared to learning controls. Rats pre-exposed to Context B failed to show the CPFE, with freezing that did not differ significant...

Spontaneous slow waves (EEG) and multiple unit activity (MUA) were recorded in the posterior cingulate cortex (area 29) and the dorsal hippocampus of the freely moving rat by means of chronically implanted electrodes. Three different wave patterns were discerned in the cingulate EEG. (1) Irregular slow waves occurred during grooming, drinking, eating (Type II behavior) and slow-wave sleep (SWS). The irregular waves also contained sharp transients of about 20 ms duration called EEG-spikes. EEG-spikes reversed their polarity within the cingulate cortex and correlated with an increase in cingulate MUA. They were probably generated by deep (layer IV to VI) neurons in the cingulate cortex. (2) Theta rhythm of 6-10 Hz accompanied walking, rearing, postural shifts, head movements (Type I behavior) and rapid-eye-movement sleep (REMS). MUA of low-amplitude units was phase-locked to the local theta waves, suggesting local generation of the slow waves. However, volume-conduction from the hippocampus would likely contribute to the cingulate theta since no reversal of the theta waves was found in the cingulate cortex. (3) Fast waves of >30 Hz were generally larger during Type I than during Type II behavior. Cellular generators for fast waves are not known. High-amplitude (>100 tzV) MUA only appeared during Type II behavior, and in particular during SWS. During REMS, these units were silent: Stimulation of the contralateral homotopic cingulate cortex gave antidromic and synaptic components in the average evoked potential (AEP). The long latency waves of the AEP varied with behaviors and appeared oscillatory (25-40 Hz) during Type I but not during Type II behavior. In summary, the cingulate cortex has a rich gamut of spontaneous and evoked electrical activities which bears some resemblance to that of the hippocampus.

Three inhibitors of glutamate decarboxylase (GAD), acting through different mechanisms, as well as pyridoxal phosphate (PLP), were microinjected unilaterally by stereotaxic procedures into the substantia nigra reticulata or the CA1 area of the hippocampus of the rat. The ...

Approximately 2 million people in the United States suffer from Alzheimer's disease (AD), which is the most common cause of chronic dementia among the aging population. During the last 7 yr, excellent opportunities to screen drugs against AD have been provided by animal models of the disease. Because even in the fastest model, AD pathology does not start before the end of the second month, it has been necessary to wait at least until that age to inject drugs into the animal to assess whether they prevent, reduce, or revert synaptic impairment, plaque formation, and increase of β-amyloid (Aβ) levels, the main features of the disease. A solution to the problems mentioned above is achieved by the present fast, efficient, and reproducible cultured cell system from animal models of AD or Aβ-associated diseases, for the screening and testing of compounds for the treatment and therapy of AD or Aβ-associated diseases.

Recent evidence suggests that a variety of environmental factors, including dietary and gastrointestinal agents, may contribute to autism spectrum disorders (ASD). Here we administered propionic acid (PPA), a short chain fatty acid that is used as a food preservative and also is a metabolic end-product of enteric bacteria in the gut, to adolescent (41 ± 4 days) male rats in a study of restricted/repetitive behavior, social behavior, and cognition. The goal was to further evaluate the effects of PPA in young rodents. PPA (4 l of 0.26 M solution) was administered intracerebroventricularly prior to each behavioral test. Rats treated with PPA displayed restricted behavioral interest to a specific object among a group of objects, impaired social behavior, and impaired reversal in a T-maze task compared to controls given phosphate buffered saline. Immunohistochemical analysis of brain tissue from PPA rats revealed reactive astrogliosis and activated microglia, indicating an innate neuroinflammatory response. These findings are consistent with our earlier findings of ASD-relevant behavioral and brain events in adult rats given PPA, and support further study of effects of PPA in young rodents by establishing similar effects in adolescent animals.

The effects of early life experience on later brain structure and function have been studied extensively in animals, yet the relationship between childhood experience and normal brain development in humans remains largely unknown. Using a unique longitudinal data set including ecologically valid in-home measures of early experience during childhood (at age 4 and 8 years) and high-resolution structural brain imaging during adolescence (mean age 14 years), we examined the effects on later brain morphology of two dimensions of early experience: parental nurturance and environmental stimulation. Parental nurturance at age 4 predicts the volume of the left hippocampus in adolescence, with better nurturance associated with smaller hippocampal volume. In contrast, environmental stimulation did not correlate with hippocampal volume. Moreover, the association between hippocampal volume and parental nurturance disappears at age 8, supporting the existence of a sensitive developmental period for brain maturation. These findings indicate that variation in normal childhood experience is associated with differences in brain morphology, and hippocampal volume is specifically associated with early parental nurturance. Our results provide neuroimaging evidence supporting the important role of warm parental care during early childhood for brain maturation.

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short-and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week followups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.

Persistent neural spiking maintains information during a working memory task when a stimulus is no longer present. During retention, this activity needs to be stable to distractors. More importantly, when retention is no longer relevant, cessation of the activity is necessary to enable processing and retention of subsequent information.