Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats

Previous work shows that sleep deprivation impairs hippocampal-dependent learning and long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF), cAMP response-element-binding (CREB) and calcium–calmodulin-dependent protein kinase II (CAMKII) are critical modulators of hippocampal-dependent learning and LTP. In the present study we compared the effects of short- (8 h) and intermediate-term (48 h) sleep deprivation ( SD ) on the expression of BDNF and its downstream targets, Synapsin I, CREB and CAMKII in the neocortex and the hippocampus. Rats were sleep deprived using an intermittent treadmill system which equated total movement in the SD and control treadmill animals (CT), but permitted sustained periods of rest in CT animals. Animals were divided into SD (treadmill schedule: 3 s on/12 s off) and two treadmill control groups, CT1 (15 min on/60 min off) and CT2 (30 min on/120 min off – permitting more sustained sleep). Real-time Taqman RT-PCR was used to measure changes in mRNA; BDNF protein levels were determined using ELISA . In the hippocampus, 8 h treatments reduced BDNF , Synapsin I, CREB and CAMKII gene expression in both SD and control groups. Following 48 h of experimental procedures, the expression of all these four molecular markers of plasticity was reduced in SD and CT1 groups compared to the CT2 and cage control groups. In the hippocampus, BDNF protein levels after 8 h and 48 h treatments paralleled the changes in mRNA. In neocortex, neither 8 h nor 48 h SD or control treatments had significant effects on BDNF , Synapsin I and CAMKII mRNA levels. Stepwise regression analysis suggested that loss of REM sleep underlies the effects of SD on hippocampal BDNF , Synapsin I and CREB mRNA levels, whereas loss of NREM sleep underlies the effects on CAMKII mRNA.     

Differential effects of neonatal norepinephrine lesions on immediate early gene expression in developing and adult rat brain

Activity regulated cytoskeletal protein (Arc), c-fos and zif268 are immediate early genes (IEGs) important for adult brain plasticity. We examined developmental expression of these IEGs and the effect of neonatal noradrenergic lesion on their expression in developing and mature brain. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a specific noradrenergic neurotoxin, was administered to rats on postnatal day (PND) 3 and in situ hybridization was used to assay Arc, c-fos and zif268 mRNA on PND 13, 25 and 60. In contrast to decreases in Arc, c-fos and zif268 expression produced by noradrenergic lesions of mature brain, lesions on PND 3 yield a strikingly different effect. Neonatal lesions produce increases in c-fos and zif268 expression in specific frontal cortical layers on PND 13, while Arc shows no change. These lesions lead to increases in zif268 expression in frontal cortical layers on PND 25, with no changes in c-fos or Arc expression, and on PND 60 they produce a significant increase in c-fos expression in hippocampus with no significant changes in Arc or zif268 expression. 2-[2-(2-Methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002), an alpha-2 adrenergic receptor (A2AR) antagonist, administered to control PND 60 animals produces elevations of Arc, zif268 and c-fos mRNAs. This response was eliminated in animals lesioned with DSP-4 on PND 3. These data indicate that norepinephrine regulation of IEG expression differs in developing and mature brain and that loss of developmental norepinephrine leads to abnormally high postnatal IEG expression. Previous studies have shown an important role for norepinephrine in brain development. Our data support the idea that norepinephrine plays an important role during CNS development and that changes in noradrenergic signaling during development may have long lasting effects, potentially on learning and memory.     

A high-fat,refined sugar diet reduces hippocampal brain-derived neurotrophic factor,neuronal plasticity,and learning

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family.Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.     

Effect of age and cognitive status on basal level AP-1 activity in rat hippocampus.

Activator protein-1 (AP-1) was examined at multiple levels (mRNA, DNA binding, composition) in hippocampus of young and aged rats that were behaviorally characterized for spatial memory. GFAP mRNA was measured as a gene product known to increase with aging and to be regulated by AP-1. The activity of Jun-amino terminal-kinase (JNK) was also assessed. Levels of c-jun and c-fos mRNAs were unchanged with aging or spatial learning ability. Abundance of GFAP mRNA was significantly increased in aged hippocampus but did not correlate with spatial learning. Total AP-1 binding activity was unaltered with age or cognitive ability. In hippocampus of young, aged unimpaired and aged impaired rats, AP-1 consists mainly of c-Jun, phosphorylated c-Jun (p-c-Jun), JunD, and smaller amounts of c-Fos. JNK is constitutively active in young and aged hippocampus. We conclude that the basal expression of c-fos and c-jun mRNA, overall AP-1 binding activity and AP-1 composition are not influenced by aging or cognitive ability.     

A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor

We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.     

Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance

Arc (also termed activity-regulated cytoskeleton-associated protein or Arg3.1), is an effector immediate early gene whose upregulation has been demonstrated during events of synaptic plasticity. In the present study, the possibility that Arc would be specifically upregulated in rats during the acquisition of a quickly learned behavioral task but not in overtrained animals was investigated. Three groups of rats, pseudotrained, newly trained and overtrained, were examined with respect to Arc expression following training on a simple operant lever-pressing task. Newly trained animals were killed 30 min following the session in which they demonstrated acquisition of the task, and overtrained animals were trained on the same task for 13–14 days and then killed. Relative to base level measures taken 6 h following the session, all three groups demonstrated significant levels of induction of Arc mRNA; however, newly trained animals exhibited heightened induction of Arc mRNA relative to both pseudotrained and overtrained animals. The increased levels of Arc mRNA in newly trained animals were located in the CA1 and CA3 fields of hippocampus, the subiculum, and the anterior cingulate, piriform, infra/prelimbic, perirhinal and entorhinal cortical areas. Additionally, Arc mRNA was expressed differentially across the above anatomic structures in a relative pattern that was the same in all three groups. Finally, levels of Arc mRNA in specific brain regions of newly trained animals correlated negatively with the rate of task acquisition, such that slow learners exhibited higher levels of Arc mRNA than fast learners.

From these results we suggest that Arc is upregulated in an experience-dependent manner, with higher levels of induction occurring during the initial stage of learning. Furthermore, the finding of increased Arc levels in slow versus fast learners indicates that Arc expression may be associated with the length of time required to: (1) form new associations or (2) remodel existing connections. These results confirm other reports that Arc is a critical substrate for the synaptic plasticity underlying the acquisition of new behaviors.     

BDNF and learning: Evidence that instrumental training promotes learning within the spinal cord by up-regulating BDNF expression

We have previously shown that the spinal cord is capable of learning a sensorimotor task in the absence of supraspinal input. Given the action of brain-derived neurotrophic factor (BDNF) on hippocampal learning, the current studies examined the role of BDNF in spinal learning. BDNF is a strong synaptic facilitator and, in association with other molecular signals (e.g. cAMP-response element binding protein (CREB), calcium/calmodulin activated protein kinase II (CaMKII) and synapsin I), important for learning. Spinally transected rats given shock to one hind leg when the leg extended beyond a selected threshold exhibited a progressive increase in flexion duration that minimized shock exposure, a simple form of instrumental learning. Instrumental learning resulted in elevated mRNA levels of BDNF, CaMKII, CREB, and synapsin I in the lumbar spinal cord region. The increases in BDNF, CREB, and CaMKII were proportional to the learning performance. Prior work has shown that instrumental training facilitates learning when subjects are tested on the contralateral leg with a higher response criterion. Pretreatment with the BDNF inhibitor TrkB-IgG blocked this facilitatory effect, as did the CaMKII inhibitor AIP. Intrathecal administration of BDNF facilitated learning when subjects were tested with a high response criterion. The findings indicate that instrumental training enables learning and elevates BDNF mRNA levels within the lumbar spinal cord. BDNF is both necessary, and sufficient, to produce the enabling effect.     

Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity

We have investigated potential mechanisms by which exercise can promote changes in neuronal plasticity via modulation of neurotrophins. Rodents were exposed to voluntary wheel running for 3 or 7 days, and their lumbar spinal cord and soleus muscle were assessed for changes in brain-derived neurotrophic factor (BDNF), its signal transduction receptor (trkB), and downstream effectors for the action of BDNF on synaptic plasticity. Exercise increased the expression of BDNF and its receptor, synapsin I (mRNA and phosphorylated protein), growth-associated protein (GAP-43) mRNA, and cyclic AMP response element-binding (CREB) mRNA in the lumbar spinal cord. Synapsin I, a synaptic mediator for the action of BDNF on neurotransmitter release, increased in proportion to GAP-43 and trkB mRNA levels. CREB mRNA levels increased in proportion to BDNF mRNA levels. In separate experiments, the soleus muscle was paralyzed unilaterally via intramuscular botulinum toxin type A (BTX-A) injection to determine the effects of reducing the neuromechanical output of a single muscle on the neurotrophin response to motor activity. In sedentary BTX-A-treated rats, BDNF and synapsin I mRNAs were reduced below control levels in the spinal cord and soleus muscle. Exercise did not change the BDNF mRNA levels in the spinal cord of BTX-A-treated rats but further reduced the BDNF mRNA levels in the paralyzed soleus relative to the levels in sedentary BTX-A-treated rats. Exercise also restored synapsin I to near control levels in the spinal cord. These results indicate that basal levels of neuromuscular activity are required to maintain normal levels of BDNF in the neuromuscular system and the potential for neuroplasticity.     

Cooperation in the iterated prisoner's dilemma is learned by operant conditioning mechanisms

The prisoner's dilemma (PD) is the leading metaphor for the evolution of cooperative behavior in populations of selfish agents. Although cooperation in the iterated prisoner's dilemma (IPD) has been studied for over twenty years, most of this research has been focused on strategies that involve nonlearned behavior. Another approach is to suppose that players' selection of the preferred reply might be enforced in the same way as feeding animals track the best way to feed in changing nonstationary environments. Learning mechanisms such as operant conditioning enable animals to acquire relevant characteristics of their environment in order to get reinforcements and to avoid punishments. In this study, the role of operant conditioning in the learning of cooperation was evaluated in the PD. We found that operant mechanisms allow the learning of IPD play against other strategies. When random moves are allowed in the game, the operant learning model showed low sensitivity. On the basis of this evidence, it is suggested that operant learning might be involved in reciprocal altruism.     

Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade

Flavonoid-rich foods have been shown to be effective at reversing age-related deficits in learning and memory in both animals and humans. However, little investigation of the preventative effects of flavonoids on the naturally aged animals was reported. In our study, 14-month-old female C57BL/6 J mice were orally administered 0.025%, 0.05% and 0.1% green tea catechins (GTC, w/v) in drinking water for 6 months; we found that a supplementation with 0.05% or 0.1% GTC prevented age-related spatial learning and memory decline of mice in the Morris water maze. Better performance of GTC-treated mice was associated with increased levels of cAMP-response element binding protein (CREB) phosphorylation in the hippocampus. The expressions of brain-derived neurotrophic factor (BDNF) and Bcl-2, two target genes of CREB which can exhibit long-term regulatory roles in synaptic plasticity and synaptic structure, were also increased. We also found that long-term 0.05% or 0.1% GTC administration prevented age-related reductions of two representative post-synaptic density proteins PSD95 and Ca²⁺/calmodulin-dependent protein kinase II, suggesting that synaptic structural changes may be involved. These results demonstrated that long-term 0.05% or 0.1% green tea catechin administration may prevent age-related spatial learning and memory decline of female C57BL/6 J mice by regulating hippocampal CREB signaling cascade.     

气味对小鼠学习记忆能力及海马cAMP反应元件结合蛋白的影响

目的:探讨不同气味(苹果、香水、樟脑)对小鼠学习记忆能力及海马cAMP反应元件结合蛋白(CREB)和磷酸化的CREB(pCREB)的影响。方法:让小鼠在不同气味的环境下生活14d,在第7d开始方形水迷宫训练,3d后进行测试,连续测试5d。测试完后断髓处死动物,取出脑组织,用免疫组织化学染色观察海马pCREB和CREB表达情况,并进行图像分析。结果:樟脑组和香水组水迷宫的潜伏期较对照组延长,错误次数增多(P＜0.05)。免疫组化染色显示鼠海马CREB的磷酸化水平大大降低(P＜0.05),但对CREB的表达无明显影响。苹果组与对照组比各指标均无显著差异(P＞0.05)。结论:樟脑气味和香水气味对小鼠记忆能力有负面作用,且这种作用可能是通过降低CREB磷酸化水平而实现的。苹果气味对小鼠记忆能力无明显影响。     

Expression and regulation of the immediate-early gene product Arc in the accessory olfactory bulb after mating in male rat

Recent studies of the accessory olfactory bulb have shown that the expression of immediate-early genes, e.g., c-fos, c-jun and egr-1, can be used as a marker of neuronal activity in response to pheromonal cues. In this study, we analyzed the expression pattern, in response to mating, of the novel immediate-early gene product Arc (an activity-regulated cytoskeleton-associated protein). Arc is hypothesized to play a role in activity-dependent neuronal plasticity in the hippocampus. In a control group of male rats, only a small number of Arc-immunoreactive cells were observed in the accessory olfactory bulb. In a mating group, however, a marked increase in the number of Arc-immunoreactive cells was observed only in the granule cell layer of the accessory olfactory bulb. The increase in the number of Arc-immunoreactive cells after mating was similar to that observed for other immediate-early genes. However, for the mating group, the increase in Arc-positive cells was limited to the granule cell layer. Granule cells have been shown to exhibit a strong synaptic plasticity in response to pheromonal stimulation.From these findings we suggest that Arc plays an important role in neuronal plasticity in the accessory olfactory bulb.     

A closed system for investigating the relationship between the gaseous environment and the behavior of small mammals

The system described in this paper permits the control of the air composition while the animals are under different behavioral situations. A special air-tight operant conditioning (Skinner) box was used. We used oxygen-18 in this system in order to measure the oxygen metabolism under different physiological and psychological situations.     

磷酸二酯酶4抑制剂咯利普兰逆转慢性酒精中毒及戒断诱导的小鼠抑郁样行为

目的:研究磷酸二酯酶4(PDE4)抑制剂咯利普兰对酒精中毒戒断诱导的抑郁样行为的作用及对小鼠海马和前额叶皮质脑区环磷酸腺苷(cAMP)、蛋白激酶A(PKA)、cAMP反应元件结合蛋白(CREB)、磷酸化CREB(p-CREB)和脑源性神经营养因子(BDNF)表达的影响。方法:取60只雄性ICR小鼠,随机分为空白对照组、空白+咯利普兰组、慢性酒精模型组和咯利普兰治疗组(0.1、0.5和1 mg/kg)。给予酒精28 d期间每周进行酒精戒断处理。慢性酒精处理后,进行强迫游泳测试(FST)和悬尾测试(TST),观察小鼠抑郁样行为;ELISA检测小鼠海马和前额叶皮质cAMP含量,Western blot检测小鼠海马和额叶皮质PKA、CREB、p-CREB和BDNF的表达。结果:随着饮酒天数及戒断次数的增加,小鼠表现出明显嗜酒现象,饮酒量增加(P0.01),FST和TST测试中的不动时间增加(P0.01)。小鼠给药咯利普兰(0.5和1 mg/kg)28 d后,FST和TST不动时间与模型组相比明显减少(P0.05),且能改善小鼠的嗜酒现象,小鼠饮酒量与模型组相比明显减少(P0.01);相比于正常组,模型组小鼠海马和前额叶皮质cAMP含量明显降低(P0.01),并且海马和额叶皮质PKA、p-CREB和BDNF也明显低于正常水平(P0.01)。咯利普兰(0.5和1 mg/kg)给药28 d后,海马与前额叶皮质cAMP含量明显增加(P0.01),酒精抑制的海马脑区PKA、p-CREB和BDNF表达被逆转(P0.05),且酒精抑制的前额叶皮质PKA和p-CREB表达被逆转(P0.05)。结论:磷酸二酯酶4抑制剂咯利普兰能明显改善酒精中毒及戒断引起的抑郁样症状,且能减轻嗜酒症状,机制可能涉及第二信使cAMP通路。咯利普兰通过抑制PDE4,增加海马与前额叶皮质cAMP水平,进而激活PKA-CREB-BDNF通路,从而产生抗抑郁作用。     

De Novo Protein Synthesis of Syntaxin-1 and Dynamin-1 in Long-Term Memory Formation Requires CREB1 Gene Transcription in <Emphasis Type="Italic">Lymnaea stagnalis</Emphasis>

Consolidation of aversive operant conditioning into long-term memory (LTM) requires CREB-dependent de novo protein synthesis. The newly synthesized proteins are distributed to the synapses in neurons that are involved in memory formation and storage. Accumulating evidence indicates that the presynaptic release mechanisms also play a role in long-term synaptic plasticity. Our understanding of whether the presynaptic proteins undergo de novo synthesis during long-term memory formation is limited. In this study, we investigated the involvement of syntaxin-1, a presynaptic exocytotic protein, and dynamin-1, an endocytotic protein, in the formation of long-term memory. We took advantage of a well-established aversive operant conditioning model of aerial respiratory behavior in the fresh water pond snail Lymnaea stagnalis, and demonstrated that the LTM formation is associated with increased expression of syntaxin-1 and dynamin-1, coincident with elevated levels of CREB1. Partial knockdown of CREB1 gene by double stranded RNA inhibition (dsRNAi) prior to operant conditioning prevented snails from memory consolidation, and reduced the expression of syntaxin-1 and dynamin-1 at both mRNA and protein levels. These findings suggest that CREB1-mediated gene expression is required for the LTM-induced up-regulation of synaptic proteins, syntaxin-1 and dynamin-1, in L. stagnalis. Our study thus offers new insights into the molecular mechanisms that mediate CREB1-dependent long-term memory formation.     

Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression

A number of previous studies have shown that chronic but not acute treatment with antidepressant drugs targeting the central 5-HT system, enhances mRNA expression for a number of genes including, brain-derived neurotrophic factor (BDNF) and the effector immediate early gene (IEG), activity-regulated, cytoskeletal-associated protein (Arc). The present study investigated the effects of 5-HT(6)-receptor activation on hippocampal and cortical levels of mRNA expression of BDNF and Arc in the rat. The selective 5-HT(6)-receptor agonist LY-586713 was administered acutely (0.1-10 mg/kg, s.c.) and mRNA levels of BDNF and Arc were measured 18 h later. Administration of LY-586713 caused a bell-shaped dose response on hippocampal BDNF mRNA expression, having no effect at 0.1 mg/kg, a significant up-regulation at 1 mg/kg and no effect at 10 mg/kg. The up-regulation in BDNF expression observed at 1 mg/kg was completely blocked by pre-treatment with the selective 5-HT(6)-receptor antagonist SB-271046 (10 mg/kg, s.c.). The effective dose (1 mg/kg) of LY-586713 on the induction of BDNF expression was also tested on Arc expression. Acute administration of LY-586713 at this dose caused marked increases of the Arc mRNA levels in cortical and hippocampal regions. These increases were also attenuated by SB-271046 (10 mg/kg) in all regions of the hippocampus, as well as the parietal cortex. However, in frontal cortical regions there was no attenuation by the antagonist. Moreover, SB-271046 alone increased Arc expression in these regions. The results presented here provide the first evidence for the involvement of the 5-HT(6) receptor in regulating BDNF and Arc mRNA expression, suggesting that LY-586713 has potential effects on neuronal plasticity. Overall, these findings suggest that, as opposed to more general 5-HT receptor activation by, for example, antidepressants, direct 5-HT(6)-receptor activation results in a more rapid rise in BDNF and Arc mRNA expression which does not require repeated administration.     

The MAPK cascade is required for mammalian associative learning

Mitogen-activated protein kinase (MAPK) is an integral component of cellular signaling during mitogenesis and differentiation of mitotic cells. Recently MAPK activation in post-mitotic cells has been implicated in hippocampal long-term potentiation (LTP), a potential cellular mechanism of learning and memory. Here we investigate the involvement of MAPK in learning and memory in behaving animals. MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning. Two other protein kinases known to be activated during hippocampal LTP, protein kinase C and alpha-calcium/calmodulin protein kinase II, also were activated in the hippocampus after learning. Inhibition of the specific upstream activator of MAPK, MAPK kinase (MEK), blocked fear conditioning. Thus, classical conditioning in mammals activates MAPK, which is necessary for consolidation of the resultant learning.     

Glucose transporter plasticity during memory processing

Various types of learning, including operant conditioning, induce an increase in cellular activation concomitant with an increase in local cerebral glucose utilization (LCGU). This increase is mediated by increased cerebral blood flow or changes in brain capillary density and diameter. Because glucose transporters are ultimately responsible for glucose uptake, we examined their plastic expression in response to cellular activation. In vitro and in vivo studies have demonstrated that cerebral glucose transporter 1 (GLUT1) expression consistently parallels changes in LCGU. The present study is the first to investigate the effect of memory processing on glucose transporters expression. Changes in GLUT expression produced by training in an operant conditioning task were measured in the brain of CD1 mice. Using semi-quantitative immunohistochemistry, Western blot and real time RT-PCR the cerebral GLUT1 and GLUT3 expression was quantified immediately, 220 min and 24 h following training. Relative to sham-trained and naive controls, operant conditioning training induced an immediate increase in GLUT1 immunoreactivity level in the hippocampus CA1 pyramidal cells as well as in the sensorimotor cortex. At longer post-learning delays, GLUT1 immunoreactivity decreased in the sensorimotor cortex and putamen. Parallel to the changes in protein levels, hippocampus GLUT1 mRNA level also increased immediately following learning. No effect of learning was found on hippocampal GLUT3 protein or mRNA expression. Measures of changes in glucose transporters expression present a link between cellular activation and glucose metabolism. The learning-induced localized increases in GLUT1 protein as well as mRNA levels observed in the present study confirm the previous findings that GLUT1 expression is plastic and respond to changes in cellular metabolic demands.     

Lack of effect of Pitressin on the learning ability of Brattleboro rats with diabetes insipidus using positively reinforced operant conditioning

Brattleboro rats with hereditary hypothalamic diabetes insipidus (BDI) received daily subcutaneous injections of vasopressin in the form of Pitressin tannate (0.5 IU/24 hr). They were initially deprived of food and then trained to work for food reward in a Skinner box to a fixed ratio of ten presses for each pellet received. Once this schedule had been learned the rats were given a discrimination task daily for seven days. The performances of these BDI rats were compared with those of rats of the parent Long Evans (LE) strain receiving daily subcutaneous injections of vehicle (arachis oil). Comparisons were also made between these two groups of treated animals and untreated BDI and LE rats studied under similar conditions. In the initial learning trial, both control and Pitressin-treated BDI rats performed significantly better, and manifested less fear initially, than the control or vehicle-injected LE rats when first placed in the Skinner box. Once the initial task had been learned there was no marked difference in the discrimination learning between control or treated BDI and LE animals. These results support the view that vasopressin is not directly involved in all types of learning behaviour, particularly those involving positively reinforced operant conditioning.