Incidental Encoding Strategies Did Not Improve Contextual Memory in Parkinson`s Disease Patients

Background. This study investigated the performance of patients with idiopathic Parkinson`s disease (PD) without dementia for incidental recognition memory and the effect of encoding strategies on contextual memory. Methods. The authors studied 21 patients with PD (ages 60-85, 12 women; Hoehn and Yahr I-III, Activities of Daily Living 70%-100%) and 22 healthy controls (ages 60-84, 18 women). Participants completed the vocabulary subtest of the Wechsler Adult Intelligence Scale and the Wisconsin Card Sorting Test (WCST). To assess the incidental recognition memory for item (object) and context (location of the object), participants of each group were assigned to 1 of 2 encoding conditions: (a) an incidental associative instruction to bind the object to its location or (b) a nonassociative, nonspecific instruction. Results. PD patients showed performance comparable to the control group`s on the vocabulary subtest and WCST. In contrast to controls, PD patients were unable to take advantage of the associative encoding instruction, which also had a deleterious effect on item recognition. Conclusion. This sample of participants with PD showed diminished item and context recognition memory and an impaired ability to use incidental memory encoding strategy, suggesting a compromised cognitive reserve. The fact that these alterations occurred in early stages of PD, and prior to more general cognitive alterations such as executive dysfunction, should be considered in the management of patients by using specific cognitive rehabilitation interventions.

Role of the hippocampus in contextual memory after classical aversive conditioning in pigeons (C. livia)

We investigated the effects of hippocampal lesions with ibotenic acid (IBO) on the memory of the sound-context-shock association during reexposure to the conditioning context. Twenty-nine adult pigeons were assigned to a non-lesioned control group (CG, N = 7), a sham-lesioned group (SG, N = 7), a hippocampus-lesioned experimental group (EG, N = 7), and to an unpaired nonlesioned group (tone-alone exposure) (NG, N = 8). All pigeons were submitted to a 20-min session in the conditioning chamber with three associations of sound (1000 Hz, 85 dB, 1 s) and shock (10 mA, 1 s). Experimental and sham lesions were performed 24 h later (EG and SG) when EG birds received three bilateral injections (anteroposterior (A), 4.5, 5.25 and 7.0) of IBO (1 µl and 1 µg/µl) and SG received one bilateral injection (A, 5.25) of PBS. The animals were reexposed to the training context 5 days after the lesion. Behavior was videotaped for 20 min and analyzed at 30-s intervals. A significantly higher percent rating of immobility was observed for CG (median, 95.1; range, 79.2 to 100.0) and SG (median, 90.0; range, 69.6 to 95.0) compared to EG (median, 11.62; range, 3.83 to 50.1) and NG (median, 7.33; range, 6.2 to 28.1) (P<0.001) in the training context. These results suggest impairment of contextual fear in birds who received lesions one day after conditioning and a role for the hippocampus in the modulation of emotional aversive memories in pigeons.

Role of entorhinal cortical plasticity in spatial and contextual memory

It is well accepted that the hippocampus (HIP) is important for spatial and contextual memories, however, it is not clear if the entorhinal cortex (EC), the main input/output structure for the hippocampus, is also necessary for memory storage. Damage to the EC in humans results in memory deficits. However, animal studies report conflicting results on whether the EC is necessary for spatial and contextual memory. Memory consolidation requires gene expression and protein synthesis, mediated by signaling cascades and transcription factors. Extracellular-signal regulated kinase (ERK) cascade activity is necessary for long-term memory in several tasks, including those that test spatial and contextual memory. In this work, we explore the role of ERK-mediated plasticity in the EC on spatial and contextual memory. ^ To evaluate this role, post-training infusions of reversible pharmacological inhibitors specific for the ERK cascade that do not affect normal neuronal activity were targeted directly to the EC of awake, behaving animals. This technique provides spatial and temporal control over the inhibition of the ERK cascade without affecting performance during training or testing. Using the Morris water maze to study spatial memory, we found that ERK inhibition in the EC resulted in long-term memory deficits consistent with a loss of spatial strategy information. When animals were allowed to learn and consolidate a spatial strategy for solving the task prior to training and ERK inhibition, the deficit was alleviated. To study contextual memory, we trained animals in a cued fear-conditioning task and saw an increase in the activation of ERK in the EC 90 minutes following training. ERK inhibition in the EC over this time point, but not at an earlier time point, resulted in increased freezing to the context, but not to the tone, during a 48-hour retention test. In addition, animals froze maximally at the time the shock was given during training; similar to naïve animals receiving additional training, suggesting that ERK-mediated plasticity in the EC normally suppresses the temporal nature of the freezing response. These findings demonstrate that plasticity in the EC is necessary for both spatial and contextual memory, specifically in the retention of behavioral strategies. ^

Beta 1-integrins are required for hippocampal AMPA receptor-dependent synaptic transmission, synaptic plasticity, and working memory.

Integrins comprise a large family of cell adhesion receptors that mediate diverse biological events through cell-cell and cell-extracellular matrix interactions. Recent studies have shown that several integrins are localized to synapses with suggested roles in synaptic plasticity and memory formation. We generated a postnatal forebrain and excitatory neuron-specific knock-out of beta1-integrin in the mouse. Electrophysiological studies demonstrated that these mutants have impaired synaptic transmission through AMPA receptors and diminished NMDA receptor-dependent long-term potentiation. Despite the impairment in hippocampal synaptic transmission, the mutants displayed normal hippocampal-dependent spatial and contextual memory but were impaired in a hippocampal-dependent, nonmatching-to-place working memory task. These phenotypes parallel those observed in animals carrying knock-outs of the GluR1 (glutamate receptor subunit 1) subunit of the AMPA receptor. These observations suggest a new function of beta1-integrins as regulators of synaptic glutamate receptor function and working memory.

Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.

Hypothalamic sites responding to predator threats - the role of the dorsal premammillary nucleus in unconditioned and conditioned antipredatory defensive behavior

In this study we provide a comprehensive analysis of the hypothalamic activation pattern during exposure to a live predator or an environment previously associated with a predator. Our results support the view that hypothalamic processing of the actual and the contextual predatory threats share the same circuit, in which the dorsal premammillary nucleus (PMd) plays a pivotal role in amplifying this processing. To further understand the role of the PMd in the circuit organizing antipredatory defensive behaviors, we studied rats with cytotoxic PMd lesions during cat exposure and examined the pattern of behavioral responses as well as how PMd lesions affect the neuronal activation of the systems engaged in predator detection, in contextual memory formation and in defensive behavioral responses. Next, we investigated how pharmacological blockade of the PMd interferes with the conditioned behavioral responses to a context previously associated with a predator, and how this blockade affects the activation pattern of periaqueductal gray (PAG) sites likely to organize the conditioned behavioral responses to the predatory context. Behavioral observations indicate that the PMd interferes with both unconditioned and conditioned antipredatory defensive behavior. Moreover, we have shown that the PMd influences the activation of its major projecting targets, i.e. the ventral part of the anteromedial thalamic nucleus which is likely to influence mnemonic processing, and PAG sites involved in the expression of antipredatory unconditioned and conditioned behavioral responses. Of particular relevance, this work provides evidence to elucidate the basic organization of the neural circuits integrating unconditioned and contextual conditioned responses to predatory threats.

Cooperation & Competition Between Navigation Systems in the Rat Brain: The Role of the Hippocampus and Striatum During a Dissociative Maze Task

While many tend to think of memory systems in the brain as a single process, in reality several experiments have supported multiple dissociations of different forms of learning, such as spatial learning and response learning. In both humans and rats, the hippocampus has long been shown to be specialized in the storage of spatial and contextual memory whereas the striatum is associated with motor responses and habitual behaviors. Previous studies have examined how damage to hippocampus or striatum has affected the acquisition of either a spatial or response navigation task. However even in a very familiar environment organisms must continuously switch between place and response strategies depending upon circumstances. The current research investigates how these two brain systems interact under normal conditions to produce navigational behavior. Rats were tested using a task developed by Jacobson and colleagues (2006) in which the two types of navigation could be controlled and studied simultaneously. Rats were trained to solve a plus maze using both a spatial and a response strategy. A cue (flashing light) was employed to indicate the correct strategy on a given trial. When no light was present, the animals were rewarded for making a 90º right turn (motor response). When the light was on, the animals were rewarded for going to a specific goal location (place strategy). After learning the task, animals had a sham surgery or dorsal striatum or hippocampus damaged. In order to investigate the individual role of each brain system and evaluate whether these brain regions compete or cooperate for control over strategy, we utilized a within-animal comparisons. The configuration of the maze allowed for the comparison of behavior in individual animals before and after specific brain areas were damaged. Animals with hippocampal lesions showed selective deficits on place trials after surgery and learned the reversal of the motor response more rapidly than striatal lesioned or sham rats. Unlike previous findings regarding maze learning, animals with striatal lesions showed deficits in both place and response trials and had difficulty learning the reversal of motor response. Therefore, the effects of lesions on the ability to switch back and forth between strategies were more complex than previously suggested. This work may reveal important new insight on the integration of hippocampal and striatal learning systems, and facilitate a better understanding of the brain dynamics underlying similar navigational processes in humans.

FGF-2 regulation of neurogenesis in adult hippocampus after brain injury

Fibroblast growth factor-2 (FGF-2) promotes proliferation of neuroprogenitor cells in culture and is up-regulated within brain after injury. Using mice genetically deficient in FGF-2 (FGF-2−/− mice), we addressed the importance of endogenously generated FGF-2 on neurogenesis within the hippocampus, a structure involved in spatial, declarative, and contextual memory, after seizures or ischemic injury. BrdUrd incorporation was used to mark dividing neuroprogenitor cells and NeuN expression to monitor their differentiation into neurons. In the wild-type strain, hippocampal FGF-2 increased after either kainic acid injection or middle cerebral artery occlusion, and the numbers of BrdUrd/NeuN-positive cells significantly increased on days 9 and 16 as compared with the controls. In FGF-2−/− mice, BrdUrd labeling was attenuated after kainic acid or middle cerebral artery occlusion, as was the number of neural cells colabeled with both BrdUrd and NeuN. After FGF-2−/− mice were injected intraventricularly with a herpes simplex virus-1 amplicon vector carrying FGF-2 gene, the number of BrdUrd-labeled cells increased significantly to values equivalent to wild-type littermates after kainate seizures. These results indicate that endogenously synthesized FGF-2 is necessary and sufficient to stimulate proliferation and differentiation of neuroprogenitor cells in the adult hippocampus after brain insult.

Selective involvement of GABAergic mechanisms of the dorsal periaqueductal gray and inferior colliculus on the memory of the contextual fear as assessed by the fear potentiated startle test

The inferior colliculus (IC) together with the dorsal periaqueductal gray (dPAG), the amygdala and the medial hypothalamus make part of the brain aversion system, which has mainly been related to the organization of unconditioned fear. However, the involvement of the IC and dPAG in the conditioned fear is still unclear. It is certain that GABA has a regulatory role on the aversive states generated and elaborated in these midbrain structures. In this study, we evaluated the effects of injections of the GABA-A receptor agonist muscimol (1.0 and 2.0 nmol/0.2 mu L) into the IC or dPAG on the freezing and fear-potentiated startle (FPS) responses of rats submitted to a context fear conditioning. Intra-IC injections of muscimol did not cause any significant effect on the FPS or conditioned freezing but enhanced the startle reflex in non-conditioned animals. In contrast, intra-dPAG injections of muscimol caused significant reduction in FPS and conditioned freezing without changing the startle reflex in non-conditioned animals. Thus, intra-dPAG injections of muscimol produced the expected inhibitory effects on the anxiety-related responses, the FPS and the freezing whereas these injections into the IC produced quite opposite effects suggesting that descending inhibitory pathways from the IC, probably mediated by GABA-A mechanisms, exert a regulatory role on the lower brainstem circuits responsible for the startle reflex. (C) 2008 Elsevier Inc. All rights reserved.

Mechanisms of contextual fear memory generalization

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2013

Contextual Information and Memory for Unfamiliar Tunes in Older and Younger Adults

We examined age differences in the effectiveness of multiple repetitions and providing associative facts on tune memory. For both tune and fact recognition, three presentations were beneficial. Age was irrelevant in fact recognition, but older adults were less successful than younger in tune recognition. The associative fact did not affect young adults' performance. Among older people, the neutral association harmed performance; the emotional fact mitigated performance back to baseline. Young adults seemed to rely solely on procedural memory, or repetition, to learn tunes. Older adults benefitted by using emotional associative information to counteract memory burdens imposed by neutral associative information.

The contributions of the hippocampal formation, perirhinal cortex and areas TH/TF to object, spatial and contextual recognition memory in primates

Adult monkeys (Macaca mulatta) with lesions of the hippocampal formation, perirhinal cortex, areas TH/TF, as well as controls were tested on tasks of object, spatial and contextual recognition memory. ^ Using a visual paired-comparison (VPC) task, all experimental groups showed a lack of object recognition relative to controls, although this impairment emerged at 10 sec with perirhinal lesions, 30 sec with areas TH/TF lesions and 60 sec with hippocampal lesions. In contrast, only perirhinal lesions impaired performance on delayed nonmatching-to-sample (DNMS), another task of object recognition memory. All groups were tested on DNMS with distraction (dDNMS) to examine whether the use of active cognitive strategies during the delay period could enable good performance on DNMS in spite of impaired recognition memory (revealed by the VPC task). Distractors affected performance of animals with perirhinal lesions at the 10-sec delay (the only delay in which their DNMS performance was above chance). They did not affect performance of animals with areas TH/TF lesions. Hippocampectomized animals were impaired at the 600-sec delay (the only delay at which prevention of active strategies would likely affect their behavior). ^ While lesions of areas TH/TF impaired spatial location memory and object-in-place memory, hippocampal lesions impaired only object-in-place memory. The pattern of results for perirhinal cortex lesions on the different task conditions indicated that this cortical area is not critical for spatial memory. ^ Finally, all three lesions impaired contextual recognition memory processes. The pattern of impairment appeared to result from the formation of only a global representation of the object and background, and suggests that all three areas are recruited for associating information across sources. ^ These results support the view that (1) the perirhinal cortex maintains storage of information about object and the context in which it is learned for a brief period of time, (2) areas TH/TF maintain information about spatial location and form associations between objects and their spatial relationship (a process that likely requires additional time) and (3) the hippocampal formation mediates associations between objects, their spatial relationship and the general context in which these associations are formed (an integrative function that requires additional time). ^

Basolateral amygdala is not critical for cognitive memory of contextual fear conditioning

Evidence that lesions of the basolateral amygdala complex (BLC) impair memory for fear conditioning in rats, measured by lack of “freezing” behavior in the presence of cues previously paired with footshocks, has suggested that the BLC may be a critical locus for the memory of fear conditioning. However, evidence that BLC lesions may impair unlearned as well as conditioned freezing makes it difficult to interpret the findings of studies assessing conditioned fear with freezing. The present study investigated whether such lesions prevent the expression of several measures of memory for contextual fear conditioning in addition to freezing. On day 1, rats with sham lesions or BLC lesions explored a Y maze. The BLC-lesioned rats (BLC rats) displayed a greater exploratory activity. On day 2, each of the rats was placed in the “shock” arm of the maze, and all of the sham and half of the BLC rats received footshocks. A 24-hr retention test assessed the freezing, time spent per arm, entries per arm, and initial entry into the shock arm. As previously reported, shocked BLC rats displayed little freezing. However, the other measures indicated that the shocked BLC rats remembered the fear conditioning. They entered less readily and less often and spent less time in the shock arm than did the control nonshocked BLC rats. Compared with the sham rats, the shocked BLC rats entered more quickly and more often and spent more time in the shock arm. These findings indicate that an intact BLC is not essential for the formation and expression of long-term cognitive/explicit memory of contextual fear conditioning.

Adolescent tobacco-related associative memory: a cross-sectional and contextual analysis

Tobacco use is prevalent in adolescents, and understanding factors that contribute to its uptake and early development remains a critical public health priority. Implicit drug-related memory associations (DMAs) are predictive of drug use in older samples, but such models have little application to adolescent tobacco use. Moreover, extant research on memory associations yields little information on contextual factors that may be instrumental in the development of DMAs. The present study examined (a) the degree to which tobacco-related memory associations (TMAs) were associated with concurrent tobacco use and (b) the extent to which TMAs mediated the association of peer and self-use. A sample of 210 Australian high school students was recruited. Participants completed TMA tasks and behavioral checklists designed to obscure the tobacco-related focus of the study. Results showed that TMAs were associated with peer use, and TMAs predicted self-use. We found no evidence that TMAs mediated the association of peer and self-use. Future research might examine the emotive valence of implicit nodes and drinking behavior. The results have implications for testing the efficacy of consciousness-raising interventions for adolescents at risk of tobacco experimentation or regular use.

Cannabinoid CB(1) receptors in the medial prefrontal cortex modulate the expression of contextual fear conditioning

The ventral portion of the medial prefrontal cortex (vMPFC) has been related to the expression of contextual fear conditioning. This study investigated the possible involvement of CB(1) receptors in this aversive response. Male Wistar rats were submitted to a contextual aversive conditioning session and 48 h later re-exposed to the aversive context in which freezing and cardiovascular responses (increase of arterial pressure and heart rate) were recorded. The expression of CB(1) receptor-mRNA in the vMPFC was also measured using real time-PCR. In the first experiment intra-vMPFC administration of the CB(1) receptor agonist anandamide (AEA, 5 pmol/200 nl) or the AEA transport inhibitor AM404 (50 pmol/200 nl) prior to re-exposure to the aversive context attenuated the fear-conditioned responses. These effects were prevented by local pretreatment with the CB(1) receptor antagonist AM251 (100 pmol/200 nl). Using the same conditioning protocol in another animal group, we observed that CB(1) receptor mRNA expression increased in the vMPFC 48 h after the conditioning session. Although AM251 did not cause any effect by itself in the first experiment, this drug facilitated freezing and cardiovascular responses when the conditioning session employed a lesser aversive condition. These results indicated that facilitation of cannabinoid-mediated neurotransmission in the vMPFC by local CB(1) receptor activation attenuates the expression of contextual fear responses. Together they suggest that local endocannabinoid-mediated neurotransmission in the vMPFC can modulate these responses.