A role for Melanin-Concentrating Hormone in learning and memory

The neurobiological substrate of learning process and persistent memory storage involves multiple brain areas. The neocortex and hippocampal formation are known as processing and storage sites for explicit memory, whereas the striatum, amygdala, neocortex and cerebellum support implicit memory. Synaptic plasticity, long-term changes in synaptic transmission efficacy and transient recruitment of intracellular signaling pathways in these brain areas have been proposed as possible mechanisms underlying short- and long-term memory retention. In addition to the classical neurotransmitters (glutamate, GABA), experimental evidence supports a role for neuropeptides in modulating memory processes. This review focuses on the role of the Melanin-Concentrating Hormone (MCH) and receptors on memory formation in animal studies. Possible mechanisms may involve direct MCH modulation of neural circuit activity that support memory storage and cognitive functions, as well as indirect effect on arousal.     

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.     

A working memory model for serial order that stores information in the intrinsic excitability properties of neurons

Models for temporary information storage in neuronal populations are dominated by mechanisms directly dependent on synaptic plasticity. There are nevertheless other mechanisms available that are well suited for creating short-term memories. Here we present a model for working memory which relies on the modulation of the intrinsic excitability properties of neurons, instead of synaptic plasticity, to retain novel information for periods of seconds to minutes. We show that it is possible to effectively use this mechanism to store the serial order in a sequence of patterns of activity. For this we introduce a functional class of neurons, named gate interneurons, which can store information in their membrane dynamics and can literally act as gates routing the flow of activations in the principal neurons population. The presented model exhibits properties which are in close agreement with experimental results in working memory. Namely, the recall process plays an important role in stabilizing and prolonging the memory trace. This means that the stored information is correctly maintained as long as it is being used. Moreover, the working memory model is adequate for storing completely new information, in time windows compatible with the notion of “one-shot” learning (hundreds of milliseconds).     

Deployment of Spatial Attention towards Locations in Memory Representations. An EEG Study

Recalling information from visual short-term memory (VSTM) involves the same neural mechanisms as attending to an actually perceived scene. In particular, retrieval from VSTM has been associated with orienting of visual attention towards a location within a spatially-organized memory representation. However, an open question concerns whether spatial attention is also recruited during VSTM retrieval even when performing the task does not require access to spatial coordinates of items in the memorized scene. The present study combined a visual search task with a modified, delayed central probe protocol, together with EEG analysis, to answer this question. We found a temporal contralateral negativity (TCN) elicited by a centrally presented go-signal which was spatially uninformative and featurally unrelated to the search target and informed participants only about a response key that they had to press to indicate a prepared target-present vs. -absent decision. This lateralization during VSTM retrieval (TCN) provides strong evidence of a shift of attention towards the target location in the memory representation, which occurred despite the fact that the present task required no spatial (or featural) information from the search to be encoded, maintained, and retrieved to produce the correct response and that the go-signal did not itself specify any information relating to the location and defining feature of the target.     

Memory Consolidation in the Cerebellar Cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA_A agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage.     

Effects of two ACTH analogs on successive odor discrimination learning in rats

Olfactory discrimination learning has been shown to provide a powerful tool to investigate the mechanisms involved in the formation, storage and retrieval of information in rodent CNS. In the present study we tested the effects of two ACTH analogs, which were previously reported to influence the processes of learning and memory, on various olfactory learning tasks. The ACTH(4-9) analog HOE 427 produced an apparent increase in storage of olfactory information as shown by the difficulty experienced by the animals to rapidly reverse their behavioral responses to previously learned odors. Similarly, the ACTH (4-9) analog ORG 2766 appears to enhance the storage of olfactory information when administered either before or after the learning trials. These data are consistent with the notion that ACTH and related analogs facilitate performance in a variety of learning tasks. In addition, our results suggest possible mechanisms by which some neuroactive peptides might modulate learning and memory processes in the CNS.     

How does PKMζ maintain long-term memory?

Most of the molecular mechanisms contributing to long-term memory have been found to consolidate information within a brief time window after learning, but not to maintain information during memory storage. However, with the discovery that synaptic long-term potentiation is maintained by the persistently active protein kinase, protein kinase Mζ (PKMζ), a possible mechanism of memory storage has been identified. Recent research shows how PKMζ might perpetuate information both at synapses and during long-term memory.     

Linking implicit and explicit memory: common encoding factors and shared representations

Dissociations between implicit and explicit memory have featured prominently in theories of human memory. However, similarities between the two forms of memory have been less studied. One open question concerns whether implicit and explicit memory share encoding resources. To explore this question, we employed a subsequent memory design in which several novel scenes were repeated once during an fMRI session and explicit memory for the scenes was unexpectedly tested afterward. Subsequently remembered scenes produced more behavioral priming and neural attenuation-two conventional measures of implicit memory-than did subsequently forgotten scenes. Moreover, brain-behavior correlations between these two implicit measures were mediated by subsequent memory. Finally, tonic activity, possibly reflecting the natural time course of attention, was predictive of subsequent memory. These results suggest that implicit and explicit memory are subject to the same encoding factors and can rely on similar perceptual processes and representations.     

Molecular mechanisms of memory retrieval

Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. 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. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.     

Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer's disease

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.     

Cellular and molecular mechanisms of memory

There has been nearly a century of interest in the idea that information is encoded in the brain as specific spatio-temporal patterns of activity in distributed networks and stored as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.     

Slow manifolds within network dynamics encode working memory efficiently and robustly

Working memory is a cognitive function involving the storage and manipulation of latent information over brief intervals of time, thus making it crucial for context-dependent computation. Here, we use a top-down modeling approach to examine network-level mechanisms of working memory, an enigmatic issue and central topic of study in neuroscience. We optimize thousands of recurrent rate-based neural networks on a working memory task and then perform dynamical systems analysis on the ensuing optimized networks, wherein we find that four distinct dynamical mechanisms can emerge. In particular, we show the prevalence of a mechanism in which memories are encoded along slow stable manifolds in the network state space, leading to a phasic neuronal activation profile during memory periods. In contrast to mechanisms in which memories are directly encoded at stable attractors, these networks naturally forget stimuli over time. Despite this seeming functional disadvantage, they are more efficient in terms of how they leverage their attractor landscape and paradoxically, are considerably more robust to noise. Our results provide new hypotheses regarding how working memory function may be encoded within the dynamics of neural circuits.     

Misattribution, false recognition and the sins of memory

Memory is sometimes a troublemaker. Schacter has classified memory's transgressions into seven fundamental 'sins': transience, absent-mindedness, blocking, misattribution, suggestibility, bias and persistence. This paper focuses on one memory sin, misattribution, that is implicated in false or illusory recognition of episodes that never occurred. We present data from cognitive, neuropsychological and neuroimaging studies that illuminate aspects of misattribution and false recognition. We first discuss cognitive research examining possible mechanisms of misattribution associated with false recognition. We also consider ways in which false recognition can be reduced or avoided, focusing in particular on the role of distinctive information. We next turn to neuropsychological research concerning patients with amnesia and Alzheimer's disease that reveals conditions under which such patients are less susceptible to false recognition than are healthy controls, thus providing clues about the brain mechanisms that drive false recognition. We then consider neuroimaging studies concerned with the neural correlates of true and false recognition, examining when the two forms of recognition can and cannot be distinguished on the basis of brain activity. Finally, we argue that even though misattribution and other memory sins are annoying and even dangerous, they can also be viewed as by-products of adaptive features of memory.     

DNA methylation and cell memory

In this paper we address the question: How do replicating mammalian cells remember with high fidelity their proper state of differentiation? Several possible mechanisms for cell memory are discussed, and it is concluded that only mechanisms involving DNA methylation are supported by strong experimental evidence. This evidence is reviewed. The establishment and modulation of methylation patterns are discussed and a hemimethylation model for stem cells is presented. The overall conclusion is that, although little is yet known about the details, there should be little doubt about the existence of a methylation system functioning at least to aid cell memory.     

Selective engagement of plasticity mechanisms for motor memory storage

The number and diversity of plasticity mechanisms in the brain raises a central question: does a neural circuit store all memories by stereotyped application of the available plasticity mechanisms, or can subsets of these mechanisms be selectively engaged for specific memories? The uniform architecture of the cerebellum has inspired the idea that plasticity mechanisms like cerebellar long-term depression (LTD) contribute universally to memory storage. To test this idea, we investigated a set of closely related, cerebellum-dependent motor memories. In mutant mice lacking Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), the maintenance of cerebellar LTD is abolished. Although memory for an increase in the gain of the vestibulo-ocular reflex (VOR) induced with high-frequency stimuli was impaired in these mice, memories for decreases in VOR gain and increases in gain induced with low-frequency stimuli were intact. Thus, a particular plasticity mechanism need not support all cerebellum-dependent memories, but can be engaged selectively according to the parameters of training.     

LTP, post or pre? A look at the evidence for the locus of long-term potentiation.

It seems self-evident that changes in the cellular synaptic function of the brain must underlie the formation and storage of cognitive memories. Because it has been identified as a brain area important in the formation of memory, the hippocampus has been a focus in the study of such synaptic changes. An activity-induced increase in hippocampal synaptic efficacy, known as long-term potentiation (LTP), has been widely studied as a potential substrate for memory. This paper briefly reviews some of the significant progress that has been made in understanding the cellular mechanisms that underlie LTP, including recent experiments dealing with its synaptic locus, or the question of whether the mechanism regulating LTP is pre- or postsynaptic.     

Synaptic Scaling Enables Dynamically Distinct Short- and Long-Term Memory Formation

Memory storage in the brain relies on mechanisms acting on time scales from minutes, for long-term synaptic potentiation, to days, for memory consolidation. During such processes, neural circuits distinguish synapses relevant for forming a long-term storage, which are consolidated, from synapses of short-term storage, which fade. How time scale integration and synaptic differentiation is simultaneously achieved remains unclear. Here we show that synaptic scaling – a slow process usually associated with the maintenance of activity homeostasis – combined with synaptic plasticity may simultaneously achieve both, thereby providing a natural separation of short- from long-term storage. The interaction between plasticity and scaling provides also an explanation for an established paradox where memory consolidation critically depends on the exact order of learning and recall. These results indicate that scaling may be fundamental for stabilizing memories, providing a dynamic link between early and late memory formation processes.     

Forgetting, reminding, and remembering: the retrieval of lost spatial memory

Retrograde amnesia can occur after brain damage because this disrupts sites of storage, interrupts memory consolidation, or interferes with memory retrieval. While the retrieval failure account has been considered in several animal studies, recent work has focused mainly on memory consolidation, and the neural mechanisms responsible for reactivating memory from stored traces remain poorly understood. We now describe a new retrieval phenomenon in which rats' memory for a spatial location in a watermaze was first weakened by partial lesions of the hippocampus to a level at which it could not be detected. The animals were then reminded by the provision of incomplete and potentially misleading information—an escape platform in a novel location. Paradoxically, both incorrect and correct place information reactivated dormant memory traces equally, such that the previously trained spatial memory was now expressed. It was also established that the reminding procedure could not itself generate new learning in either the original environment, or in a new training situation. The key finding is the development of a protocol that definitively distinguishes reminding from new place learning and thereby reveals that a failure of memory during watermaze testing can arise, at least in part, from a disruption of memory retrieval.     

Understanding the physical basis of memory: Molecular mechanisms of the engram

Memory, defined as the storage and use of learned information in the brain, is necessary to modulate behavior and critical for animals to adapt to their environments and survive. Despite being a cornerstone of brain function, questions surrounding the molecular and cellular mechanisms of how information is encoded, stored, and recalled remain largely unanswered. One widely held theory is that an engram is formed by a group of neurons that are active during learning, which undergoes biochemical and physical changes to store information in a stable state, and that are later reactivated during recall of the memory. In the past decade, the development of engram labeling methodologies has proven useful to investigate the biology of memory at the molecular and cellular levels. Engram technology allows the study of individual memories associated with particular experiences and their evolution over time, with enough experimental resolution to discriminate between different memory processes: learning (encoding), consolidation (the passage from short-term to long-term memories), and storage (the maintenance of memory in the brain). Here, we review the current understanding of memory formation at a molecular and cellular level by focusing on insights provided using engram technology.