The role of telencephalic NO and cGMP in avoidance conditioning in goldfish (Carassius auratus).

Our previous study with N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5 suggested that NMDA receptors were involved in learning but not memory consolidation of avoidance conditioning. The present study investigated whether nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were involved in memory consolidation but not learning of avoidance conditioning in goldfish. Experiments 1 to 3 investigated amnestic and performance effects of NO inhibitor L-NAME and cGMP inhibitor LY-83583. Experiment 4 investigated whether posttraining intratelencephalic injection of NO donor SNAP ameliorated anterograde amnestic effects of pretraining NO inhibitor L-NAME. The results showed that L-NAME and LY-83583 produced significant anterograde and retrograde amnesia at doses that did not impair performance processes, and the drugs produced more severe retrograde than anterograde amnesia. Furthermore, posttraining SNAP significantly ameliorated anterograde amnestic effects of pretraining L-NAME. Thus, our previous results with D-AP5 and current results with L-NAME and LY-83583 together suggest that the NMDA receptors are involved in learning or the process that is completed during training, whereas the NO and cGMP are involved in memory consolidation or the process that is normally completed sometime following the learning experience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the amnestic effects on NMDA receptor antagonist MK-801 and nitric oxide synthase inhibitors: L-NAME and L-NOARG in goldfish.

Investigations indicate that the induction of long-term potentiation (LTP) may be mediated by postsynaptic N-methyl-D-aspartate (NMDA) receptors and that the maintenance of LTP may be initiated by nitric oxide (NO), a retrograde messenger carrying signals backward from the postsynaptic to the presynaptic neuron. The present study compared amnestic effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, and nitro-L-arginine-methyl-ester (L-NAME) and N-nitro-L-arginine (L-NOARG), nitric oxide (NO) inhibitors, in goldfish, using active-avoidance conditioning as the learning paradigm. The results showed that MK-801 and NO inhibitors produced anterograde amnesia at doses that did not impair performance processes necessary for learning to occur. Furthermore, MK-801 did not produce retrograde amnesia, whereas L-NAME did, suggesting that MK-801 impaired learning whereas NO inhibitors impaired memory consolidation and possibly also learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Implicit and explicit memory in amnesia: some explanations and predictions by the TraceLink model

After a brief overview of some of the characteristics and neuroanatomy of amnesia, a new model of amnesia is described: the TraceLink model. One novel aspect of the model is that it makes specific and testable predictions regarding semantic dementia, a recently described disorder that is viewed here as being related to amnesia. The TraceLink model consists of: a trace system (roughly the neocortix), a link system (hippocampus and adjacent areas), and a modulatory system (certain basal forebrain nuclei). Different forms of learning in the TraceLink model are explained, followed by a discussion of implicit and explicit memory, prominence (ease of recall) and persistence (resistance to brain damage), consolidation, and Ribot gradients in retrograde amnesia. Patterns of recovery from retrograde amnesia are also discussed, and novel predictions are derived regarding implicit memory and various forms of amnesia.     

Growth points in research on memory and hippocampus.

We present an overview of two of our ongoing projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.     

Deficient Spatial Memory Induced by Blockade of Beta-Adrenoceptors in the Hippocampal CA1 Region.

A previous study showed that intra-CAl infusion of the beta-adrenergic antagonist DL-propranolol interfered with consolidation of memory for contextual fear conditioning (J.-Z. Ji, X.-M. Wang, & B.-M. Li, 2003). The present study investigated the effect of similarly administered DL-propranolol on consolidation of spatial memory for the water maze. DL-propranolol infused 5 min, but not 6 hr, posttraining caused a deficit in 48-hr memory for the spatial water maze task, whereas similarly administered D-propranolol, which has an equipotent "local-anesthetic" activity but significantly lower beta-blocking activity, induced no amnesia. However, DL-propranolol administered 5 min posttraining did not impair 48-hr memory for the cued water maze task. Thus, beta-adrenoceptor in area CA1 is involved in regulating consolidation of spatial memory for the water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.     

Conditioned taste aversion is disrupted by prolonged retrograde effects of intracerebral injection of tetrodotoxin in rats.

Acquisition of conditioned taste aversion (CTA) is disrupted when 10 ng tetrodotoxin (TTX) is injected into both parabrachial nuclei of rats immediately after saccharin drinking and before LiCl poisoning (S. F. Ivanova & J. Bure?, in press). Further analysis of this finding showed that parabrachial TTX injection (1) elicited retrograde amnesia also when applied 1, 2, or 4 days but not 8 days after CTA acquisition; (2) did not abolish CTA produced by 2 or 3 saccharin–LiCl pairings; (3) did not cause persistent increase of quinine threshold; and (4) elicited anterograde CTA amnesia when applied 1 but not 2, 4, or 8 days before CTA acquisition. TTX-induced amnesia is not due to persistent gustatory agnosia but rather to disruption of the protracted consolidation of the permanent CTA engram by prolonged cessation of impulse activity in the information storing network. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: Immunization against amnesia by context preexposure.

Hippocampal lesions in rats produce both a retrograde and an anterograde amnesia of contextual fear conditioning. The present experiments examined the anterograde deficit in context conditioning involving a total of 113 rats in 4 experiments. The deficit produced by electrolytic hippocampal lesions was apparent when training occurred on 7, 14, or 28 days following surgery, confirming the durability of the amnesia. The role of the hippocampus in context conditioning may be related to an N-methyl-D-aspartate (NMDA) receptor-mediated process. Both NMDA hippocampal lesions and intrahippocampal administration of an NMDA antagonist produced anterograde amnesia. Ss preexposed to the conditioning context 28 days prior to hippocampal lesioning were protected from the deficit normally produced by the lesions. Thus, the hippocampus must form a contextual representation during preexposure that is subsequently stored elsewhere. Once formed this representation of the context can be associated with an unconditioned stimulus/stimuli (UCS). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuroprotective and anti-amnesic potentials of sigma (sigma) receptor ligands

1. Although the physical nature of sigma (sigma) receptors have not yet been fully defined, several classes of selective ligands have been characterised, demonstrating a plethora of physiological actions. In the present review, the authors have set out to highlight two important aspects of the biological activities of sigma ligands, their neuroprotective and anti-amnesic effects. 2. The sigma ligands present a therapeutic potential as neuroprotective agents in brain ischemia. The neuroprotective activity of many non-selective sigma ligands is primarily a result of their affinity for the NMDA receptor complex. However, selective sigma ligands are also neuroprotective, possibly by inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. 3. The sigma 1 ligands prevent the experimental amnesia induced by muscarinic cholinergic antagonists at either the learning, consolidation or retention phase of the mnesic process. This effect involves a potentation of acetylcholine release induced by sigma 1 ligands selectively in the hippocampal formation and cortex. 4. The sigma 1 receptor ligands also attenuate the learning impairment induced by dizocilpine, a non-competitive antagonist of the NMDA receptor, and may relate to the potentiating effect of sigma 1 ligands on several NMDA receptor-mediated responses previously described in vitro and in vivo in the hippocampus. This effect is shared by NPY- and CGRP-related peptides and by neuroactive steroids, confirming the in vitro evidences of functional interactions between the sigma 1 receptors and these different systems. 5. Additional amnesia models also seem to be alleviated by sigma 1 ligands, such as phencyclidine-induced cognitive dysfunctions, and amnesia induced by the calcium channel blocker nimodipine, or by exposure to carbon monoxide. Furthermore, a preliminary study in an animal model of age-related memory deficits, the senescence-accelerated mouse, strengthened the therapeutic potentials of selective sigma 1 receptor ligands in aging-related pathologies.     

Different temporal profiles of amnesia after intra-hippocampus and intra-amygdala infusions of anisomycin.

Systemic or intra-hippocampal administration of the protein synthesis inhibitor anisomycin generally leads to impairments in memory tested 24 hr or more after training but spares memory for a few hours after training. Thus, amnesia does not appear immediately after training but develops with time, findings most often interpreted as evidence for distinct short- and long-term memory processes. However, time courses for the onset of amnesia vary substantially after treatment with protein synthesis inhibitors. Some of the variability across experiments may reflect task-related differences or, perhaps relatedly, may reflect memory processing mediated by different neural systems. In the present experiments, anisomycin was infused into either the hippocampus or the amygdala 20 min before inhibitory avoidance training. Similar to previous findings, intra-hippocampus injections of anisomycin impaired memory tested 48 hr after training yet spared memory tested 4 hr after training. In contrast, intra-amygdala injections of anisomycin impaired memory tested at 0.5, 4, and 48 hr after training, revealing no evidence for spared memory at short times after training. The distinct temporal properties for amnesia following anisomycin injections into the hippocampus or amygdala may reflect different consequences for memory of perturbations of the neural system in which the manipulation is made. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway

Rats implanted bilaterally with cannulae in the entorhinal or posterior parietal cortex or in the amygdaloid nucleus were trained in one-trial step-down inhibitory (passive) avoidance using a 0.3 mA footshock. At 0, 3, 6 or 9 h after training, they received localized 0.5 microliter infusions into these areas of a vehicle, or of 8-Br-cAMP, forskolin (adenylyl cyclase activator), KT5720 (protein kinase A inhibitor), SKF38393 (dopamine D1 receptor agonist), SCH23390 (D1 antagonist), norepinephrine hydrochloride, timolol hydrochloride (beta blocker), 8-HO-DPAT (5-HT1A receptor agonist) or NAN-190 (5-HT1A antagonist) dissolved in 20% dimethylsulfoxide (DMSO) in saline (vehicle). Rats were tested for retention 24 h after training. 8-Br-cAMP, forskolin, SKF 38393 and norepinephrine caused memory facilitation and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia when given into the entorhinal cortex 0, 3 or 6 h but not 9 h after training. When given into the posterior parietal cortex 0, 3 or 6 but not 9 h after training, KT5720 was amnestic. When given into this structure 3 or 6 h but not 0 or 9 h after training 8-Br-cAMP, forskolin and norepinephrine caused memory facilitation and KT5720, SCH23390 and timolol caused retrograde amnesia. All treatments given into the amygdala 0, 3 or 6 h after training were ineffective except for norepinephrine given at 0 h, which caused facilitation. The data point to a role of cAMP/protein kinase A-dependent mechanisms in memory formation in the entorhinal and parietal cortex, but not the amygdala, from 0 to 6 h after training, and to a strong modulation of these mechanisms by dopaminergic D1, beta-noradrenergic and 5-HT1A receptors. The lack of effect of NAN-190 but not 8-HO-DPAT in both cortical regions suggests that 5-HT1A receptors do not play a physiological role but can be activated pharmacologically. The fact that SCH23390 was amnestic but SKF38393 had no effect when given into the parietal cortex suggests that D1 receptors may play a maintenance rather than a stimulant role in this area.     

Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice.

This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17β-estradiol (E?)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E?, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 μg/side), or the cAMP inhibitor Rp-cAMPS (18.0 μg/side). Retention was tested 48 hours later. The enhanced object memory and increased ERK phosphorylation observed with E? alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of the conditional fear.

The acquisition of conditional freezing is abolished by N-methyl-D-aspartate (NMDA) receptor antagonism in the basolateral complex of the amygdala (BLA) during fear conditioning, suggesting that memory formation is prevented. The present study examined whether there is residual memory, or "savings," for fear conditioning in rats trained under amygdaloid NMDA receptor blockade. Rats infused with D,L-2-amino-5-phosphonovalerate (APV) into the BLA or central nucleus of the amygdala (CEA) during fear conditioning did not acquire either auditory or contextual fear conditioning. However, savings of conditional fear was exhibited by rats infused with APV into the CEA but not the BLA. These results suggest that both the BLA and CEA play a critical role in the acquisition of conditional fear but that the BLA is able to process and retain some aspects of aversive memories in the absence of the CEA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long gradient of retrograde amnesia in mice: Continuity with the findings in humans.

560 male albino mice were given a single training trial and then received either sham treatment or 4 ECS treatments at hourly intervals at 1 of 7 times (1–70 days) after training. Retention was always tested 2 wks after treatment. Controls exhibited gradual forgetting with increasing retention intervals. Ss given ECS exhibited severe retrograde amnesia, which diminished as the interval between training and ECS increased from 1 to 21 days. ECS given 21–70 days after training had no effect on memory. The finding of long, temporally graded retrograde amnesia in mice establishes continuity between the results for laboratory animals and those for humans and indicates that the neural changes involved in the consolidation of memory can continue for a significant portion of the lifetime of a memory. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transient global amnesia: memory and metamemory

Twenty patients (mean age 64 years) with a previous episode of transient global amnesia (TGA) were examined to assess the functioning of objective memory (by using the Randt Memory Test), the metamemory capacities (Sehulster Memory Scale), the residual level of retrograde amnesia (Questionnaire of Remote Events), and the level of depression (Geriatric Depression Scale). Patients with residual retrograde amnesia scored significantly lower than non-amnesic ones on indices of both short-term and long-term memory, and for one of three main metamemory components, namely self-rating of memory functioning through comparison with memory functioning of peers (Set3). Age, time interval from TGA attack and TGA duration did not prove to influence memory and metamemory scores. Retrograde amnesia and depression were rather substantially associated (1/5), and this association was found to negatively influence nearly all memory and metamemory scores. Depression level showed a positive correlation with short-term memory functioning in non-amnesics. The different pattern and strength of the relationships between metamemory components and objective memory dimensions observed in amnesics and non-amnesics indicate that metamemory evaluations are more closely related to memory functioning in amnesics than in non-amnesics.     

Severe amnesia: an usual late complication after temporal lobectomy

A patient developed the severe amnesic syndrome 8 years after temporal lobe surgery for epilepsy. He underwent left temporal lobectomy (6 cm, 43.5 g; hippocampal sclerosis) aged 19, and remained seizure free for 8 years until a convulsion followed a head injury. He became severely amnesic after a fourth convulsion 16 months later. He was right-handed, pre-operative IQ was average, verbal memory poor and non-verbal memory normal. Post-operatively, these were unchanged. After the first post-operative seizure he began professional training. After onset of amnesia IQ was unchanged, anterograde memory severely impaired and retrograde amnesia dense for at least 16 months. He died 2 years later. Magnetic resonance imaging before amnesia showed absence of anterior left temporal lobe, atrophy of left fornix and mamillary body, and normal right temporal lobe. Four months after onset of amnesia, right hippocampal volume had reduced by 36%. Autopsy showed: previous left temporal lobectomy with absence of left amygdala and hippocampus, atrophy of fornix and mamillary body; neuronal loss in the right hippocampus, severe in CA1 and CA4; intact right amygdala and parahippocampal gyrus; recent diffuse damage associated with cause of death. A convulsion can cause severe hippocampal damage in adult life. Hippocampal zones CA1 and/or CA4 are critical for maintaining memory and the amygdala and parahippocampal gyrus cortex alone cannot support acquisition of new memories.     

The Amygdala Modulates Hippocampus-Dependent Context Memory Formation and Stores Cue-Shock Associations.

Preexposing rats to the context facilitates subsequent contextual fear conditioning. This effect depends on the hippocampus (J. W. Rudy, R. M. Barrientos, & R. C. O'Reilly, 2002). The authors report that inactivating the basolateral region of the amygdala (BLA) by injecting muscimol, a GABAA agonist, before or after preexposure reduced this effect. In contrast, bilateral injections of anisomycin, a protein synthesis inhibitor, into BLA did not impair the consolidation of the context memory. However, when injected after fear conditioning, anisomycin impaired consolidation of both contextual and auditory-cue fear conditioning. Results are consistent with 2 ideas about the amygdala's contribution to memory: (a) It modulates memory formation in other regions of the brain, and (b) it is a storage site for cue-shock associations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrograde amnesia for spatial information: a dissociation between intra and extramaze cues following hippocampus lesions in rats

Several recent studies have shown a flat retrograde amnesia for spatial information following lesions to the hippocampus in rats and mice. However, the results of the present investigation demonstrate that in rats that presurgically learned a spatial reference memory task based on extramaze cues, a temporally graded retrograde amnesia is evident following lesions to the hippocampus (1, 16, 32 or 64 days after learning) if two conditions are met. First, that a wide range of retention intervals is used, and second, that independent groups of rats are tested, not a single group that learns different spatial discrimination tasks at different times (expt 1). The results of expt 2 show that the hippocampus does not serve as a consolidating mechanism when the spatial task learned presurgically is based on intramaze cues. Taken together, these results indicate that the hippocampus is critical for the storage and/or retrieval of spatial reference information that was learned up to 1 month before hippocampus damage; however, in the absence of the hippocampus, efficient retention can still occur provided that the spatial knowledge was learned in a simple associative manner.