Memory Systems In Brain Research Articles

Time cells in the retrosplenial cortex.

The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T-maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T-maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off-response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T-maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory.

Role of dorsal hippocampal muscarinic receptor activity in acquisition and retention of single- versus multiple-trial contextual fear conditioning in adolescent rats.

The present study examined the effects of the muscarinic acetylcholine receptor (mAChR) antagonist, scopolamine, on standard contextual fear conditioning (sCFC). It compared effects of the drug on acquisition (post-shock freezing) versus 24-hr retention of a context-shock association acquired after one or three pairings of a context with unsignaled shock. During single-trial sCFC, systemic scopolamine (0.5 mg/kg, i.p.) prior to training abolished both post-shock and retention freezing (Experiment 1). This same injection during multiple-trial sCFC also abolished post-shock freezing and impaired 24-hr retention freezing (Experiment 2). These results indicate that cholinergic signaling mediates both acquisition and 24-hr retention of a context-shock association across different trial parameters. Experiment 3 further explored these effects by infusing scopolamine (35 μg per side) into the dorsal hippocampus (dHPC) prior to training in single versus multiple-trial sCFC. This infusion spared post-shock but abolished retention test freezing in single-trial sCFC (Experiment 3A), and had no effect on multiple-trial sCFC (Experiment 3B). The current findings suggest that brain-wide cholinergic signaling mediates acquisition and retention of single-trial sCFC. Despite this, while muscarinic cholinergic signaling in the dHPC does mediate retention of single-trial sCFC, it is not required for acquisition of either variant, or retention of multiple-trial sCFC. These findings also rule out impaired sensory processing of contextual cues as a mechanism of impaired context learning by dHPC scopolamine. The results are discussed in relation to the role of cholinergic function across multiple brain memory systems in elemental versus configural forms of contextual fear conditioning (Fanselow, 2010; Rudy, 2009). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice.

Alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning; however, the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction retrieval impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair the retrieval an extinction memory, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

Spatiotemporal Dynamics of Multiple Memory Systems During Category Learning.

The brain utilizes distinct neural mechanisms that ease the transition through different stages of learning. Furthermore, evidence from category learning has shown that dissociable memory systems are engaged, depending on the structure of a task. This can even hold true for tasks that are very similar to each other, which complicates the process of classifying brain activity as relating to changes that are associated with learning or reflecting the engagement of a memory system suited for the task. The primary goals of these studies were to characterize the mechanisms that are associated with category learning and understand the extent to which different memory systems are recruited within a single task. Two studies providing spatial and temporal distinctions between learning-related changes in the brain and category-dependent memory systems are presented. The results from these experiments support the notion that exemplar memorization, rule-based, and perceptual similarity-based categorization are flexibly recruited in order to optimize performance during a single task. We conclude that these three methods, along with the memory systems they rely on, aid in the development of expertise, but their engagement might depend on the level of familiarity with a category.

Parietal low beta rhythm provides a dynamical substrate for a working memory buffer

Working memory (WM) is a component of the brain's memory systems vital for interpretation of sequential sensory inputs and consequent decision making. Anatomically, WM is highly distributed over the prefrontal cortex (PFC) and the parietal cortex (PC). Here we present a biophysically detailed dynamical systems model for a WM buffer situated in the PC, making use of dynamical properties believed to be unique to this area. We show that the natural beta1 rhythm (12 to 20 Hz) of the PC provides a substrate for an episodic buffer that can synergistically combine executive commands (e.g., from PFC) and multimodal information into a flexible and updatable representation of recent sensory inputs. This representation is sensitive to distractors, it allows for a readout mechanism, and it can be readily terminated by executive input. The model provides a demonstration of how information can be usefully stored in the temporal patterns of activity in a neuronal network rather than just synaptic weights between the neurons in that network.

Plasticity at Thalamo-amygdala Synapses Regulates Cocaine-Cue Memory Formation and Extinction

Repeated drug use has long-lasting effects on plasticity throughout the brain's reward and memory systems. Environmental cues that are associated with drugs of abuse can elicit craving and relapse, but the neural circuits responsible for driving drug-cue-related behaviors have not been well delineated, creating a hurdle for the development of effective relapse prevention therapies. In this study, we used a cocaine+cue self-administration paradigm followed by cue re-exposure to establish that the strength of the drug cue association corresponds to the strength of synapses between the medial geniculate nucleus (MGN) of the thalamus and the lateral amygdala (LA). Furthermore, we demonstrate, via optogenetically induced LTD of MGN-LA synapses, that reversing cocaine-induced potentiation of this pathway is sufficient to inhibit cue-induced relapse-like behavior.

Amyloid-independent functional neural correlates of episodic memory in amnestic mild cognitive impairment

Although amnestic mild cognitive impairment (aMCI) could have various biological characteristics, little attention has been given to the nature of episodic memory decline in aMCI with pathophysiologies other than Alzheimer's disease (AD), i.e., aMCI with low beta-amyloid (Aβ) burden. This study aimed to identify the functional neural basis of episodic memory impairment in aMCI with Aβ burden negative (aMCI-Aβ-) and to compare these results with aMCI with Aβ burden positive (aMCI-Aβ+). Individuals with aMCI (n = 498) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Based on the mean florbetapir standard uptake value ratio, participants were classified as aMCI-Aβ- or aMCI-Aβ+. Correlations between memory scores and regional cerebral glucose metabolism (rCMglc) were analyzed separately for the two subgroups using a multiple regression model. For aMCI-Aβ-, significant positive correlations between memory and rCMglc were found in the bilateral claustrum, right thalamus, left anterior cingulate cortex, left insula, and right posterior cingulate. For aMCI-Aβ+, significant positive correlations between memory and rCMglc were found in the temporoparietal areas. These correlation patterns remained unchanged when clinical severity was added as a covariate Our findings indicate that memory impairment in aMCI-Aβ- is related to multimodal integrative processing and the attentional control system, whereas memory impairment in aMCI-Aβ+ is related to the typical brain memory systems and AD signature. These results suggest that although the two subgroups are clinically in the same category as aMCI, the memory impairment process depends on completely different functional brain regions according to their Aβ burden level.

Mineralocorticoid Receptor Blockade Prevents Stress-Induced Modulation of Multiple Memory Systems in the Human Brain

Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR. Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum. Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance. Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR.

Intracranial self-stimulation facilitates active-avoidance retention and induces expression of c-Fos and Nurr1 in rat brain memory systems

Intracranial self-stimulation (ICSS), a special form of deep brain stimulation in which subjects self-administered electrical stimulation in brain reward areas as the lateral hypothalamus, facilitates learning and memory in a wide variety of tasks. Assuming that ICSS improves learning and memory increasing the activation of memory-related brain areas, the present work examined whether rats receiving an ICSS treatment immediately after the acquisition session of a two-way active avoidance conditioning (TWAA) show both an improved retention and a pattern of increased c-Fos and Nurr1 protein expression in the amygdala, hippocampus, dorsal striatum and/or lateral hypothalamus. The response of both activity-induced IEGs to ICSS was examined not only as markers of neural activation, but because of their reported role in the neural plasticity occurring during learning and memory formation. Results showed that the TWAA conditioning alone increased the expression of the two analysed IEGs in several hippocampal areas, and TWAA retention increased Nurr1 expression in amygdala. ICSS treatment increased the number of c-Fos and Nurr1 positive cells in almost all the brain regions studied when it was measured 70min, but not 48h, after the stimulation. Post-training ICSS treatment, as expected, facilitated the 48h retention of the conditioning. It is noteworthy that in CA3 conditioning and ICSS separately increased c-Fos expression, but this increasing was greater when both, conditioning and ICSS, were combined. Present results suggest that rapid and transient increased expression of these two synaptic plasticity and memory related IEGs in some hippocampal areas, such as CA3, could mediate the facilitative effects of ICSS on learning and memory consolidation.

Initiation of olfactory memory in patients after successful treatment of patients with congenital hyposmia – the role of neuroplasticity

Congenital hyposmia is a genetic disorder associated with adenylyl cyclase deficiencies. These deficiencies cause smell loss (hyposmia) in these patients. These deficiencies are manifested by lower than normal levels of cAMP and cGMP in nasal mucus which cause olfactory receptor failure. Treatment with phosphodiesterase inhibitors (e.g., theophylline) increases nasal mucus cAMP and cGMP, corrects olfactory failure and initiates detection of olfactory sensory signals. While they can then detect odors they have difficulty in recognizing character of these odors since they have no past experience or memory of these odors. These signals were not previously integrated by limbic and other brain memory systems. However, over time patients learn to associate novel odors with specific objects and learn to recognize the appropriate character of various environmental olfactory stimuli. This usually begins with sweet odors since the largest receptor number in the olfactory epithelium deals with sweet detection. This is the first report of recovery of olfactory recognition with repair of congenital hyposmia. While the olfactory system is hard wired into brain in utero correction of receptor defects is only the first step in the complex process of regaining normal smell function. The second step is activation of central nervous system neuroplasticity by which olfactory recognition occurs. These results were confirmed by functional magnetic resonance imaging studies in which both detection and brain integration of olfactory stimuli were measured.

Drug Addiction and the Memory Systems of the Brain

We review drug addiction from the perspective of the hypothesis that drugs of abuse interact with distinct brain memory systems. We focus on emotional and procedural forms of memory, encompassing Pavlovian and instrumental conditioning, both for action-outcome and for stimulus-response associations. Neural structures encompassed by these systems include the amygdala, hippocampus, nucleus accumbens, and dorsal striatum. Additional influences emanate from the anterior cingulate and prefrontal cortex, which are implicated in the encoding and retrieval of drug-related memories that lead to drug craving and drug use. Finally, we consider the ancillary point that chronic abuse of many drugs may impact directly on neural memory systems via neuroadaptive and neurotoxic effects that lead to cognitive impairments in which memory dysfunction is prominent.

Eyeblink conditioning in 12-day-old rats using pontine stimulation as the conditioned stimulus

A fundamental issue in developmental science is whether ontogenetic changes in memory are caused by the development of cellular plasticity mechanisms within the brain's memory systems or maturation of sensory inputs to the memory systems. Here, we provide evidence that the development of eyeblink conditioning, a form of associative learning that depends on the cerebellum, is driven by the development of sensory inputs rather than the development of neuronal plasticity mechanisms. We find that rats as young as 12 days old show associative eyeblink conditioning when pontine stimulation is used in place of an external (e.g., a tone) conditioned stimulus. Eyeblink-conditioned responses established with pontine stimulation in 12-day-old rats were reversibly abolished by an infusion of muscimol into the cerebellar interpositus nucleus. The findings suggest that cerebellar neurons are capable of supporting associative learning-specific plasticity in vivo in very immature animals if given sufficient afferent stimulation.

The Sleeping Brain's Influence on Memory

The Sleeping Brain's Influence on 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.

Parallel processing across neural systems: Implications for a multiple memory system hypothesis

A common conceptualization of the organization of memory systems in brain is that different types of memory are mediated by distinct neural systems. Strong support for this view comes from studies that show double (or triple) dissociations between spatial, response, and emotional memories following selective lesions of hippocampus, striatum, and the amygdala. Here, we examine the extent to which hippocampal and striatal neural activity patterns support the multiple memory systems view. A comparison is made between hippocampal and striatal neural correlates with behavior during asymptotic performance of spatial and response maze tasks. Location- (or place), movement, and reward-specific firing patterns were found in both structures regardless of the task demands. Many, but not all, place fields of hippocampal and striatal neurons were similarly affected by changes in the visual and reward context regardless of the cognitive demands. Also, many, but not all, hippocampal and striatal movement-sensitive neurons showed significant changes in their behavioral correlates after a change in visual context, irrespective of cognitive strategy. Similar partial reorganization was observed following manipulations of the reward condition for cells recorded from both structures, again regardless of task. Assuming that representations that persist across context changes reflect learned information, we make the following conclusions. First, the consistent pattern of partial reorganization supports a view that the analysis of spatial, response, and reinforcement information is accomplished via an error-driven, or match–mismatch, algorithm across neural systems. Second, task-relevant processing occurs continuously within hippocampus and striatum regardless of the cognitive demands of the task. Third, given the high degree of parallel processing across allegedly different memory systems, we propose that different neural systems may effectively compete for control of a behavioral expression system. The strength of the influence of any one neural system on behavioral output is likely modulated by factors such as motivation, experience, or hormone status.

Multiple memory systems: The power of interactions

Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour, and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and psychiatric disorders.

Differential effects of cerebellar, amygdalar, and hippocampal lesions on classical eyeblink conditioning in rats.

Eyeblink conditioning has been hypothesized to engage two successive stages of nonspecific emotional (fear) and specific musculature (eyelid) learning, during which the nonspecific component influences the acquisition of the specific component. Here we test this notion by investigating the relative contributions of the cerebellum, the amygdala, and the hippocampus to the emergence of conditioned eyelid and fear responses during delay eyeblink conditioning in freely moving rats. Periorbital electromyography (EMG) and 22 kHz ultrasonic vocalization (USV) activities were measured concurrently from the same subjects and served as indices of conditioned eyeblink and fear responses, respectively. In control animals, conditioned EMG responses increased across training sessions, whereas USV responses were initially robust but decreased across training sessions. Animals with electrolytic lesions to their cerebellum (targeting the interpositus nucleus) were completely unable to acquire conditioned EMG responses but exhibited normal USV behavior, whereas animals with lesions to the amygdala showed decelerated acquisition of conditioned EMG responses and displayed practically no USV behavior. In contrast, hippocampal lesioned rats demonstrated facilitated acquisition of conditioned EMG responses, whereas the USV behavior was unaffected. The amygdalar involvement in eyeblink conditioning was examined further by applying the GABA(A) agonist muscimol directly into the amygdala either before or immediately after training sessions. Although pretraining muscimol infusions impaired conditioned EMG responses, post-training infusions did not. Together, these results suggest that, even during a simple delay eyeblink conditioning, animals learn about different aspects associated with the behavioral task that are subserved by multiple brain-memory systems that interact to produce the overall behavior.

The neural basis of lexicon and grammar in first and second language: the declarative/procedural model

Theoretical and empirical aspects of the neural bases of the mental lexicon and the mental grammar in first and second language (L1 and L2) are discussed. It is argued that in L1, the learning, representation, and processing of lexicon and grammar depend on two well-studied brain memory systems. According to the declarative/procedural model, lexical memory depends upon declarative memory, which is rooted in temporal lobe structures, and has been implicated in the learning and use of fact and event knowledge. Aspects of grammar are subserved by procedural memory, which is rooted in left frontal/basal-ganglia structures, and has been implicated in the acquisition and expression of motor and cognitive skills and habits. This view is supported by psycholinguistic and neurolinguistic evidence. In contrast, linguistic forms whose grammatical computation depends upon procedural memory in L1 are posited to be largely dependent upon declarative/lexical memory in L2. They may be either memorized or constructed by explicit rules learned in declarative memory. Thus in L2, such linguistic forms should be less dependent on procedural memory, and more dependent on declarative memory, than in L1. Moreover, this shift to declarative memory is expected to increase with increasing age of exposure to L2, and with less experience (practice) with the language, which is predicted to improve the learning of grammatical rules by procedural memory. A retrospective examination of lesion, neuroimaging, and electrophysiological studies investigating the neural bases of L2 is presented. It is argued that the data from these studies support the predictions of the declarative/procedural model.

The declarative/procedural model of lexicon and grammar.

Our use of language depends upon two capacities: a mental lexicon of memorized words and a mental grammar of rules that underlie the sequential and hierarchical composition of lexical forms into predictably structured larger words, phrases, and sentences. The declarative/procedural model posits that the lexicon/grammar distinction in language is tied to the distinction between two well-studied brain memory systems. On this view, the memorization and use of at least simple words (those with noncompositional, that is, arbitrary form-meaning pairings) depends upon an associative memory of distributed representations that is subserved by temporal-lobe circuits previously implicated in the learning and use of fact and event knowledge. This "declarative memory" system appears to be specialized for learning arbitrarily related information (i.e., for associative binding). In contrast, the acquisition and use of grammatical rules that underlie symbol manipulation is subserved by frontal/basal-ganglia circuits previously implicated in the implicit (nonconscious) learning and expression of motor and cognitive "skills" and "habits" (e.g., from simple motor acts to skilled game playing). This "procedural" system may be specialized for computing sequences. This novel view of lexicon and grammar offers an alternative to the two main competing theoretical frameworks. It shares the perspective of traditional dual-mechanism theories in positing that the mental lexicon and a symbol-manipulating mental grammar are subserved by distinct computational components that may be linked to distinct brain structures. However, it diverges from these theories where they assume components dedicated to each of the two language capacities (that is, domain-specific) and in their common assumption that lexical memory is a rote list of items. Conversely, while it shares with single-mechanism theories the perspective that the two capacities are subserved by domain-independent computational mechanisms, it diverges from them where they link both capacities to a single associative memory system with broad anatomic distribution. The declarative/procedural model, but neither traditional dual- nor single-mechanism models, predicts double dissociations between lexicon and grammar, with associations among associative memory properties, memorized words and facts, and temporal-lobe structures, and among symbol-manipulation properties, grammatical rule products, motor skills, and frontal/basal-ganglia structures. In order to contrast lexicon and grammar while holding other factors constant, we have focused our investigations of the declarative/procedural model on morphologically complex word forms. Morphological transformations that are (largely) unproductive (e.g., in go-went, solemn-solemnity) are hypothesized to depend upon declarative memory. These have been contrasted with morphological transformations that are fully productive (e.g., in walk-walked, happy-happiness), whose computation is posited to be solely dependent upon grammatical rules subserved by the procedural system. Here evidence is presented from studies that use a range of psycholinguistic and neurolinguistic approaches with children and adults. It is argued that converging evidence from these studies supports the declarative/procedural model of lexicon and grammar.

New Directions For a Classical Paradigm: Human Eyeblink Conditioning

The knowledge base on neural substrates and mechanisms involved in classical eyeblink conditioning makes it an ideal paradigm for investigating fundamental issues in learning and memory. New applications for the model system presented here include its use in (a) assessment to evaluate neurocognitive development in infancy, (b) theory building in abnormal psychology to test relationships between obsessive-compulsive behavior and learning rate, (c) evaluation of hypotheses about brain memory systems, and (d) exploration of the role of brain structures such as the cerebellum in learning and timing. Human eyeblink conditioning is a prototype of the utility of a model system that has become well characterized at both the behavioral and the neurobiological levels.