On the role of the hippocampus in the acquisition, long-term retention and semanticisation of memory

Institute for Adaptive and Neural ComputationA consensus on how to characterise the anterograde and retrograde memory processes that are lost or spared after hippocampal damage has not been reached. In this thesis, I critically re-examine the empirical literature and the assumptions behind current theories. I formulate a coherent view of what makes a task hippocampally dependent at acquisition and how this relates to its long-term fate. Findings from a neural net simulation indicate the plausibility of my proposals. My proposals both extend and constrain current views on the role of the hippocampus in the rapid acquisition of information and in learning complex associations. In general, tasks are most likely to require the hippocampus for acquisition if they involve rapid, associative learning about unfamiliar, complex, low salience stimuli. However, none of these factors alone is sufficient to obligatorily implicate the hippocampus in acquisition. With the exception of associations with supra-modal information that are always dependent on the hippocampus, it is the combination of factors that is important. Detailed, complex information that is obligatorily hippocampally-dependent at acquisition remains so for its lifetime. However, all memories are semanticised as they age through the loss of detailed context-specific information and because generic cortically-represented information starts to dominate recall. Initially hippocampally dependent memories may appear to become independent of the hippocampus over time, but recall changes qualitatively. Multi-stage, lifelong post-acquisition memory processes produce semanticised re-representations of memories of differing specificity and complexity, that can serve different purposes. The model simulates hippocampal and cortical interactions in the acquisition and maintenance of episodic and semantic events, and behaves in accordance with my proposals. In particular, conceptualising episodic and semantic memory as representing points on a continuum of memory types appears viable. Support is also found for proposals on the relative importance of the hippocampus and cortex in the rapid acquisition of information and the acquisition of complex multi-model information; and the effect of existing knowledge on new learning. Furthermore, episodic and semantic events become differentially dependent on cortical and hippocampal components. Finally, as a memory ages, it is automatically semanticised and becomes cortically dependent

Integrating Spatial Working Memory and Remote Memory: Interactions between the Medial Prefrontal Cortex and Hippocampus

In recent years, two separate research streams have focused on information sharing between the medial prefrontal cortex (mPFC) and hippocampus (HC). Research into spatial working memory has shown that successful execution of many types of behaviors requires synchronous activity in the theta range between the mPFC and HC, whereas studies of memory consolidation have shown that shifts in area dependency may be temporally modulated. While the nature of information that is being communicated is still unclear, spatial working memory and remote memory recall is reliant on interactions between these two areas. This review will present recent evidence that shows that these two processes are not as separate as they first appeared. We will also present a novel conceptualization of the nature of the medial prefrontal representation and how this might help explain this area’s role in spatial working memory and remote memory recall

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

The hippocampus and cerebellum in adaptively timed learning, recognition, and movement

The concepts of declarative memory and procedural memory have been used to distinguish two basic types of learning. A neural network model suggests how such memory processes work together as recognition learning, reinforcement learning, and sensory-motor learning take place during adaptive behaviors. To coordinate these processes, the hippocampal formation and cerebellum each contain circuits that learn to adaptively time their outputs. Within the model, hippocampal timing helps to maintain attention on motivationally salient goal objects during variable task-related delays, and cerebellar timing controls the release of conditioned responses. This property is part of the model's description of how cognitive-emotional interactions focus attention on motivationally valued cues, and how this process breaks down due to hippocampal ablation. The model suggests that the hippocampal mechanisms that help to rapidly draw attention to salient cues could prematurely release motor commands were not the release of these commands adaptively timed by the cerebellum. The model hippocampal system modulates cortical recognition learning without actually encoding the representational information that the cortex encodes. These properties avoid the difficulties faced by several models that propose a direct hippocampal role in recognition learning. Learning within the model hippocampal system controls adaptive timing and spatial orientation. Model properties hereby clarify how hippocampal ablations cause amnesic symptoms and difficulties with tasks which combine task delays, novelty detection, and attention towards goal objects amid distractions. When these model recognition, reinforcement, sensory-motor, and timing processes work together, they suggest how the brain can accomplish conditioning of multiple sensory events to delayed rewards, as during serial compound conditioning.Air Force Office of Scientific Research (F49620-92-J-0225, F49620-86-C-0037, 90-0128); Advanced Research Projects Agency (ONR N00014-92-J-4015); Office of Naval Research (N00014-91-J-4100, N00014-92-J-1309, N00014-92-J-1904); National Institute of Mental Health (MH-42900

Changes in Hippocampal-Anterior Cingulate Cortex Interactions During Remote Memory Recall

Spatial memory is an important cognitive process that relies on extensive neural networks throughout the brain. The hippocampus (HC) is important for the formation of these memories but over time, in a process referred to as consolidation, recall becomes increasingly reliant on other brain areas. The anterior cingulate cortex (ACC), a region within the medial prefrontal cortex, is important for spatial learning, spatial working memory, and remote memory recall, but the mechanisms underlying recall processes are still unknown. To better understand the role of the ACC and HC during memory recall, we introduced rodents into a series of spatially and texturally unique environments at differing delay periods (day 1 (learning), day 11 (recent), and day 18 (remote)) while simultaneously recording local field potentials (LFPs) from both areas. We found significant increases in theta band coherence between ipsilateral ACC and HC LFPs during remote memory recall but not recent memory recall. In addition to these changes, directional analysis revealed a reversal in signal initiation, such that during the learning and recent recall condition, hippocampal theta oscillations led ACC theta oscillations. However, during the remote recall condition, the direction changed, and ACC theta led hippocampal theta activity. This experiment provides evidence of time-dependent changes in ACC – hippocampal network interactions, and illustrates a possible mechanism that describes how the ACC mediates recall of remote spatial memories

A neural network model of adaptively timed reinforcement learning and hippocampal dynamics

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and NMDA receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala, and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking, and causes symptoms of medial temporal amnesia. It suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus "speeds up the clock", but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditioning are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISis, partial reinforcement, and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.Air Force Office of Scientific Research (90-0175, 90-0128); Defense Advanced Research Projects Agency (90-0083); National Science Foundation (IRI-87-16960); Office of Naval Research (N00014-91-J-4100

The roles of hippocampal and neocortical learning mechanisms in the human brain

Contemporary models of declarative memory state that when initially learned, all novel information is encoded by the hippocampal system before being consolidated or transformed to depend on neocortical structures subserving semantic memory. Based on observations with functional magnetic resonance imaging (fMRI), this thesis presents evidence that novel associations may be directly encoded by the semantic system in humans. While the hippocampus is often involved in information processing at the early stages of learning, the semantic system is seen to encode associative memory traces in the first instance (chapter 2). Furthermore, it is proposed that the hippocampus is not involved in learning when associative information is gradually accumulated across a series of ambiguous events. This is characteristic of cross-situational learning (xSL) which allows for the acquisition of word-object associations (i.e. nouns) during infancy. It is shown that xSL is not well accounted for by a prominent model of contextual learning - the temporal context model (chapter 3). Additionally, fMRI data suggest that neocortical structures rather than components of the hippocampal system are preferentially involved in xSL compared to traditional methods of training (chapter 4). Finally, it is suggested that rapid hippocampal learning mechanisms rely on specialised neuronal-microglial interactions. The administration of a microglial inhibitor (minocycline) was found to modulate hippocampal function and bias its use when other learning systems would have been more advantageous (chapter 5). Collectively, these findings suggest that the hippocampal system is specialised for rapidly encoding information that is explicitly provided, yet may not be recruited when associative information is collated across ambiguous events. At the same time, the neocortical semantic system may be able to learn new information at faster rates than previously thought. As such, it is hypothesised that amnestic patients may be able to acquire some forms of declarative material if presented in an appropriate manner

Fibroblast growth factor-2: a novel enhancer of memory

This thesis investigated the role of Fibroblast Growth Factor-2 (FGF2), a potent neurotrophic factor that is involved in brain development, on the formation of long-term memory in developing rats. The first series of experiments examined the effects of early-life exposure to systemically administered FGF2 on learning that occurred later in life (Chapter 2). While a single injection of FGF2 on post natal day (PND) 1 did not lead to any detectable changes in contextual fear later in life, five days of FGF2 exposure (on PNDs 1-5) led to enhanced long-term memory for contextual fear in rats trained at PND 16 and 23. Furthermore, repeated early-life FGF2 allowed PND 16 rats to use contextual information in more complex ways, leading to precocious context-dependent extinction of conditioned fear. The second series of experiments examined the effects of acute systemic FGF2, administered at the time of training, on long-term memory (Chapter 3). FGF2 enhanced contextual and cued fear conditioning when administered prior to or immediately after training in rats of a variety of ages. The observed facilitation in fear was not due to FGF2 increasing sensitivity to footshock. The third and fourth series of experiments examined the effects of acute FGF2 on extinction of conditioned fear in PND 23 rats. FGF2 enhanced extinction when administered before or immediately (but not four hours) after extinction, and only when observable within-session extinction occurred (Chapter 4). FGF2-treated rats also showed reduced susceptibility to reinstatement and renewal, two common forms of relapse, and FGF2-treated rats also showed NMDA-dependent re-extinction, suggesting that FGF2 may fundamentally change the quality of extinction (Chapter 5). These experiments are the first to implicate exogenous FGF2 in the formation of long-term memory. The theoretical and clinical implications of these findings are discussed in light of current models of the development of memory and models of fear extinction