Stress hormones enhance retrieval of fear conditioning acquired either one day or many months before.

It has been known for years that systemic administration of the stress hormones, adrenocorticotrophin (ACTH), lysine-vasopressin, adrenaline, or beta-endorphin, enhances retrieval of aversive behaviours acquired one or a few days before. Here we show that the pre-test i.p. injection of the hormones in rats can also enhance retrieval when given months after the original training. The effectiveness of the treatments changed with time. When animals were tested 3 months after training the hormones enhanced retrieval only at doses five times higher than those needed 1 day after training. Between 6 and 9 months from training the hormones either lost their effect (vasopressin, beta-endorphin) or actually inhibited retrieval (ACTH, adrenaline). The effects of the hormones cannot be explained by a decrease in locomotor activity: none of the treatments had such an effect, as measured in an open field. However, when the animals were tested between 12 and 19 months after training, the hormones once again became as effective as they had been 1 day after training. This was so in spite of the fact that control retention levels became very low with age, probably as a result of extinction. The oscillation of the sensitivity of retrieval to the hormones does not appear to depend on changes in anxiety levels with ageing or to effects of the hormones on locomotor activity.

Bupropion and sertraline enhance retrieval of recent and remote long-term memory in rats.

Wistar rats were trained in step-down inhibitory avoidance at the age of 3 months, and tested for retrieval either 1 day later or 3, 6, 9, 12, 15 or 19 months later, when the animals were 6, 9, 12, 15, 18 or 22 months old, respectively. Bupropion (20 or 60 mg/kg) and sertraline (3.3 or 10 mg/kg) given orally 6 or 3 h before retention testing, respectively, enhanced retrieval of this task at all training-test intervals, despite the fact that retrieval at the longest intervals was practically not seen in control animals. The effect cannot be explained by influences of the drugs on locomotor activity; the treatments had no effect on open field behaviour at the age of 3, 8 or 21 months. The findings may be relevant to the use of these drugs as cognitive enhancers in elderly subjects.

In utero demonstration of aberrant systemic blood supply in lung sequestration: a case report

Prenatal diagnosis of a potentially lethal condition as shown and confirmed with color flow Doppler; demonstration of an aberrant systemic blood supply

Novelty enhances retrieval: molecular mechanisms involved in rat hippocampus.

Rats exposed to a novel environment just prior to or 1-2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one-trial inhibitory avoidance training. The bilateral intrahippocampal infusion of PD098059, an inhibitor of mitogen-activated protein kinase (MAPK), the specific upstream activator of p42 and p44 MAPKs, given 10 min before the exposure to the novel environment, blocked the enhancing effect of novelty on memory retrieval. In addition, prenovelty infusion of DL-2-amino-5-phosphonovalerate (APV), an antagonist of glutamate NMDA receptors, produced similar effects. The exposure to the novel environment is associated with an activation of p42 and p44 MAPKs and an increase in the phosphorylation state of the transcription factor cAMP response element binding protein (CREB). No changes were observed in cAMP-dependent protein kinase (PKA) activity or in alpha-CAMKII activation. Taken together, our results indicate that novelty activates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.

Pharmacological differences between memory consolidation of habituation to an open field and inhibitory avoidance learning.

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or the entorhinal cortex were submitted to either a one-trial inhibitory avoidance task, or to 5 min of habituation to an open field. Immediately after training, they received intrahippocampal or intraentorhinal 0.5-microl infusions of saline, of a vehicle (2% dimethylsulfoxide in saline), of the glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphono pentanoic acid (AP5), of the protein kinase A inhibitor Rp-cAMPs (0.5 microg/side), of the calcium-calmodulin protein kinase II inhibitor KN-62, of the dopaminergic D1 antagonist SCH23390, or of the mitogen-activated protein kinase kinase inhibitor PD098059. Animals were tested in each task 24 h after training. Intrahippocampal KN-62 was amnestic for habituation; none of the other treatments had any effect on the retention of this task. In contrast, all of them strongly affected memory of the avoidance task. Intrahippocampal Rp-cAMPs, KN-62 and AP5, and intraentorhinal Rp-cAMPs, KN-62, PD098059 and SCH23390 caused retrograde amnesia. In view of the known actions of the treatments used, the present findings point to important biochemical differences in memory consolidation processes of the two tasks.

Pharmacological differences between memory consolidation of habituation to an open field and inhibitory avoidance learning

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or the entorhinal cortex were submitted to either a one-trial inhibitory avoidance task, or to 5 min of habituation to an open field. Immediately after training, they received intrahippocampal or intraentorhinal 0.5-æl infusions of saline, of a vehicle (2 percent dimethylsulfoxide in saline), of the glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphono pentanoic acid (AP5), of the protein kinase A inhibitor Rp-cAMPs (0.5 æg/side), of the calcium-calmodulin protein kinase II inhibitor KN-62, of the dopaminergic D1 antagonist SCH23390, or of the mitogen-activated protein kinase kinase inhibitor PD098059. Animals were tested in each task 24 h after training. Intrahippocampal KN-62 was amnestic for habituation; none of the other treatments had any effect on the retention of this task. In contrast, all of them strongly affected memory of the avoidance task. Intrahippocampal Rp-cAMPs, KN-62 and AP5, and intraentorhinal Rp-cAMPs, KN-62, PD098059 and SCH23390 caused retrograde amnesia. In view of the known actions of the treatments used, the present findings point to important biochemical differences in memory consolidation processes of the two tasks

In utero demonstration of aberrant systemic blood supply in lung sequestration: a case report.

Prenatal diagnosis of a potentially lethal condition as shown and confirmed with color flow Doppler; demonstration of an aberrant systemic blood supply.

Novelty enhances retrieval of one-trial avoidance learning in rats 1 or 31 days after training unless the hippocampus is inactivated by different receptor antagonists and enzyme inhibitors.

Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus. The animals were trained in one-trial step-down inhibitory avoidance and tested either 1 or 31 days later. Some of the animals were exposed, 1 h prior to retention testing, to a novel environment. This was a 50-cm high, 50-cm wide and 39-cm high wooden box covered on the inside with black plastic. Through the cannulae, 10 min prior to the retention test, the rats received 0.5-microl infusions of saline, of a vehicle (2% dimethylsulfoxide in saline), or of the following drugs: the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5, 5.0 microg), the AMPA receptor blocker, 6,7-cyanonitroquinoxaline-2,3-dione (CNQX, 1.25 microg), the generic glutamate metabotropic receptor antagonist, alpha-methyl-(4-carboxyphenyl)glycine (MCPG), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK), PD098059 (10 or 50 microM). CNQX and PD098059 were dissolved in the vehicle; AP5 and Rp-cAMPs were dissolved in saline. All these drugs except AP5 had been previously found to alter retrieval of this task. Novelty markedly enhanced retention test performance of the avoidance task. The drugs, in accordance with previous results, and with the exception of AP5 at any of the two training-test intervals and of CNQX at the 31-day interval, hindered retention test performance. The results indicate that the effect of novelty on retrieval can not be observed if the major biochemical mechanisms of retrieval (AMPA receptors, PKA, MAPK) are blocked, i.e. if the hippocampus was temporarily inactivated by drugs that inhibit those mechanisms.

Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty.

From mollusks to mammals the activation of cAMP response element-binding protein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (open field) 1 hr after acquisition of a one-trial inhibitory avoidance training hinders both the formation of LTM for the avoidance task and the increase in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bilaterally cannulated to deliver Sp-adenosine 3', 5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic monophosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels and restored normal LTM of avoidance learning in rats exposed to novelty. Moreover, a 5 min exposure to the open field 10 min before the avoidance training interferes with the amnesic effect of a second 5 min exposure to the open field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extracellular signal-regulated kinases (p42 and p44 mitogen-activated protein kinases) in the hippocampus is not altered by novelty. Together, these findings suggest that novelty regulates LTM formation by modulating the phosphorylation state of CREB in the hippocampus.

Short- and long-term memory: differential involvement of neurotransmitter systems and signal transduction cascades.

Since William James (1890) first distinguished primary from secondary memory, equivalent to short- and long-term memory, respectively, it has been assumed that short-term memory processes are in charge of cognition while long-term memory is being consolidated. From those days a major question has been whether short-term memory is merely a initial phase of long-term memory, or a separate phenomena. Recent experiments have shown that many treatments with specific molecular actions given into the hippocampus and related brain areas after one-trial avoidance learning can effectively cancel short-term memory without affecting long-term memory formation. This shows that short-term memory and long-term memory involve separate mechanisms and are independently processed. Other treatments, however, influence both memory types similarly, suggesting links between both at the receptor and at the post-receptor level, which should not be surprising as they both deal with nearly the same sensorimotor representations. This review examines recent advances in short- and long-term memory mechanisms based on the effect of intra-hippocampal infusion of drugs acting upon neurotransmitter and signal transduction systems on both memory types.

Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats.

Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus, the entorhinal cortex, anterior cingulate cortex, posterior parietal cortex, or the basolateral complex of the amygdala. The animals were trained in one-trial step-down inhibitory avoidance and tested 24 h later. Prior (10 min) to the retention test, through the cannulae, they received 0.5 microl infusions of a vehicle (2% dimethylsulfoxide in saline), or of the following drugs dissolved in the vehicle: the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5, 2.0 or 5.0 microg), the AMPA receptor blocker, 6,7-dinitroquinoxaline-2,3 (1H,4H)dione (DNQX, 0.4 or 1.0 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG, 0.5 or 2.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the PKA stimulant, Sp-cAMPs (0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK), PD098059 (10 or 50 microM). All these drugs, at the same doses, had been previously found to alter long-term memory formation of this task. Here, retrieval test performance was blocked by DNQX, MCPG, Rp-cAMPs and PD098059 and enhanced by Sp-cAMPs infused into CA1 or the entorhinal cortex. The drugs had similar effects when infused into the parietal or anterior cingulate cortex, except that in these two areas AP5 also blocked retrieval, and in the cingulate cortex DNQX had no effect. Infusions into the basolateral amygdala were ineffective except for DNQX, which hindered retrieval. None of the treatments that affected retrieval had any influence on performance in an open field or in a plus maze; therefore, their effect on retention testing can not be attributed to an influence on locomotion, exploration or anxiety. The results indicate that the four cortical regions studied participate actively in, and are necessary for, retrieval of the one-trial avoidance task. They require metabotropic and/or NMDA glutamate receptors and PKA and MAPK activity. In contrast, the basolateral amygdala appears to participate only through a maintenance of its regular excitatory transmission mediated by glutamate AMPA receptors.

Participation of hippocampal metabotropic glutamate receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval.

The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. In contrast to memory formation, the information about the molecular mechanisms of memory retrieval is surprisingly scarce and fragmentary. Here we show that pretest inhibition of the specific upstream activator of mitogen-activated protein kinase kinase, or of protein kinase A in the hippocampus, blocked retrieval of long-term memory for an inhibitory avoidance task, a hippocampal-dependent learning task. An activator of protein kinase A enhanced retrieval. Mitogen-activated protein kinase activation increased in the hippocampus during retrieval, while protein kinase A activity remained unchanged. Pretest intrahippocampal blockade of metabotropic glutamate receptors or alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, but not N-methyl-D-aspartate receptors or calcium/calmodulin dependent-protein kinase II, impaired retrieval. Thus, recall of inhibitory avoidance activates mitogen-activated protein kinase, which is necessary, along with metabotropic glutamate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propionic acid/kainate receptors, and protein kinase A, for long-term memory expression. Our results indicate that memory formation and retrieval may share some molecular mechanisms in the hippocampus.

Differential role of hippocampal cAMP-dependent protein kinase in short- and long-term memory.

One-trial step-down inhibitory (passive) avoidance training is followed by two peaks of cAMP-dependent protein kinase (PKA) activity in rat CA1: one immediately after training and the other 3 h later. The second peak relies on the first: Immediate posttraining infusion into CA1 of the inhibitor of the regulatory subunit of PKA, Rp-cAMPS, at a dose that reduces PKA activity during less than 90 min, cancelled both peaks. Long-term memory (LTM) of this task measured at 24 h depends on the two peaks: Rp-cAMPS given into CA1 0 or 175 min posttraining, but not between those times, blocked LTM. However, the effect of immediate posttraining Rp-cAMPS on LTM could not be reversed by the activator of the regulatory subunit of PKA, Sp-cAMPS, given at 180 min, which suggests that, for LTM, the first peak may be more important than the second. When given at 0, 22, 45, or 90, but not at 175 min from training, Rp-cAMPS blocked short-term memory (STM) measured at 90 or 180 min. This effect of immediate posttraining Rp-cAMPS infusion on STM but not that on LTM was readily reversed by Sp-cAMPS infused 22 min later. On its own, Sp-cAMPS had effects exactly opposite to those of the inhibitor. It enhanced LTM when given at 0 or 175 min from training, and it enhanced STM when given at 0, 22, 45, or 90 min from training. These findings show that STM and LTM formation require separate PKA-dependent processes in CA1. STM relies on the continued activity of the enzyme during the first 90 min. LTM relies on the two peaks of PKA activity that occur immediately and 180 min posttraining.

Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning.

Rats were trained in one-trial step-down inhibitory avoidance and tested either 3 h or 31 days later. Ten minutes prior to the retention test, through indwelling cannulae placed in the CA1 region of the dorsal hippocampus, they received 0.5 microl infusions of: saline, a vehicle (2% dimethylsulfoxide in saline), the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5) (5.0 microg), the AMPA/kainate receptor blocker, cyanonitroquinoxaline dione (CNQX) (0.25 or 1.25 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG) (0.5 or 2.5 microg), the inhibitor of calcium/calmodulin-dependent protein kinase II (KN62) (3.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the stimulant of the same enzyme, Sp-cAMPs (0.1 or 0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK) kinase, PD098059 (10 or 50 microM). CNQX, KN62 and PD098059 were dissolved in the vehicle; the other drugs were dissolved in saline. All these drugs, at the same doses, had been previously found to affect short- and long-term memory formation of this task. Retrieval measured 3 h after training (short-term memory) was blocked by CNQX and MCPG, and was unaffected by all the other drugs. In contrast, retrieval measured at 31 days was blocked by MCPG, Rp-cAMPs and PD098059, enhanced by Sp-cAMPs, and unaffected by CNQX, AP5 or KN62. The results indicate that, in CA1, glutamate metabotropic receptors are necessary for the retrieval of both short- and long-term memory; AMPA/kainate receptors are necessary for short-term but not long-term memory retrieval, and NMDA receptors are uninvolved in retrieval. Both the PKA and MAPK signalling pathways are required for the retrieval of long-term but not short-term memory.

Short- and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal cortex.

Rats were implanted with cannulae in the CA1 area of the dorsal hippocampus or in the entorhinal cortex and trained in one-trial step-down inhibitory avoidance. Two retention tests were carried out in each animal, one at 1.5 h to measure short-term memory (STM) and another at 24 h to measure long-term memory (LTM). The purpose of the present study was to screen the effect on STM of various drugs previously shown to affect LTM of this task when given posttraining at the same doses that were used here. The drugs and doses were the guanylyl cyclase inhibitor LY83583 (LY, 2.5 microMg), the inhibitor of Tyr-protein kinase at low concentrations and of protein kinase G (PKG) at higher concentrations lavendustin A (LAV, 0.1 and 0.5 microMg), the PKG inhibitor KT5823 (2.0 microMg), the protein kinase C (PKC) inhibitor staurosporin (STAU, 2.5 microMg), the inhibitor of calcium/ calmodulin protein kinase II (CaMKII) KN62 (3.6 microMg), the protein kinase A (PKA) inhibitor KT5720 (0.5 microMg), and the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059 (PD, 0.05 microMg). PD was dissolved in saline; all the other drugs were dissolved in 20% dimethyl sulfoxide. In all cases the drugs affected LTM as had been described in previous papers. The drugs affected STM and LTM differentially depending on the brain structure into which they were infused. STM was inhibited by KT5720, LY, and PD given into CA1 and by STAU and KT5720 given into the entorhinal cortex. PD given into the entorhinal cortex enhanced STM. LTM was inhibited by STAU, KN62, KT5720, KT5823, and LAV (0.5 microMg) given into CA1 and by STAU, KT5720, and PD given into the entorhinal cortex. The results suggest that STM and LTM involve different physiological mechanisms but are to an extent linked. STM appears to require PKA, guanylyl cyclase, and MAPKK activity in CA1 and PKA and PKC activity in the entorhinal cortex; MAPKK seems to play an inhibitory role in STM in the entorhinal cortex. In contrast, LTM appears to require PKA and PKC activity in both structures, guanylyl cyclase, PKG, and CaMKII activity in CA1, and MAPKK activity in the entorhinal cortex.

Separate mechanisms for short- and long-term memory.

It has been assumed for over a century that short-term memory (STM) processes are in charge of cognition while long-term memory (LTM) is being formed, a process that takes hours. A major question is whether STM is merely a step towards LTM, or a separate entity. Recent experiments have shown that many treatments with specific molecular actions given into the hippocampus, entorhinal or parietal cortex immediately after one-trial avoidance training can effectively block STM without affecting LTM formation. This shows that STM and LTM involve separate mechanisms. Some treatments even affect STM and LTM in opposite directions. Others, however, influence both memory types similarly, suggesting links between the two both at the receptor and at the post-receptor level. Drug effects on working memory (WM) were also studied. In some brain regions WM is affected by receptor blockers that alter either STM or LTM; in others it is not. This suggests links between the three memory types at the receptor level. The anterolateral prefrontal cortex is crucial for WM and LTM but is not involved in STM. The hippocampus, entorhinal and parietal cortex are crucial for the three types of memory, in some cases using different receptors for each. The amygdala is not involved in WM or STM, but it plays a key role in the modulation of the early phase of LTM.

Ultrasound evaluation of the fetal heart: is it possible?

Ultrasound evaluation of the fetal heart can be performed. Knowledge of the embryology, anatomy, and function of the heart have led us to understand the pathophysiology of congenital heart disease. In this review we discuss the indications as well as some basic principles of fetal echocardiography.

Stimulators of the cAMP cascade reverse amnesia induced by intra-amygdala but not intrahippocampal KN-62 administration.

Infusion of the calcium-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 (3.5 ng/side) 0 h after training into rat hippocampus CA1 or amygdala has been known for years to cause retrograde amnesia for step-down inhibitory avoidance. On the other hand, drugs that indirectly stimulate protein kinase A (PKA) (8-Br-cAMP, 1.25 microg/side; norepinephrine, 0.3 microg/side; the dopamine D1 receptor agonist, SKF38393, 7.5 microg/side) infused 3 h posttraining into CA1 but not amygdala markedly facilitate retention of this task. Here we find that 8-Br-cAMP, norepinephrine, or SKF38393 given 3 h posttraining into rat CA1 reverses the amnestic effect of KN-62 given into the amygdala 0 h after training, but not that of KN-62 given into CA1 0 h posttraining. The findings bear on the participation of CaMKII and of the cAMP/PKA cascade in memory processes in the hippocampus and the amygdala. Both cascades have been proposed to play a role in memory: CaMKII in the early phase and PKA in the transition between the early phase and long-term memory. Clearly, in CA1, both cascades are involved and are crucial, and the CaMKII cascade must precede the PKA cascade. In contrast, in the amygdala, only the CaMKII cascade is active, and it does not play a central role in memory, inasmuch as its deleterious effect may be fully recovered by stimulation of the PKA cascade in the hippocampus. This further supports the contention that the hippocampus is essential for memory formation of this task, as it is for many others, whereas the amygdala appears to play instead an early modulatory role.

Intra-hippocampal KN-62 hinders the memory of habituation acquired alone, but not simultaneously with a water-finding task.

Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus. After recovery from surgery, they were submitted to a water-finding task, which required detecting a water tube in an open field, and then remembering its location under conditions of thirst. This task was acquired simultaneously with habituation to the open field. Training and test sessions lasted 2 min, in addition to the time spent at the water tube. The training-test interval was 24 h, during which the animals were deprived of water. Immediate post-training intra-hippocampal administration of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 (3.6 ng/side) attenuated memory of the water-finding task, but not that of the habituation acquired concomitantly. However, when the habituation was carried out alone in the absence of the water-finding task, its retention was inhibited by KN-62. Thus, depending on circumstances, habituation can be memorized with or without hippocampal CaMKII activity. In the post-training period, CA1 neurones appear to 'choose' which task will be processed by a metabolic pathway that includes CaMKII.

Intrahippocampal infusion of an inhibitor of protein kinase A separates short- from long-term memory.

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory (passive) avoidance, and tested for short- and long-term memory of this task at 1.5-3.0 and at 24 h from training, respectively. At various times after training (0, 22, 45, 90, 135 or 175 min) they received a 0.5 microl infusion of the protein kinase A (PKA) inhibitor, KT5720 (0.1 or 0.5 microg), or of its vehicle (20% dimethylsulfoxide in saline). At the higher dose, KT5720 inhibited PKA activity by 90%. KT5720 blocked long-term memory (LTM) when given either 0 or 175 min posttraining, and short-term memory (STM) when given 0, 22, 45 or 90 min post-training. Therefore, PKA plays a different role in the process of formation of the two types of memory. Its role in LTM may be related to the peak of PKA activity, and to the levels of its substrate, nuclear P-CREB, that have been described in a previous paper to occur at 0 and again at 3 h after training. The role of PKA in STM may well involve other substrates of the enzyme. This finding points to a cleavage between the mechanisms of STM and LTM formation.