Patterns of verbal memory performance in mild cognitive impairment, Alzheimer disease, and normal aging.

OBJECTIVE: Individuals with mild cognitive impairment (MCI) typically demonstrate memory loss that falls between normal aging (NA) and Alzheimer disease (AD), but little is known about the pattern of memory dysfunction in MCI. METHOD: To explore this issue, California Verbal Learning Test (CVLT) performance was examined across groups of MCI, AD, and NA. RESULTS: MCI subjects displayed a pattern of deficits closely resembling that of AD, characterized by reduced learning, rapid forgetting, increased recency recall, elevated intrusion errors, and poor recognition discriminability with increased false-positives. MCI performance was significantly worse than that of controls and better than that of AD patients across memory indices. Although qualitative analysis of CVLT profiles may be useful in individual cases, discriminant function analysis revealed that delayed recall and total learning were the best aspects of learning/memory on the CVLT in differentiating MCI, AD, and NA. CONCLUSIONS: These findings support the position that amnestic MCI represents an early point of decline on the continuum of AD that is different from normal aging.     

Behavioural plasticity and the cholinergic system

1. Evidence for the involvement of the cholinergic system in behavioural plasticity is reviewed by considering three forms of behavioural plasticity: habituation, learning and memory, and tolerance development.2. Although the cholinergic system may modulate the response tendencies of an animal, it does not appear to be involved in the process of habituation.3. A number of studies have indicated that the cholinergic system may be involved in learning and memory processes in infrahuman animals. In general, cholinergic antagonists tend to disrupt memory while agonists may, under the appropriate conditions, facilitate memory. Recent studies have pointed to a relation between dysfunctions of the cholinergic system and dysfunctions of memory in aged animals.4. Studies of tolerance development suggest that the cholinergic system may undergo plastic changes which may underlie the development of tolerance to some drugs, with receptor alterations being the most reproducible finding. However, more work is necessary to establish the degree of plasticity.5. The cholinergic system also appears to be involved in learning and memory processes in humans. However, attempts to correct the memory deficits in aged humans by manipulating the cholinergic system have met with limited success. The reasons for this lack of success are briefly considered.     

Genetic evidence for noradrenergic control of long-term memory consolidation

Memory formation involves dynamic interactions among many brain structures and their linking pathways. The noradrenaline (NA) system in the CNS plays an important role in a wide variety of neurological and psychological functions. Alteration in the NA system is implicated in the pathological states of some neuropsychiatric disorders. Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines. The regulatory mechanism of the TH reaction is generally considered to play a key role in controlling the catecholaminergic actions. Mice heterozygous for the mutation of the gene encoding TH exhibit the reduced TH activity in tissues. These mice have a moderate reduction in NA accumulation and release in brain regions. The mutant mice exhibit deficits in the water-finding task associated with latent learning performance, suggesting the impairment in memory formation. Spatial learning performance measured by the water maze task is normal in the mutants. However, they display deficits in long-term memory formation of conditioned learning evaluated with three distinct behavioral paradigms, including active avoidance, cued fear conditioning, and conditioned taste aversion, without affecting short-term memory. These memory deficits are restored by the drug-induced stimulation of NA activity at the postconditioning phase. Analysis of the mutant mice indicates that the central NA system is essential for the consolidation process in long-term memory of conditioned learning. The process appears to be implicated in the NA activity in the cerebral cortex and/or amygdaloid complex.     

Human hippocampus establishes associations in memory

Studies of amnesia have demonstrated that the hippocampus is necessary for long-term memory, but its precise role in memory is unknown. We designed a positron emission tomography experiment with tailored encoding and retrieval tasks that permitted the isolation of different mnemonic functions theorized to be mediated by the hippocampus. These functions included encoding single items, establishing interitem associations, novelty detection, and retrieving recently formed associations. Of these, we found hippocampal and parahippocampal activation only during associative learning. Our results indicate that the hippocampal formation may be particularly involved in the establishment of associations among components of an episode in memory. Hippocampus 7:249–256, 1997. © 1997 Wiley-Liss, Inc.     

Learning and memory

Memory is broadly divided into declarative and nondeclarative forms of memory. The hippocampus is required for the formation of declarative memories, while a number of other brain regions including the striatum, amygdala and nucleus accumbens are involved in the formation of nondeclarative memories. The formation of all memories require morphological changes of synapses: new ones must be formed or old ones strengthened. These changes are thought to reflect the underlying cellular basis for persistent memories. Considerable advances have occurred over the last decade in our understanding of the molecular bases of how these memories are formed. A key regulator of synaptic plasticity is a signaling pathway that includes the mitogen activated protein (MAP) kinase. As this pathway is required for normal memory and learning, it is not surprising that mutations in members of this pathway lead to disruptions in learning. Neurofibromatosis, Coffin-Lowry syndrome and Rubinstein-Taybi syndrome are three examples of developmental disorders that have mutations in key components of the MAP kinase signaling pathway.     

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer''s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC–NA axons coincides with the heightened β-AR function at medial perforant path–dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer''s disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.     

Involvement of nitric oxide in low glucose-mediated inhibition of hippocampal long-term potentiation

Hypoglycemia is associated with deficits in learning and memory, yet there is little information about how changes in extracellular glucose alter processes involved in memory. To address these issues, we examined the effects of low glucose on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. When slices were exposed to 2–3.3 mM glucose for 5–30 min before tetanic stimulation, baseline synaptic responses were unaltered, but LTP could not be induced. However, exposure to 2 mM glucose immediately following a tetanus failed to inhibit LTP. An inhibitor of N-methyl-D-aspartate (NMDA) receptors prevented the inhibition of LTP by 3.3 mM glucose, but was ineffective against 2 mM glucose. Similarly, nitric oxide synthase (NOS) inhibitors prevented LTP inhibition by 3.3 mM but not by 2 mM glucose. These results suggest that untimely activation of NMDA receptors and release of NO contributes to low glucose-mediated LTP inhibition, but that different mechanisms may be responsible for LTP inhibition depending on the severity of hypoglycemia. Synapse 25:258–262, 1997. © 1997 Wiley-Liss, Inc.     

Neuropsychological evidence for multiple implicit memory systems: a comparison of Alzheimer's, Huntington's, and Parkinson's disease patients

The performances of patients with dementia of the Alzheimer type (DAT), patients with Huntington's disease (HD), and demented and nondemented patients with Parkinson's disease (PD) were compared on 2 tests of implicit memory that do not require the conscious recollection of prior study episodes: (1) a pursuit-rotor motor learning task and (2) a lexical priming test. The HD patients were found to be impaired on the motor learning but not the lexical priming task, whereas the DAT patients evidenced the opposite relationship on these tasks. The demented, but not the nondemented, PD patients were found to be impaired on both tests of implicit memory. For both the HD and PD patients, deficits on the motor learning task correlated significantly with severity of dementia but not with level of primary motor dysfunction. The noted double dissociation between HD and DAT patients indicates that different forms of implicit memory, all of which are intact in amnesia, are dependent upon distinct neuroanatomic systems. Motor skill learning may be mediated by a corticostriatal system, whereas verbal priming may depend upon the integrity of the neocortical association areas involved in the storage of semantic knowledge. The results for the PD patients suggest that the demented PD patients have endured damage to the neurologic systems subserving both motor learning and lexical priming.     

The plasticity-pathology continuum: defining a role for the LTP phenomenon.

Long-term potentiation (LTP) is the most widely studied form of neuroplasticity and is believed by many in the field to be the substrate for learning and memory. For this reason, an understanding of the mechanisms underlying LTP is thought to be of fundamental importance to the neurosciences, but a definitive linkage of LTP to learning or memory has not been achieved. Much of the correlational data used to support this claim is ambiguous and controversial, precluding any solid conclusion about the functional relevance of this often artificially induced form of neuroplasticity. In spite of this fact, the belief that LTP is a mechanism subserving learning and/or memory has become so dominant in the field that the investigation of other potential roles or actions of LTP-like phenomena in the nervous system has been seriously hindered. The multiple subtypes of the phenomena and the myriad molecules apparently involved in these subtypes raise the possibility that observed forms of LTP may represent very different types of modification events, with vastly different consequences for neural function and survival. A relationship between LTP and neuropathology is suggested in part by the fact that many of the molecular processes involved in LTP induction or maintenance are the same as those activated during excitotoxic events in neurons. In addition, some LTP subtypes are clearly induced by pathological stimuli, e.g., anoxic LTP. Such data raise the possibility that LTP is part of a continuum of types of neural modification, some leading to beneficial alterations such as may occur in learning and others that may be primarily pathological in nature, as in kindling and excitotoxicity. In this article, we introduce a plasticity-pathology continuum model that is designed to place the various forms of neural modification into proper context. In vitro and kindling receptor regulation studies are used to provide a basis for evaluating the specific synaptic/cellular response modification along the continuum of events, from beneficial to detrimental, that will be induced by a particular stimulus.     

The effect of cortisol on emotional responses depends on order of cortisol and placebo administration in a within-subject design

Cortisol does not exhibit a straightforward relationship with mood states; administration of glucocorticoids to human subjects has produced mixed effects on mood and emotional processing. In this study, participants (N=46) received intravenous hydrocortisone (synthetic cortisol; 0.1mg/kg body weight) and placebo in randomized order over two sessions 48h apart. Following the infusion, participants rated neutral and unpleasant pictures. In Session 1, participants reported elevated negative affect (NA) following the picture-rating task, regardless of treatment. In Session 2, however, only participants who received cortisol (and thus who had received placebo in Session 1) reported elevated NA. Arousal ratings for unpleasant pictures followed a similar pattern. These findings suggest that the effects of cortisol on emotion vary based on situational factors, such as drug administration order or familiarity with the tasks and setting. Such factors can influence cortisol's effects on emotion in two ways: (A) cortisol may only potentiate NA and arousal ratings in the absence of other, overwhelming influences on affect, such as the novelty of the setting and tasks in Session 1; and (B) cortisol in Session 1 may facilitate learning processes (e.g., habituation to the stimuli and setting; extinction of aversive responses) such that emotional responses to the pictures are lessened in Session 2. This interpretation is compatible with a body of literature on the effects of glucocorticoids on learning and memory processes.     

Short-term and long-term plasticity at corticostriatal synapses: implications for learning and memory

The striatum is the major division of the basal ganglia, representing the input station of the circuit and arguably the principal site within the basal ganglia where information processing occurs. Striatal activity is critically involved in motor control and learning. Many parts of the striatum are involved in reward processing and in various forms of learning and memory, such as reward-association learning. Moreover, the striatum appears to be a brain center for habit formation and is likely to be involved in advanced stages of addiction. The critical role played by the striatum in learning and cognitive processes is thought to be based on changes in neuronal activity when specific behavioral tasks are being learned. Accordingly, excitatory corticostriatal synapses onto both striatal projecting spiny neurons and interneurons are able to undergo the main forms of synaptic plasticity, including long-term potentiation, long-term depression, short-term forms of intrinsic plasticity and spike timing-dependent plasticity. These specific forms of neuroplasticity allow the short-term and long-term selection and differential amplification of cortical neural signals modulating the processes of motor and behavioral selection within the basal ganglia neural circuit.     

Nitric oxide synthase in learning-relevant nuclei of the chick brain: Morphology,distribution, and relation to transmitter phenotypes

Nitric oxide (NO) has been implicated in learning in the hatchling chicken. To examine morphological and neurochemical properties of neurons that contain NO synthase (NOS) in brain regions known to be involved in learning and memory, the NADPH-diaphorase technique was used in conjunction with immunocytochemistry and tract tracing. A distinct cell type was NOS-labeled in the lobus parolfactorius (LPO) in the telencephalon, and neurons were labeled in the area ventralis of Tsai (AVT), the substantia nigra (nucleus tegmenti pedunculo-pontinus, pars compacta, TPc), and the locus coeruleus in the brainstem. Thus, NO may influence processes of learning and memory in the forebrain after release from intrinsic neurons and/or from extrinsic NOS-projections originating from the brainstem. DiI-tracing revealed that most of the NOS-positive neurons in the AVT/TPc project to the basal forebrain. The majority of tyrosine hydroxylase-positive (presumptive dopaminergic) neurons in the AVT and TPc expressed NOS. Double-labeling with antibodies to tyrosine hydroxylase, choline acetyltransferase, somatostatin, and the neurotrophin receptor as a marker for noradrenergic coeruleus neurons showed that NOS was not colocalized with noradrenergic or somatostatinergic neurons, and that less than a third of the cholinergic neurons were double-labeled for NOS. Injections of 6-hydroxydopamine into the brainstem did not reduce the density of NOS-labeled fibers in the LPO, indicating that most of the NO in the LPO originates from intrinsic neurons in the basal forebrain. Thus, NOS-containing presumptive local circuit neurons in the LPO are the most likely source of NO involved in learning of passive avoidance tasks in hatchling chicks. J. Comp. Neurol. 383:135–152, 1997. © 1997 Wiley-Liss Inc.     

The beta-amyloid precursor protein and its derivatives: from biology to learning and memory processes

Intensive investigation towards the understanding of the biology and physiological functions of the beta-amyloid precursor protein (APP) have been supported since it is known that a 39-43 amino acid fragment of APP, called the beta-amyloid protein (Abeta), accumulates in the brain parenchyma to form the typical lesions associated with Alzheimer's disease (AD). It emerges from extensive data that APP and its derivatives show a wide range of contrasting physiological properties and therefore might be involved in distinct physiological functions. Abeta has been shown to disrupt neuronal activity and to demonstrate neurotoxic properties in a wide range of experimental procedures. In contrast, both in vitro and in vivo studies suggest that APP and/or its secreted forms are important factors involved in the viability, growth and morphological and functional plasticity of nerve cells. Furthermore, several recent studies suggest that APP and its derivatives have an important role in learning and memory processes. Memory impairments can be induced in animals by intracerebral treatment with Abeta. Altered expression of the APP gene in aged animals or in genetically-modified animals also leads to memory deficits. By contrast, secreted forms of APP have recently been shown to facilitate learning and memory processes in mice. These interesting findings open novel perspectives to understand the involvement of APP in the development of cognitive deficits associated with AD. In this review, we summarize the current data concerning the biology and the behavioral effects of APP and its derivatives which may be relevant to the roles of these proteins in memory and in AD pathology.     

Sleep states and memory processes in humans: procedural versus declarative memory systems

The present paper focuses on human studies attempting to relate sleep states to memory processes. These studies typically present learning material to participants and then examine their ability to recall this material after intervening post-training sleep or sleep deprivation. Most experiments utilize either sleep recording or sleep deprivation following task acquisition to reach their conclusions, although cueing and position emission tomography (PET) scan studies have also been done. Results strongly suggest that REM sleep is involved with the efficient memory processing of cognitive procedural material but not declarative material. Although there are some data to suggest that stage 3/4 or NREM sleep is necessary for declarative memory consolidation, NREM may in fact simply be occurring at the same time as another factor that is actually involved in the memory processing. Preliminary results suggest that the length of the NREM–REM sleep cycle may be important for declarative memory. Preliminary data also suggest that stage 2 sleep may be involved with the memory for motor procedural but not cognitive procedural tasks. Sleep researchers would do well to capitalize on the latest advancements in memory research by choosing tasks that represent special memory systems and examining their relationships to sleep states.     

Kindled seizures enhance young neuron survival in the adult rat dentate gyrus

New neurons continue to be generated throughout adulthood in the dentate gyrus of mammals. This process of neurogenesis is believed to play a role in some forms of learning and memory. Hippocampal-dependent learning tasks have been shown to specifically enhance the survival of new granule neurons. The present study examined the effects of kindled seizures in rats on the survival of young neurons born before the kindling began. Kindled seizures within the perforant path input to the dentate gyrus triggered between 1 and 2 weeks following the injection of bromodeoxyuridine (BrdU), were found to increase the number of BrdU and NeuN co-labeled cells in the granule cell layer by 128% 1 month later. The number of co-labeled cells was not correlated with measures of seizure severity. These results demonstrate that kindled seizures enhance the survival of new born neurons in the adult rat dentate gyrus which may reflect the actions of an activity-dependent mechanism normally involved in hippocampal-dependent learning and memory.     

Long-term stability of fear memory depends on the synthesis of protein but not mRNA in the amygdala

Synaptic modification supporting memory formation is thought to depend on gene expression and protein synthesis. Disrupting either process around the time of learning prevents the formation of long-term memory. Recent evidence suggests that memory also becomes susceptible to disruption upon retrieval. Whether or not the molecular events involved in the formation of new memory are the same as what is needed for memory to persist after retrieval has yet to be determined. In the present set of experiments, rats were given inhibitors of protein or messenger ribonucleic acid (mRNA) synthesis into the amygdala just after training or retrieval of fear memory. Results showed that blocking mRNA or protein synthesis immediately after learning prevented the formation of long-term memory, while stability of memory after retrieval required protein, but not mRNA, synthesis. These data suggest that the protein needed for memory reconsolidation after retrieval may be transcribed from pre-existing stores of mRNA.     

NADPH oxidase mediates β-amyloid peptide-induced activation of ERK in hippocampal organotypic cultures

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.     

Nicotine exposure in vivo induces long-lasting enhancement of NMDA receptor-mediated currents in the hippocampus

The use of nicotine via cigarette smoking forms long-lasting memories that are recalled in response to environmental cues associated with previous nicotine use. However, the changes in brain memory systems that underlie these long-lasting memories are not well understood. The N-methyl-D-aspartate receptor (NMDAR) is critical for long-lasting modifications of synapses. Here we show that in vivo nicotine exposure induces the enhancement of NR2B-containing NMDAR-mediated currents in the hippocampus, a brain region associated with the formation of memories. This nicotine effect is maintained during continued nicotine exposure and is accompanied by increased tyrosine phosphorylation of NR2B. Furthermore, long-term potentiation (LTP), which is considered to be a cellular substrate of learning and memory, induced in nicotine-exposed hippocampi contains a protein synthesis-independent long-lasting component. An NR2B-selective antagonist blocks a long-lasting component of LTP, but not LTP. These results suggest that exposure to nicotine provides conditions that promote the induction of long-lasting modifications of synapses, which may be involved in the formation of memories involving nicotine use.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.