Storage, recall, and novelty detection of sequences by the hippocampus: Elaborating on the SOCRATIC model to account for normal and aberrant effects of dopamine

Abstract

ABSTRACT:In order to understand how the molecular or cellular defects that underlie a disease of the nervous system lead to the observable symptoms, it is necessary to develop a large-scale neural model. Such a model must specify how specific molecular processes contribute to neuronal function, how neurons contribute to network function, and how networks interact to produce behavior. This is a challenging undertaking, but some limited progress has been made in understanding the memory functions of the hippocampus with this degree of detail. There is increasing evidence that the hippocampus has a special role in the learning of sequences and the linkage of specific memories to context. In the first part of this paper, we review a model (the SOCRATIC model) that describes how the dentate and CA3 hippocampal regions could store and recall memory sequences in context. A major line of evidence for sequence recall is the "phase precession" of hippocampal place cells. In the second part of the paper, we review the evidence for theta-gamma phase coding. According to a framework that incorporates this form of coding, the phase precession is interpreted as cued recall of a discrete sequence of items from long-term memory. The third part of the paper deals with the issue of how the hippocampus could learn memory sequences. We show that if multiple items can be active within a theta cycle through the action of a short-term "buffer," NMDA-dependent plasticity can lead to the learning of sequences presented at realistic item separation intervals. The evidence for such a buffer function is reviewed. An important underlying issue is whether the hippocampal circuitry is configured differently for learning and recall. We argue that there are indeed separate states for learning and recall, but that both involve theta oscillations, albeit in possibly different forms. This raises the question of how neuromodulatory input might switch the hippocampus between learning and recall states and more generally how different neuromodulatory inputs reconfigure the hippocampus for different functions. In the fifth part of this paper we review our studies of dopamine and dopamine/NMDA interactions in the control of synaptic function. Our results show that dopamine dramatically reduces the direct cortical input to CA1 (the perforant path input), while having little effect on the input from CA3. In order to interpret the functional consequences of this pathway-specific modulation, it is necessary to understand the function of CA1 and the role of dopaminergic input from the ventral tegmental area (VTA). In the sixth part of this paper we consider several possibilities and address the issue of how dopamine hyperfunction or NMDA hypofunction, abnormalities that may underlie schizophrenia, might lead to the symptoms of the disease. Relevant to this issue is the demonstrated role of the hippocampus in novelty detection, a function that is likely to depend on sequence recall by the hippocampus. Novelty signals are generated when reality does not match ...

Input-dependent learning rule for the memory of spatiotemporal sequences in hippocampal network with theta phase precession

“…This is contrary to the previous idea that asymmetry of synaptic connections contributes to the mechanism of phase precession (Jensen and Lisman 1996;Tsodyks et al 1996;Wallenstein and Hasselmo 1997;Lisman 1999;Lisman and Otmakhova 2001). To resolve this contradiction, we should first address an interesting question.…”

The potential role of lamotrigine in schizophrenia

“…We can propose that lamotrigine regulates the firing of pyramidal neurons and the release of glutamate, whereas the antipsychotic drugs have their principal effect on dopamine transmission. The interaction between glutamate and dopamine in the schizophrenic brain has been a subject of significant discussion (Laruelle et al 2003;Kapur 2003;Lisman and Otmakhova 2001). Dopamine is proposed to have a facilitatory rather than causal role in the generation of the symptoms of schizophrenia (Laruelle and AbiDargham 1999;Lisman and Otmakhova 2001;Kapur 2003).…”

“…Laruelle and Abi-Dargham (1999) and Kapur (2003) have described dopamine as the "wind of the psychotic fire", increasing the salience of abnormal thoughts or hallucinations. Lisman and Otmakhova (2001) suggest that dopaminergic activity signals novelty, perhaps again increasing the impact of aberrant cortical activity on conscious thought. A consequence of this view is that psychosis is only temporarily subdued by dopamine-blocking drugs (Kapur 2003), which seems to be borne out by the frequent observation that identical symptoms remerge if the antipsychotic medication is withdrawn.…”

“…The interaction between glutamate and dopamine in the schizophrenic brain has been a subject of significant discussion (Laruelle et al 2003;Kapur 2003;Lisman and Otmakhova 2001). Dopamine is proposed to have a facilitatory rather than causal role in the generation of the symptoms of schizophrenia (Laruelle and AbiDargham 1999;Lisman and Otmakhova 2001;Kapur 2003). In support of this, d-amphetamine induces a form of psychosis in volunteers (Griffith et al 1972;Angrist and Gershon 1970), but the symptoms are not considered to be fully similar to those of the schizophrenic patient.…”

The rodent hippocampus and spatial memory: from synapses to systems

“…One suggestion is that the direct cortical input to the CA subregions and the intrinsic hippocampal circuitry play distinct roles in encoding and retrieval processes [89,92,187]. For instance, based on physiological data, it has been proposed that the hippocampal theta rhythm serves to separate encoding from retrieval, with encoding occurring at the troughs of the rhythm (recorded at the hippocampal fissure) and retrieval occurring at the peaks [188].…”