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Dopamine-dependent facilitation of LTP induction in hippocampal CA1 by exposure to spatial novelty
Abstract
In addition to its role in memory formation, the hippocampus may act as a novelty detector. Here we investigated whether attention to novel events can promote the associative synaptic plasticity mechanisms believed to be necessary for storing those events in memory. We therefore examined whether exposure to a novel spatial environment promoted the induction of activity-dependent persistent increases in glutamatergic transmission (long-term potentiation, LTP) at CA1 synapses in the rat hippocampus. We found that brief exposure to a novel environment lowered the threshold for the induction of LTP. This facilitatory effect was present for a short period following novelty exposure but was absent in animals that explored a familiar environment. Furthermore, the facilitation was dependent on activation of D1/D5 receptors. These findings support an important role for dopamine-regulated synaptic plasticity in the storage of unpredicted information in the CA1 area.
... In animal studies, novelty often is manipulated by placing an animal in a novel compared to a familiar environment (e.g., a new cage with unknown elements [a novel condition] rather than the home cage [a familiar condition]). This type of novelty has been referred to as spatial or environmental novelty [3][4][5][6][7]. Earlier human research focused on stimulus novelty (e.g., including novel images, sounds, or vibrotactile stimuli) typically reported distraction from ongoing tasks when task-irrelevant novelty is presented [8][9][10][11]. ...
... Rodent studies have shown that the beneficial effects of spatial novelty on memory may last up to 30 min and can also operate retrospectively, i.e., enhancing memory of material that was encountered before exposure to novelty [5]. Apart from the typically short-lived effects of stimulus novelty, with distracting and facilitating effects typically lasting less than a second, also relatively long-lasting effects of novelty on memory have been documented in humans (in the order of tens of minutes; [1]. ...
... Exploration of novel environments can lead to enhanced brain plasticity in non-human animals [3][4][5][6][7]. Prolonged enhancement of synaptic plasticity can be the result of increased stimulation of hippocampal neurons; a process referred to as long-term potentiation Fig. 2. Sagittal view of a human brain showing two potential mechanisms that may underlie novelty-dependent dopamine release in the hippocampus and beneficial effects of novelty on memory in the human brain [43]. ...
Novel information potentially signals danger or reward and behavioral and psychophysiological studies have suggested that the brain prioritizes its processing. Some effects of novelty even go beyond the stimulus itself. Studies in animals have robustly shown that exposure to novel stimulation can promote memory for information presented before or after this exposure. Research regarding effects of novelty on memory in humans is lagging, but in the last few years, several studies have emerged that suggest that memory-facilitating effects of novelty also exist in humans. Here, we provide a comprehensive overview of these studies. We identified several factors that have been shown to influence whether novelty promotes memory or not, including the timing between the novel experience and the learning events, the involvement with the novel material, and population characteristics (such as clinical diagnosis or age). Finally, we link the behavioral findings to potential neurobiological mechanisms and discuss the relevance of specific findings in light of potential clinical and educational applications that could leverage novelty to improve memory.
... Dopaminergic inputs are crucial for long-term changes in synaptic efficacy in the hippocampus (Huang and Kandel, 1995;Li et al., 2003). Dopamine controls the stability of synaptic facilitation at Schaffer collaterals. ...
... However, in contrast to our young adult group's results, Stramiello et al. showed that applying a dopamine agonist (SKF38393) to 40-90 day-old (young adult) rat slices significantly increased LTP (Stramiello and Wagner, 2008). In addition, dopamine agonists changed the threshold of LTP in 7-11 month-old Wistar rats, so that even a weak stimulation that couldn't induce LTP, generated LTP following application of a D 1 receptor agonist (Li et al., 2003). ...
... For example, novelty may increase reward processing (Bunzeck et al., 2012), enhance memory encoding (Mayer et al., 2011;Kormi-Nouri et al., 2005), and improve visual perception (Schomaker and Meeter, 2014). Animal studies also reveal that exploring new environments increases long-term potentiation in the hippocampus, leading to improved memory encoding (Davis et al., 2004;Li et al., 2003). Moreover, in a recent study openness as a personality trait reflecting the tendency to novel experiences, has been found to be significantly linked with CR (Karsazi et al., 2021). ...
... Novelty is a factor that numerous studies have supported its improving role in cognitive function (Mayer et al., 2011;Kormi-Nouri et al., 2005;Schomaker and Meeter 2014). The enrichment of the environment via novelty has led to neural plasticity and cognitive improvement in animal studies (Davis et al., 2004;Li et al., 2003). Productivity was another factor that the present study supported in its unique role in cognitive reserve. ...
Background
A common belief among people and some researchers is that keeping yourself mentally active may decrease the risk of dementia. Over the past years, despite widespread efforts to identify proxies for protecting cognitive reserve against age-related changes, it is still not clear what type of intellectual activity would be beneficial for cognitive reserve. To fill this gap, we propose a three-dimensional model of intellectual activity. According to this conceptual model, intellectual activities could be distinguished based on their locations in a three-dimensions space, including; (1) Activation: active vs. passive, (2) Novelty: novel vs. familiar, and (3) Productivity: productive vs. receptive. We assumed that the activities that are categorized as more active, novel, and productive could be considered as a cognitive reserve proxy.
Methods
To test this hypothesis, a sample of 237 participants older than 50 years (Mage = 58.76 ± 6.66; 63.7% women) was recruited to take part in the study. Episodic, semantic and working memory were assessed with computerized battery tests (Sepidar) and a self-report questionnaire was used to assess intellectual activities. Activities were categorized in terms of; (1) passive, familiar, and receptive activities (radio/watching TV), (2) active, familiar, and receptive activities (solving crosswords), (3) active, novel, and receptive activities (reading), and (4) active, novel, and productive activities (writing).
Results
The results indicated that writing moderates the effect of age on episodic and semantic memory. Reading only moderates the effect of age on semantic memory, and radio/watching TV and solving crosswords do not play a role in moderation analysis.
Conclusions
Our finding suggests that intellectual activities have different moderating effects on the relationships between age and memory performance. Individuals with high levels of participation in novel and productive activities over the life course are less likely to clinically demonstrate cognitive impairments. Our results support the potential benefit of the three-dimensional model to provide a better insight into the complex role of intellectual activities in cognitive reserve, particularly for older adults. Further research is needed to evaluate the efficacy and the benefits of the model.
... Exposure to environmental novelty leads to an increase in dopamine in the dorsal hippocampus [47] and promotes synaptic plasticity [48,11], hippocampal replay [21,49] and memory persistence [48,50]. In our experiment, exposure to a novel environment caused an increase in LC axon activity but not in VTA DA axon activity, supporting findings that novel experiences induce activity of LC neurons [17]. ...
... Exposure to environmental novelty leads to an increase in dopamine in the dorsal hippocampus [47] and promotes synaptic plasticity [48,11], hippocampal replay [21,49] and memory persistence [48,50]. In our experiment, exposure to a novel environment caused an increase in LC axon activity but not in VTA DA axon activity, supporting findings that novel experiences induce activity of LC neurons [17]. ...
Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impact of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized 2-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animal's running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, likely contributing to differential modulation of hippocampal activity during behavior and learning.
... In rodents, long-term spatial memory and novelty detection rely on hippocampus function [10,11] and are strongly modulated by mesohippocampal connections and hippocampal dopamine receptors [12][13][14]. Dopamine acts on two classes of G-protein coupled receptors, D1-like-D 1 /D5-and D2-like -D 2 /D 3 /D4-that have distinct downstream signaling pathways [15]. Even before dopamine neuromodulatory function was firmly established and dopamine receptors identified, antipsychotic drugs (APD) were used in clinical psychiatry to tame psychotic manifestations of schizophrenia. ...
... The dopaminergic mesohippocampal pathway is strongly implicated in novelty detection [10,11]. Both D1Rs and D2Rs in the hippocampus have been shown to modulate synaptic plasticity occurring during novelty exploration and the consolidation of novel spatial representations in mice [12][13][14]. We submitted ventral-CA1 GBR-treated mice to two classical object-recognition paradigms that rely on spontaneous novelty detection, the NORT and the OPRT that are recommended tasks to screen for memory impairments in animal models of schizophrenia [3]. ...
Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.
... In rodents, long-term spatial memory and novelty detection rely on hippocampus function 10,11 and are strongly modulated by mesohippocampal connections and hippocampal dopamine receptors [12][13][14] . Dopamine acts on two classes of G-protein coupled receptors, D1-like -D1/D5 -and D2-like -D2/D3/D4 -that have distinct downstream signaling pathways 15 . ...
... The dopaminergic mesohippocampal pathway is strongly implicated in novelty detection 10,11 . Both D1Rs and D2Rs in the hippocampus have been shown to modulate synaptic plasticity occurring during novelty exploration and the consolidation of novel spatial representations in mice [12][13][14] . We submitted ventral-CA1 GBR-treated mice to two classical objectrecognition paradigms that rely on spontaneous novelty detection, the NORT and the OPRT that are recommended tasks to screen for memory impairments in animal models of schizophrenia 3 . ...
Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.
... Surprise, produced by expectation violation, has been shown to engage hippocampal encoding (Axmacher et al., 2010;Kafkas and Montaldi, 2015;Long et al., 2016;Frank et al., 2020b), which together with the midbrain dopaminergic system (Lisman and Grace, 2005;Shohamy and Wagner, 2008;Kafkas and Montaldi, 2018a) and enhanced perceptual processing (Stoppel et al., 2009;Hawco and Lepage, 2014;Kafkas andMontaldi, 2014, 2015), supports adaptive memory formation. Evidence for this adaptive mechanism comes mostly from paradigms in which expectation violation takes place before or during learning (Li et al., 2003;Garrido et al., 2015;Long et al., 2016;Greve et al., 2017;Kafkas, 2021). Therefore, any additional resources diverted toward encoding in these scenarios is likely to boost later memory performance (e.g., attention effects, see Aly and Turk-Browne, 2017). ...
... Taken together, these findings suggest that a surprise-driven increased weight on bottom-up inputs is goal-independent, but its mnemonic consequences appear to depend on the task at hand. During learning or exploration, further encoding supports later memory for the unexpected event (Li et al., 2003;Garrido et al., 2015;Long et al., 2016;Greve et al., 2017;Frank and Kafkas, 2021). When retrieval is the goal (as in the current paradigm), the implicit shift toward encoding, despite increased perceptual processing, results in numerically worse memory performance for the current to-be-retrieved information (Duncan et al., 2012;Kim et al., 2014). ...
To efficiently process information, the brain shifts between encoding and retrieval states, prioritizing bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI, we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events' expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected similar events also triggered occipital engagement; however, this did not enhance memory performance. Taken together, our findings suggest that when the goal is to retrieve, encountering surprising events engages an encoding mechanism, supported by bottom-up processing, that may enhance memory for future related events.SIGNIFICANCE STATEMENTOptimizing the balance between new learning and the retrieval of existing knowledge is an ongoing process, at the core of human cognition. Previous research into memory encoding suggests experiencing surprise leads to the prioritization of the leaning of new memories, forming an adaptive encoding mechanism. We examined whether this mechanism is also engaged when the current goal is to retrieve information. Our results demonstrate that an expectation-driven shift toward an encoding state, supported by enhanced perceptual processing, is beneficial for the correct identification of subsequent expected similar events. These findings have important implications for our understanding of the temporal dynamics of the adaptive encoding of information into memory.
... In sharp contrast, the bulk of animal studies support the idea that novelty has a significant impact on several physiological correlates of memory processes (Lisman & Grace, 2005;Lisman, Grace & Duzel, 2011). Electrophysiological and molecular changes have been shown to occur in the hippocampi of rats placed in novel environments: for example, a study has revealed an increase in the inducibility and the longevity of long-term potentiation (LTP) in the dentate gyrus (Davis, Jones & Derrick, 2004;, while another experiment has demonstrated a dopamine-receptor dependent increase in the inducibility of LTP in the CA1 region of the hippocampus (Li, Cullen, Anwyl & Rowan, 2003). These studies used behaviorally relevant stimuli, as the animals were placed in a novel environment, which reliably elicits engagement, or in other words, exploration. ...
... These studies used behaviorally relevant stimuli, as the animals were placed in a novel environment, which reliably elicits engagement, or in other words, exploration. More importantly, these experiments were never repeated with the same animals (Li et al., 2003;Straube, Korz, Balschun & Frey, 2003), ensuring the novelty factor of the manipulations, which is in strong contrast with studies done with humans that tend to utilize repetitive experimental procedures. ...
Novelty is defined as the part of an experience that is not yet represented by memory systems. Novelty has been claimed to exert various memory‐enhancing effects. A pioneering study by Wittmann et al. (2007) has shown that memory formation may even benefit from the expectation of novelty. We aimed to replicate this assumed memory effect in four behavioral studies. However, our results do not support the idea that anticipated novel stimuli are more memorable than unexpected novelty. In our experiments, we systematically manipulated the novelty predicting cues to ensure that the expectations were correctly formed by the participants, however, the results showed that there was no memory enhancement for expected novel pictures in any of the examined indices, thus we could not replicate the main behavioral finding of Wittmann et al. (2007). These results call into question the original effect, and we argue that this fits more into current thinking on memory formation and brain function in general. Our results are more consistent with the view that unexpected stimuli are more likely to be retained by memory systems. Predictive coding theory suggests that unexpected stimuli are prioritized by the nervous system and this may also benefit memory processes. Novel stimuli may be unexpected and thus recognized better in some experimental setups, yet novelty and unexpectedness do not always coincide. We hope that our work can bring more consistency in the literature on novelty, as educational methods in general could also benefit from this clarification.
... processing, dopamine release in hippocampus has been implicated in stabilizing place 60 fields (Kentros et al., 2004), gating the increase in plasticity in dorsal CA1 synapses by 61 novel experiences (Li et al., 2003), and improving memory retention via increasing 62 ...
Sequenced reactivations of hippocampal neurons called replays, concomitant with sharp-wave ripples in the local field potential, are critical for the consolidation of episodic memory, but whether replays depend on the brain's reward or novelty signals is unknown. Here we combined chemogenetic silencing of dopamine neurons in ventral tegmental area (VTA) and simultaneous electrophysiological recordings in dorsal hippocampal CA1, in freely behaving rats experiencing changes to reward magnitude and environmental novelty. Surprisingly, VTA silencing did not prevent ripple increases where reward was increased, but caused dramatic, aberrant ripple increases where reward was unchanged. These increases were associated with increased reverse-ordered replays. On familiar tracks this effect disappeared, and ripples tracked reward prediction error, indicating that non-VTA reward signals were sufficient to direct replay. Our results reveal a novel dependence of hippocampal replay on dopamine, and a role for a VTA-independent reward prediction error signal that is reliable only in familiar environments.
... DA plays a role in mediating this process by influencing the prioritization and integration of memories related to surprising, unexpected events within the hippocampus [9]. This modulation occurs through the activation of D1-type receptors in the hippocampus, ultimately inducing long-term potentiation (LTP), a form of synaptic plasticity [9], [93], [94]. ...
Creativity and memory are intertwined: memory accesses existing knowledge, while
creativity enhances it. Recent evidence links memory enhancement with insight or
"Aha!" moments, often accompanying creative solutions. Behavioral studies have
shown that solutions with accompanied insight are better remembered later.
While neuroscientific evidence regarding this insight memory advantage (IMA)
remains limited, we propose three underlying mechanisms: a noradrenergic arousal
circuitry involving the amygdala, dopaminergic reward-prediction pathways in
SN/VTA, ventral striatum and hippocampus, and efficient integration of novel
information into existing schemas mediated by medial prefrontal cortex.
These mechanisms likely synergistically enable rapid learning with insights.
Understanding the neural basis of the IMA holds implications for education and
problem-solving strategies. Further research is essential for leveraging this IMA in
practical contexts.
... Further, this positive increase in neuroplasticity is not limited to the time of exposure to new information but can extend to events occurring within a certain period afterward (Moncada et al., 2015). The positive effects of novelty on memory are well known, and animal studies have shown that spatial novelty may trigger the dopaminergic mesolimbic system and promote the release of dopamine in the hippocampus, with longer-lasting effects on motivation, reward processing, learning, and memory for tens of minutes (Li et al., 2003;Straube et al., 2003). With the development of technology, virtual reality can easily control for spatial novelty and familiarity. ...
Background: The retrieval–extinction paradigm based on memory reconsolidation can prevent fear memory recurrence more effectively than the extinction paradigm. High-intensity fear memories tend to resist reconso- lidation. Novelty–retrieval–extinction can promote the reconsolidation of fear memory lacking neuroplasticity in rodents; however, whether it could effectively promote high-intensity fear memory reconsolidation in humans remains unclear.
Methods: Using 120 human participants, we implemented the use of the environment (novel vs. familiar) with the help of virtual reality technology. Novelty environment exploration was combined with retrieval–extinction in fear memory of two intensity levels (normal vs. high) to examine whether novelty facilitates the reconsolidation of high-intensity fear memory and prevents recurrence. Skin conductance responses were used to clarify nov- elty–retrieval–extinction effects at the behavioral level across three experiments.
Results: Retrieval–extinction could prevent the reinstatement of normal-intensity fear memory; however, for high-intensity fear memory, only the novelty–retrieval–extinction could prevent recurrence; we further validated that novelty–retrieval–extinction may be effective only when the environment is novel.
Limitations: Although the high-intensity fear memory is higher than normal-intensity in this study, it may be insufficient relative to fear experienced in real-world contexts or by individuals with mental disorders. Conclusions: To some extent, these findings indicate that the novelty–retrieval–extinction paradigm could prevent the recurrence of high-intensity fear memory, and we infer that novelty of environment may play an important role in novelty–retrieval–extinction paradigm. The results of this study have positive implications for the existing retrieval extinction paradigm and the clinical treatment of phobia.
... Far less is understood about dopamine's roles outside of the striatum, where lower dopamine levels make accurate measurement difficult. Numerous studies have found that dopamine is necessary for hippocampal-dependent learning, perhaps by stabilizing long-term plasticity or memory consolidation [7][8][9] . However, the exact role dopamine plays is unclear since crucial information is missing: when and where is dopamine released in the hippocampus? ...
Numerous studies have identified dopamine signaling in the hippocampus as necessary for certain types of learning and memory. Since dopamine in the striatum is strongly tied to rewards, dopamine in the hippocampus is thought to reinforce reward learning. Despite the critical influence of dopamine on hippocampal function, little is known about dopamine release in the hippocampus or the specific ways dopamine can influence hippocampal function. Based on the functional complexity of hippocampal circuitry, we hypothesized the existence of multiple dopamine signaling domains. Using optical dopamine sensors, two-photon imaging, and head-fixed behaviors, we identified two functionally and spatially distinct dopamine domains in the hippocampus. The "superficial" domain (cell somata and apical dendrites) showed reward-related dopamine transients early in Pavlovian conditioning but were replaced by "deep" domain transients (basal dendritic layer) with experience. These two domains also play distinct roles in a hippocampal-dependent, goal-directed virtual reality task where mice use exploratory licks to discover the location of a hidden reward zone. Here, positive dopamine ramps appeared in the superficial domain as mice approached the reward zone, similar to those seen in the striatum. At the same time, the deep domain showed strong reward-related transients. These results reveal small-scale, anatomically segregated, dopamine domains in the hippocampus. Furthermore dopamine domain activity had temporal-specificity for different phases of behavior. Finally, the subcellular scale of dopamine domains suggests specialized postsynaptic pathways for processing and integrating functionally distinct dopaminergic influences.
... The theoretical layout of the SMMA model aligns more closely with the concept of salience modulating learning, by weighting the reward prediction-error learning/updating signals (Keiflin & Janak, 2015;Schultz et al., 1997;Steinberg, Keiflin, Boivin, Witten, Deisseroth et al., 2013). This learning interpretation fits well with data suggesting that dopamine modulates neural plasticity by facilitating late long-term potentiation and may increase addictive behaviours through these long term learning and memory mechanisms (Berke & Hyman, 2000;Hyman, 2005;Li, Cullen, Anwyl, & Rowan, 2003;Lisman, Grace, & Duzel, 2011;Mockett, Brooks, Tate, & Abraham, 2004;Sajikumar & Frey, 2004). However, there is a strong possibility that the salience factor in the current model is also playing a role in motivation/performance. ...
Dysfunction in learning and motivational systems are thought to contribute to addictive behaviours. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviours through pharmacological manipulations that provide excess dopaminergic signalling towards these learning and motivational systems. Redish 2004 suggested a role based on dopaminergic signals of value prediction error, while Zhang et al. 2009 suggested a role based on dopaminergic signals of motivation. However, both models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviours, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviours. Here, we propose a novel mathematical definition of salience, that combines aspects of dopamine’s role in both learning and motivation within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviours that the Zhang et al. 2009 and Redish 2004 models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviours and aspects of behavioural/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviours by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.
... Habituation, which is defined as the gradual weakening of behavioral reactions to recurrent harmless or weak stimuli, is one of the key categories of biological learning mechanisms [17,18]. Since habituation allows for filtering out redundant information and thereby emphasize the important one, it would offer an effective mechanism for many cognitive tasks such as disease or cancer findings [18][19][20]. The non-linear characteristics and programmability of memristor circuits have enabled significant advancements in the implementation of artificial intelligence, medical diagnosis and screening [21][22][23]. ...
Lung cancer screening is critical to the diagnosis and treatment of patients. Today, computed tomography (CT) scanning technology provides a promising approach for the screening of lung cancer. Nevertheless, the redundant information in CT images often limits the efficiency and accuracy of screening. The biological sensory nervous system has an important mechanism for screening out redundant information, namely habituation. Here, we designed a second-order memristor model with habituation characteristics. Some of the habituation behavior of the memristor model has been demonstrated with LTspice simulation. Furthermore, the habituation memristor model is incorporated in a volatile memristor based leaky integrate and fire (LIF) neuron circuit to construct a simple neural system. The simulation results indicate that the neural system exhibits reliable habituation behaviors. Finally, lung cancer screening tasks have been implemented based on the neural system with habituation behavior. The habituation memristor circuit serves as a data preprocessing layer that filters out relevant information from lung cancer images. The results indicate that the performance and accuracy of lung cancer screening performance are noticeably better than the neural system without habituation behavior. This work provides a new idea for lung cancer screening implementation.
... 49 Further, exposure to novelty induces mesolimbic dopaminergic neuron activation 55 which, in turn, can elicit dopamine-dependent LTP in the HIP via D1-like receptors. 56 Additionally, activation of D1-like receptors using the agonist SKF81297 infused into the PFC has been shown to enhance HIP-PFC LTP. 57 This modulation of HIP-PFC circuits by D1-like receptors has been previously shown to play a crucial role in the working memory in rats. ...
Introduction
The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase‐3 (GSK‐3β), processes integral to cognitive function.
Materials and Methods
Using an adeno‐associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK‐3β, a downstream effector of the D5R, was evaluated.
Results
AAV‐mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC‐OFC coherence, reduced PFC‐thalamus gamma coherence, and increased PFC GSK‐3β activity.
Conclusion
This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK‐3β activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK‐3β.
... Tonic firing under low-frequency stimulation can only activate D2-like receptors with relatively high affinity, whereas phasic firing under high-frequency stimulation can transiently activate D1-like receptors with low affinity (Edelmann and Lessmann 2018). Activation of D1-like receptors has been found to promote enhanced synaptic glutamatergic transmission of LTP in the CA1 region of the rat hippocampus (Li et al. 2003). In conclusion, dopamine acts as a hippocampal neurotransmitter that binds to D1-and D2-like receptors and regulates synaptic plasticity involved in depression-related mood. ...
Post-stroke depression (PSD), a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, PSD treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to PSD; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases, and neurotransmitters influence depressive behavior by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in PSD by summarizing recent research and analyzing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and PSD helps to better understand the pathological process of PSD and improve its treatment.
... ;https://doi.org/10.1101https://doi.org/10. /2023 learning interpretation fits well with data suggesting that dopamine modulates neural plasticity by facilitating late long-term potentiation and may increase addictive behaviors through these long term learning and memory mechanisms (Berke & Hyman, 2000;Hyman, 2005;Li et al., 2003;Lisman et al., 2011;Mockett et al., 2004;Sajikumar & Frey, 2004). However, there is a strong possibility that the salience factor in the current model is also playing a role in motivation/performance. ...
Dysfunction in learning and motivational systems are thought to contribute to addictive behaviors. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviors through pharmacological manipulations that provide excess dopaminergic signaling towards these learning and motivational systems. Redish 2004 suggested a role based on dopaminergic signals of value prediction error, while Zhang et al. 2009 suggested a role based on dopaminergic signals of motivation. Both these models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviors, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviors. Here, we propose a novel mathematical definition of salience, that combines aspects of dopaminergic function in both, learning and motivation, within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviors that the Zhang et al. 2009 and Redish 2004 models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviors and aspects of behavioral/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviors by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.
... Recent investigations have shown that LC modulation can induce modest LTP in the hippocampus after HFS or optogenetic stimulation of LC somata (81,82). Additionally, DA and NA levels in the CA1 region could modify LTP induced by HFS (83,84). Similarly, administration of catecholaminergic agonists or antagonists increases or decreases LTP, respectively (45,(85)(86)(87). ...
Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating.
... dopamine transmission in many structures in the brain including the prefrontal cortex, hippocampus and nucleus accumbens. Dopamine released during novelty can facilitate the induction of LTP induced by HFS in CA1(Li et al. 2003) and render a short lasting weakly triggered E-LTP into a long lasting L-LTP through D1/5 receptors(Lemon and Manahan- Vaughan 2006), a result that was replicated in different hippocampal structures and using different technics Manahan-Vaughan 2012, 2016;Takeuchi et al. 2016;Wagatsuma et al. 2017). ...
The hippocampus is the main brain structure involved in episodic memory formation. The role of the hippocampus in learning, memory and their underlying mechanisms has been studied extensively in rodents, in particular by using contextual learning. Long-Term Potentiation (LTP) is an increase in synaptic transmission of glutamatergic afferents that lasts for hours, days or months and is thought to underlie hippocampal memory formation. It can be triggered in the hippocampus by an artificial High frequency Stimulation (HFS). This mechanism helped in deciphering memory mechanisms, showing that both memory and LTP rely firstly on phosphorylation and later on de novo protein synthesis. The link between memory and LTP was confirmed by showing that blocking LTP mechanisms hinders memory formation, and that contextual learning induces LTP in the CA1 of the hippocampus. Since LTP, just like memory, can be saturated, the nervous system cannot store every sensory input that the animal encounters. Moreover, HFS is not compatible with neuronal activity. Hence, there must be a teaching signal that would be the natural molecular trigger of LTP during learning, acting as a filter choosing the pertinent inputs to store. Dopamine is a neuromodulator that has historically been thought of as a value signal, for dopamine gets released during rewarding events. However, dopamine has later been shown to be released whenever a salient unrewarding, or even punishing, event occurs. Dopamine receptors can trigger both phosphorylation and de novo protein formation in most brain structures showing plasticity, and D1/5 Dopaminergic receptors are necessary for LTP maintenance and long-term memory. Moreover, dopaminergic stimulation in vitro can modulate synaptic transmission in CA1. Thus, we hypothesized that dopamine could act as a teaching signal. In this work, we use behavior and electrophysiology coupled with optogenetic manipulations of midbrain dopamine afferents and pharmacology inhibition of D1/5 dopaminergic receptors in order to study the role of dopamine as a teaching signal triggering LTP so that pertinent sensory inputs get stored. Using electrophysiology, we show that coupling optogenetic stimulations of midbrain dopamine with glutamatergic inputs in CA1 induces a progressive LTP that reaches its plateau 90 minutes after the pairing. This LTP endures at least 5 hours, is dependent on D1/5 receptors and partially occludes HFS-triggered LTP. Then, using contextual fear conditioning coupled with auditory cue conditioning we show that intraperitoneal injection of D1/5 receptor inhibitor, SHC23390, hinders both contextual and cue fear memories. Alternatively, intra-hippocampal infusion of SCH23390 blocks contextual memory but preserves cue fear memory intact. These results allowed us to conclude that hippocampal D1/5 receptors are necessary for contextual fear memories and in another brain structure for associative fear memories. Finally, we use a variation of contextual fear conditioning called contextual pre-exposure facilitation effect, which separates contextual learning from fear conditioning since the animal in this task learns each of them on two consecutive days. This allows studying dopamine as a teaching signal without the interference of any value inputs. We show that mice require between 2-8 minutes to encode contextual information. Furthermore, we show that D1/5 receptors are necessary for contextual and fear learning. Finally, we show that optogenetic stimulation of dopaminergic axons in the hippocampus promotes contextual learning and, conversely, their inhibition hinders contextual learning. [...]
... It is unclear how, or whether, such meta-plastic changes would translate to metabolic demand, and thus changes in univariate BOLD activity during encoding. However, neuromodulation by dopamine can also alter the physiological properties of the hippocampus 1,8,9 . We reasoned that while an fMRI analytical approach cannot provide evidence about meta-plastic changes not reflected in BOLD, it is well-suited to detect modulatory influences that establish a distributed state across the hippocampus conducive to memory formation, including the convergence state we hypothesized. ...
The hippocampus has been a focus of memory research since H.M’s surgery abolished his ability to form new memories, yet its mechanistic role in memory remains debated. Here, we identify a candidate memory mechanism: an anticipatory hippocampal “convergence state”, observed while awaiting valuable information, and which predicts subsequent learning. During fMRI, participants viewed trivia questions eliciting high or low curiosity, followed seconds later by its answer. We reasoned that encoding success requires a confluence of conditions, so that hippocampal states more conducive to memory formation should converge in state space. To operationalize convergence of neural states, we quantified the typicality of multivoxel patterns in the medial temporal lobes during anticipation and encoding of trivia answers. We found that the typicality of anticipatory hippocampal patterns increased during high curiosity. Crucially, anticipatory hippocampal pattern typicality increased with dopaminergic midbrain activation and uniquely accounted for the association between midbrain activation and subsequent recall. We propose that hippocampal convergence states may complete a cascade from motivation and midbrain activation to memory enhancement, and may be a general predictor of memory formation.
... LTP and LTD are the cellular mechanisms that enable the storage of this kind of information [88][89][90]93,179,180]. Numerous studies have described the specific kinds of spatial information encoded by LTP and LTD, whereby a differentiation of the relative elements of spatial memory enabled by LTP and LTD has become evident. For example, LTP is expressed in response to the de novo acquisition of knowledge about a novel spatial environment [88,93,[180][181][182][183][184][185], whereas LTD is facilitated upon the acquisition, or updating, of knowledge about discrete content features of an environment [4,[88][89][90]180,[186][187][188][189]. All hippocampal subfields reportedly show the same LTP-specific stimulus response related to novel spatial learning [88,180,186]. ...
The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (> 24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.
... It is known that neuromodulators must be present for successful memory formation [28][29][30] as well as for initial memory consolidation (synaptic consolidation), for which there is a time window of up to hours in which neuromodulation has an effect [31][32][33][34][35][36] . Neuromodulator signals can even retroactively affect a memory trace in the minutes to hours after the related event took place 27,[37][38][39][40] . Thus, the effect of selective neuromodulation on consolidation makes it an ideal candidate for retroactively changing the neural representation of an experience. ...
Events that are important to an individual’s life trigger neuromodulator release in brain areas responsible for cognitive and behavioral function. While it is well known that the presence of neuromodulators such as dopamine and norepinephrine is required for memory consolidation, the impact of neuromodulator concentration is, however, less understood. In a recurrent spiking neural network model featuring neuromodulator-dependent synaptic tagging and capture, we study how synaptic memory consolidation depends on the amount of neuromodulator present in the minutes to hours after learning. We find that the storage of rate-based and spike timing-based information is controlled by the level of neuromodulation. Specifically, we find better recall of temporal information for high levels of neuromodulation, while we find better recall of rate-coded spatial patterns for lower neuromodulation, mediated by the selection of different groups of synapses for consolidation. Hence, our results indicate that in minutes to hours after learning, the level of neuromodulation may alter the process of synaptic consolidation to ultimately control which type of information becomes consolidated in the recurrent neural network.
... Indeed, application of D1 receptor agonist to the PfC increased attention [19]. When attention is attracted to a new spatial environment, LTP is induced in the hippocampal CA1 field, which depends on the activation of D1/D5 receptors [20]. In turn, an increase in activity of CA1 pyramidal cells should lead to a rise in the efficacy of connections between the hippocampus and PfC through the thalamic nucleus reuniens, which is reciprocally connected with both structures (Fig. 2). ...
A hypothetical mechanism for processing and awareness of sensory information is proposed. According to this mechanism, attention is an integral part of sensory processing and is implemented into the same neural network. Direction of voluntary attention to a stimulus is caused by activation of the prefrontal cortex that evokes dopamine release and subsequent dopamine-dependent long-term reorganizations of the efficacy of synaptic transmission between different elements of the neural network, which consists of topographically connected areas of the neocortex, hippocampus, basal ganglia, thalamus and cerebellum. These reorganizations result in disinhibition of thalamic cells by the output basal ganglia nuclei and subsequent increase in firing of their targets neurons in the neocortex, hippocampus and cerebellum, thereby facilitating activity circulation and re-excitation of cortical areas required for the conscious perception of stimulus. Due to the similarity of the functional organization of networks involved in the processing of stimuli of different sensory modalities, the mechanisms of their processing and inclusion of voluntary attention into this processing should be of the same type. The proposed mechanism differs from the known theory of visual attention and consciousness in the global workspace which is limited by cortico-cortical and cortical-pulvinar interactions.
KeywordsVoluntary attentionSynaptic plasticityDopamineConscious perceptionInattentional blindness
... Such developmental changes in mesolimbic system function have been linked to adolescents' increased risky, impulsive, and effortful behaviors in response to rewards (Galván, 2013;Luna et al., 2015;Doremus-Fitzwater and Spear, 2016). Given the central role of dopamine-dependent plasticity and VTA functional connectivity in adult memory formation (Huang and Kandel, 1995;Li et al., 2003;Morris et al., 2003;Duncan et al., 2014;Tompary et al., 2015), nonlinear developmental changes in mesolimbic system function may lead to more robust reward-related memory during adolescence. ...
Reward motivation enhances memory through interactions between mesolimbic, hippocampal, and cortical systems - both during and after encoding. Developmental changes in these distributed neural circuits may lead to age-related differences in reward-motivated memory and the underlying neural mechanisms. Converging evidence from cross-species studies suggests that subcortical dopamine signaling is increased during adolescence, which may lead to stronger memory representations of rewarding, relative to mundane, events and changes in the contributions of underlying subcortical and cortical brain mechanisms across age. Here, we used fMRI to examine how reward motivation influences the "online" encoding and "offline" post-encoding brain mechanisms that support long-term associative memory from childhood to adulthood in human participants of both sexes. We found that reward motivation led to both age-invariant enhancements and nonlinear age-related differences in associative memory after 24 hours. Furthermore, reward-related memory benefits were linked to age-varying neural mechanisms. During encoding, interactions between the prefrontal cortex and ventral tegmental area (VTA) were associated with better high-reward memory to a greater degree with increasing age. Pre- to post-encoding changes in functional connectivity between the anterior hippocampus and VTA were also associated with better high-reward memory, but more so at younger ages. Our findings suggest that there may be developmental differences in the contributions of offline subcortical and online cortical brain mechanisms supporting reward-motivated memory.SIGNIFICANCE STATEMENTA substantial body of research has examined the neural mechanisms through which reward influences memory formation in adults. However, despite extensive evidence that both reward processing and associative memory undergo dynamic change across development, few studies have examined age-related changes in these processes. We found both age-invariant and nonlinear age-related differences in reward-motivated memory. Moreover, our findings point to developmental differences in the processes through which reward modulates the prioritization of information in long-term memory - with greater early reliance on offline subcortical consolidation mechanisms and increased contribution of systems-level online encoding circuitry with increasing age. These results highlight dynamic developmental changes in the cognitive and neural mechanisms through which motivationally salient information is prioritized in memory from childhood to adulthood.
... One explanation may be that the dopaminergic tone generated by VTA neurons that innervate the hippocampus (Gasbarri et al., 1997), which is also very rich in dopaminergic receptors (see Eagle et al., 2015;Kempadoo et al., 2016), is stronger in RHA than RLA rats, as already proposed and extensively discussed for other limbic areas (Acb and mPFC) of the two rat lines. In line with this explanation (i) dopamine from the VTA may regulate the induction of ΔFosB providing a message to hippocampal neurons that relate to the salience and novelty of events (Lisman & Grace, 2005), (ii) dopamine enhances plasticity in CA1 pyramidal neurons (Li et al., 2003) and mediates network-level activity and memory persistence (McNamara et al., 2014), and (iii) the higher mesocorticolimbic dopaminergic tone of RHA versus RLA rats has been already considered responsible of F I G U R E 7 Regional distribution (a-x, a 1 -r 1 ) and densitometric analysis (y-b 0 , s 1 -u 1 ) of changes induced by sexual activity in the Arc-like immunoreactivity (LI) in coronal sections of the dorsal and ventral hippocampus of male RHA and RLA rats under control (Ctrl) (no copulation), sexually naïve (Naïve) (after the first copulatory test), and experienced (Exp) (after five copulatory tests) conditions. (a-f, a 1 -f 1 ) CA1 sector; (g-l) CA2 sector; (m-r, g 1 -l 1 ) CA3 sector of the Ammon's horn; (s-x, m 1 -r 1 ) dentate gyrus (DG). ...
Sexual activity causes differential changes in the expression of markers of neural activation (c‐Fos and ΔFosB) and neural plasticity (Arc and BDNF/trkB), as determined either by Western Blot (BDNF, trkB, Arc, and ΔFosB) or immunohistochemistry (BDNF, trkB, Arc, and c‐Fos), in the hippocampus of male Roman high (RHA) and low avoidance (RLA) rats, two psychogenetically selected rat lines that display marked differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). Both methods showed (with some differences) that sexual activity modifies the expression levels of these markers in the hippocampus of Roman rats depending on: (i) the level of sexual experience, that is, changes were usually more evident in sexually naïve than in experienced rats; (ii) the hippocampal partition, that is, BDNF and Arc increased in the dorsal but tended to decrease in the ventral hippocampus; (iii) the marker considered, that is, in sexually experienced animals BDNF, c‐Fos, and Arc levels were similar to those of controls, while ΔFosB levels increased; and (iv) the rat line, that is, changes were usually larger in RHA than RLA rats. These findings resemble those of early studies in RHA and RLA rats showing that sexual activity influences the expression of these markers in the nucleus accumbens, medial prefrontal cortex, and ventral tegmental area, and show for the first time that also in the hippocampus sexual activity induces neural activation and plasticity, events that occur mainly during the first phase of the acquisition of sexual experience and depend on the genotypic/phenotypic characteristics of the animals.
... In fact, findings support that brief exposure to a novel environment reduces the threshold to induce longterm potentiation. This facilitatory effect occurs for a short period of time following novelty exposure and depends on the activation of D1-like receptors but is absent in animals that explore a familiar environment (Li et al., 2003). Moreover, it has been demonstrated that aversive stimuli selectively modify synapses on dopaminergic neurons that project to cortical areas (Lammel et al., 2011). ...
Taste memory involves storing information through plasticity changes in the neural network of taste, including the insular cortex (IC) and ventral tegmental area (VTA), a critical provider of dopamine. Although a VTA-IC dopaminergic pathway has been demonstrated, its role to consolidate taste recognition memory remains poorly understood. We found that photostimulation of dopaminergic neurons in the VTA or VTA-IC dopaminergic terminals of TH-Cre mice improves the salience to consolidate a subthreshold novel taste stimulus regardless of its hedonic value, without altering their taste palatability. Importantly, the inhibition of the D1-like receptor into the IC impairs the salience to facilitate consolidation of an aversive taste recognition memory. Finally, our results showed that VTA photostimulation improves the salience to consolidate a conditioned taste aversion memory through the D1-like receptor into the IC. It is concluded that the dopamine activity from the VTA into IC is required to increase the salience enabling the consolidation of a taste recognition memory. Notably, the D1-like receptor activity into the IC is required to consolidate both innate and learned aversive taste memories but not appetitive taste memory.
... In animals, novelty exposure before and after the initial learning phase 58 drives memory performance via dopaminergic processes. [58][59][60][61] Therefore, enhanced subsequent recollection for expected versus unexpected novel images (Fig. 2) fits into a wide range of empirical work and provides further evidence to foster our theoretical understanding of novelty processing. ...
Novelty anticipation activates the mesolimbic system and promotes subsequent long‐term memory in younger adults. Importantly, mesolimbic structures typically degenerate with age, which might reduce positive effects of novelty anticipation. Here, we used electroencephalography in combination with an established paradigm in healthy young (19–33 years old, n = 28) and older (53–84, n = 27) humans. Colored cues predicted the subsequent presentation of either a novel or previously familiarized image (75% cue validity). On the subsequent day, recognition memory for the novel images was tested. Behaviorally, novelty anticipation improved recollection‐based but not familiarity‐based recognition memory in both groups, and this effect was more pronounced in older subjects. Furthermore, novelty and familiarity cues increased theta (4–8 Hz) and decreased alpha/beta power (9–20 Hz); at outcome, expected novel and familiar images both increased beta power (13–25 Hz). Finally, a subsequent memory effect for expected novel images was associated with increases in beta power independent of age. Together, novelty anticipation drives hippocampus‐dependent long‐term recognition memory across the life span, and this effect appears to be related to neural beta oscillations.
... Dopamine, for instance, which has a central behavioral and functional role in the primary motor cortex (Barnes et al., 2005;Dang et al., 2006), has been shown to modulate synapses through dendritic spine enlargement during a very narrow time window (Dang et al., 2006). It is behaviorally related to novelty and reward prediction (S. Li et al., 2003;Schultz, 2007) by gating neuroplasticity of corticostriatal (Reynolds, Hyland, and Wickens, 2001;Reynolds and Wickens, 2002) and ventral tegmental (VTA) synapses (Bao, Chan, and Merzenich, 2001). In the VTA, dopaminergic neurons respond to learning signals in a highly localized manner that is specific for local populations of neurons (Engelhard et al., 2019). ...
Spiking neural networks (SNNs) in neuromorphic systems are more energy efficient compared to deep learning-based methods, but there is no clear competitive learning algorithm for training such SNNs. Eligibility propagation (e-prop) offers an efficient and biologically plausible way to train competitive recurrent SNNs in low-power neuromorphic hardware. In this report, previous performance of e-prop on a speech classification task is reproduced, and the effects of including STDP-like behavior are analyzed. Including STDP to the ALIF neuron model improves the classification performance, but this is not the case for the Izhikevich e-prop neuron. Finally, it was found that e-prop implemented in a single-layer recurrent SNN consistently outperforms a multi-layer variant.
... In the hippocampus, genetic, and pharmacological evidence suggests that D1Rs play an important role in regulating longterm potentiation and specific forms of learning and memory (Huang and Kandel, 1995;Smith et al., 1998;El-Ghundi et al., 1999;Li et al., 2003;Hansen and Manahan-Vaughan, 2014). Although both D1R and D5R are present in the hippocampus, targeted deletion of the D1R but not D5R results in deficits in hippocampal LTP (Granado et al., 2008;Ortiz et al., 2010), contextual fear conditioning (Ortiz et al., 2010;Sariñana et al., 2014) and spatial learning (Granado et al., 2008;Ortiz et al., 2010;Sariñana and Tonegawa, 2016), therefore suggesting a predominant role for the D1R in these processes. ...
The dopamine D1 receptor (D1R) is a Gα s/olf -coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gα s or Gα olf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.
In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals – the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.
The ability to remember changes in the surroundings is fundamental for daily life. It has been proposed that novel events producing dopamine release in the hippocampal CA1 region could modulate spatial memory formation. However, the role of hippocampal dopamine increase on weak or strong spatial memories remains unclear. We show that male mice exploring two objects located in a familiar environment for 5 min created a short-term memory (weak) that cannot be retrieved 1 d later, whereas 10 min exploration created a long-term memory (strong) that can be retrieved 1 d later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval 1 d later but dopamine elevation during the encoding of strong OLMs promoted the preference for a familiar object location over a novel object location after 24 h. Moreover, dopamine uncaging after the encoding of OLMs did not have effect on weak memories whereas on strong memories diminished the exploration of the novel object location. Additionally, hippocampal dopamine elevation during the retrieval of OLMs did not allow the recovery of weak memories and did not affect the retrieval of strong memory traces. Finally, dopamine elevation increased hippocampal theta oscillations, indicating that dopamine promotes the recurrent activation of specific groups of neurons. Our experiments demonstrate that hippocampal dopaminergic modulation during the encoding of OLMs depends on memory strength indicating that hyperdopaminergic levels that enhance weak experiences could compromise the normal storage of strong memories.
Dopamine is a neurotransmitter that plays a crucial role in regulating diverse functions, such as motor control, mood, sleep, attention, reward systems, reinforcing behavior, and certain higher cognitive functions. Physiological and behavioral evidence indicates that dopamine receptor signaling has been shown to modulate hippocampus-dependent synaptic plasticity and learning and memory. Although the role of dopamine in regulating the hippocampus is well-established, the precise molecular and cellular mechanisms by which dopamine coordinates these processes in the hippocampus are not yet fully understood. This chapter presents a concise overview of dopaminergic neuromodulation required for the establishment of hippocampal late LTP (L-LTP) and its late-associative processes such as synaptic tagging and capture (STC) in CA1 pyramidal neurons. Additionally, the source of dopaminergic signals in the hippocampus and the mechanism by which dopamine neuromodulation induces the synthesis of plasticity-related proteins (PRPs) is detailed, along with its involvement in establishing STC.
Infancy is a critical period that shapes an individual’s emotional and developmental trajectory. Indeed, negative early life experiences have been suggested to form the foundation for later-life mental health function with many anxiety disorders having their onset during childhood or adolescence. Despite this, there are still many unanswered questions regarding how these early life experiences are retained. This is surprising given that, unlike adult animals, infants exhibit an impaired ability to form long-term memories. More recently, several studies have demonstrated that exposure to a novel environment may stabilize the persistence of weak memories, a phenomenon often attributed to a process referred to as behavioral tagging. While behavioral tagging processes have been repeatedly demonstrated in adult animals, few studies have examined whether it occurs in the developing animal, which is somewhat puzzling given the typically weak memory in the young. In this chapter, we explore whether behavioral tagging processes may also underlie the formation of long-term memories in infant animals. We also examine whether the processes underlying behavioral tagging in the adult animal may be similar in the developing animal.
One of the fundamental attributes of memory is the synaptic plasticity change that happens at the cellular level and thereby behavioral change at the system level. The discovery of spatially tuned cells such as place cells and grid cells involved in modulating spatial memory contributed to the comprehension of how the brain controls navigation. Research studies over the years have pointed to the understanding that the hippocampal-entorhinal system encodes much of it resulting in the formation of a cognitive/spatial map. Such a spatial map allows for representations of relations, in terms of the range and directions between locations and in discerning what exists where. This chapter discusses the relevance of behavioral tagging, wherein the formation of a neural tag as a result of a weak memory could possibly result in the formation of longer-lasting associative spatial memories by utilizing plasticity-related proteins orchestrated by spatially modulated cells. It also explores the possible mechanisms through which such an orchestration could be made possible through memory allocation, neuromodulation, metaplasticity, synaptic clustering and the like.
Memories are experience-dependent internal representations of the world that can last from short periods of time to a whole life. The formation of long-term memories relies on several biochemical changes, which inducing modifications in the synaptic efficiency change the way the neurons communicate each other. Interestingly, the formation of a lasting memory does not entirely depend on learning itself; different events occurring before or after a particular experience can affect its processing, impairing, improving or even inducing lasting memories. The overlapping of neuronal networks involved in the processing of different types of learning might explain why different experiences interact at neuronal level. However, how and where this does really happen is an issue of study.
In 1997, the Synaptic Tagging and Capture hypothesis provided a strong framework to explain how synaptic specificity can be achieved when inducing long-lasting changes in electrophysiological models of functional plasticity. Ten years later, an analogous argument was used in learning and memory models to postulate the Behavioral Tagging hypothesis. This framework provided solid explanation of how weak events, only capable of inducing transient forms of memories, can result in lasting memories when occurring in the context of other behaviorally relevant experiences. The hypothesis postulates that the formation of lasting memories rely on at least two parallel processes: (1) the setting of a learning tag that determines which memory could be stored and where and (2) the synthesis of plasticity-related proteins, which once captured at tagged sites will allow the consolidation of a memory for long periods of time. Therefore, a weak learning, only able to induce transient forms of memories but also capable of setting a learning tag, could be benefited from the proteins synthesized by a different strong event, processed in the same areas, by using them to consolidate its own lasting memory.
In this chapter, we detail the postulates and predictions of the Behavioral Tagging hypothesis. We review the bibliography covering the 15 years from the postulation of the hypothesis to deepen into the mechanisms associated with tag setting and the synthesis of proteins. And we discuss its implications on memory formation and its persistence.
Here, we review the basis of contextual memory at a conceptual and cellular level. We begin with an overview of the philosophical foundations of traversing space, followed by theories covering the material bases of contextual representations in the hippocampus (engrams), exploring functional characteristics of the cells and subfields within. Next, we explore various methodological approaches for investigating contextual memory engrams, emphasizing plasticity mechanisms. This leads us to discuss the role of neuromodulatory inputs in governing these dynamic changes. We then outline a recent hypothesis involving noradrenergic and dopaminergic projections from the locus coeruleus (LC) to different subregions of the hippocampus, in sculpting contextual representations, giving a brief description of the neuroanatomical and physiological properties of the LC. Finally, we examine how activity in the LC influences contextual memory processes through synaptic plasticity mechanisms to alter hippocampal engrams. Overall, we find that phasic activation of the LC plays an important role in promoting new learning and altering mnemonic processes at the behavioral and cellular level through the neuromodulatory influence of NE/DA in the hippocampus. These findings may provide insight into mechanisms of hippocampal remapping and memory updating, memory processes that are potentially dysregulated in certain psychiatric and neurodegenerative disorders.
Memory is essential in defining our identity by guiding behavior based on past experiences. However, aging leads to declining memory, disrupting older adult's lives. Memories are encoded through experience-dependent modifications of synaptic strength, which are regulated by the catecholamines dopamine and noradrenaline. While cognitive aging research demonstrates how dopaminergic neuromodulation from the substantia nigra-ventral tegmental area regulates hippocampal synaptic plasticity and memory, recent findings indicate that the noradrenergic locus coeruleus sends denser inputs to the hippocampus. The locus coeruleus produces dopamine as biosynthetic precursor of noradrenaline, and releases both to modulate hippocampal plasticity and memory. Crucially, the locus coeruleus is also the first site to accumulate Alzheimer's-related abnormal tau and severely degenerates with disease development. New in-vivo assessments of locus coeruleus integrity reveal associations with Alzheimer's markers and late-life memory impairments, which likely stem from impaired dopaminergic and noradrenergic neurotransmission. Bridging research across species, the reviewed findings suggest that degeneration of the locus coeruleus results in deficient dopaminergic and noradrenergic modulation of hippocampal plasticity and thus memory decline.
Post-stroke depression, a common complication after stroke, severely affects the recovery and quality of life of patients with stroke. Owing to its complex mechanisms, post-stroke depression treatment remains highly challenging. Hippocampal synaptic plasticity is one of the key factors leading to post-stroke depression; however, the precise molecular mechanisms remain unclear. Numerous studies have found that neurotrophic factors, protein kinases and neurotransmitters influence depressive behaviour by modulating hippocampal synaptic plasticity. This review further elaborates on the role of hippocampal synaptic plasticity in post-stroke depression by summarizing recent research and analysing possible molecular mechanisms. Evidence for the correlation between hippocampal mechanisms and post-stroke depression helps to better understand the pathological process of post-stroke depression and improve its treatment.
Events associated with aversive or rewarding outcomes are prioritized in memory. This memory boost is commonly attributed to the elicited affective response, closely linked to noradrenergic and dopaminergic modulation of hippocampal plasticity. Herein we review and compare this 'affect' mechanism to an additional, recently discovered, 'prediction' mechanism whereby memories are strengthened by the extent to which outcomes deviate from expectations, that is, by prediction errors (PEs). The mnemonic impact of PEs is separate from the affective outcome itself and has a distinct neural signature. While both routes enhance memory, these mechanisms are linked to different - and sometimes opposing - predictions for memory integration. We discuss new findings that highlight mechanisms by which emotional events strengthen, integrate, and segment memory.
Real-life behavioral tasks are often complex and depend on abstract combinations of sensory stimuli and internal logic. To successfully learn these tasks, animals must pair actions or decisions to the task's complex structure. The hippocampus has been shown to contain fields which represent complex environmental and task variables, including place, lap, evidence accumulation, etc. Altogether, these representations have been hypothesized to form a "cognitive map" which encodes the complex real-world structure underlying behavior. However, it is still unclear how biophysical plasticity mechanisms at the single-cell level can lead to the population-wide evolution of task-relevant maps. In this work we present a biophysically plausible model comprised of a recurrent hippocampal network and an action network, in which the latent representational structure co-evolves with behavior in a task-dependent manner. We demonstrate that the network develops latent structures that are needed for solving the task and does not integrate latent structures which do not support task learning. We show that, in agreement with experimental data, cue-dependent "splitters" can only be induced at the single-cell level if the task requires a split representation to solve. Finally, our model makes specific predictions on how biases in behavior result from experimentally testable biases in the underlying latent representation.
Via modulation of neuronal activity by cannabinoid receptor type-1 (CB1), the endocannabinoid system represents a major brain modulatory system controlling memory functions. On the other hand, several reports point out a crucial role of hippocampal dopamine signaling in the regulation of memory related processes. Furthermore, recent evidence suggests that hippocampal cells expressing dopamine receptors do also posses CB1 receptors.The work presented in this Thesis aims at establishing a functional connection between CB1 receptor and dopaminoceptive signaling in the regulation of hippocampal related memory processes with particular enfasis on the cellular and sub-cellular mechanisms involved.In the first part of the thesis we observed that a mouse line lacking CB1 in dopamine receptor type- 1 cells (D1-CB1-KO) displayed impaired long-term novel object recognition memory (NOR) and, interestingly, viral-mediated re-expression of CB1 in D1-positive cells in the hippocampus of D1-CB1- KO mice reversed the NOR impairment present in these mice. Furthermore, we pointed out execessive hippocampal GABAA receptor activation and impaired in vivo long-term potentiation (LTP) in the CA3-CA1 pathway as the main cellular mechanisms for memory impairment in D1-CB1- KO. Thus, we provided functional evidence for the involvement of a small subclass of type-1 cannabinoid receptor (CB1)-expressing hippocampal interneurons in the modulation of specific hippocampal circuits in memory processes.The second part of the Thesis focused on subcellular location of CB1 activation in D1 positive cells. Indeed, besides the canonical regulation of neuronal activity by plasma membrane CB1 receptor, recent evidence suggests the involvement of mitochondrial CB1 receptor (mtCB1) in the regulation of bioenergetic processes which impacts on synaptic transmission and amnesic effects of cannabinoids. We found that mtCB1 receptors in hippocampal D1-positive neurons is not required for physiological regulation of memory formation per se but its activation is required for THC- induced memory impairment. Looking for the intracellular and intra-mitochondrial G-protein signaling involved in these processes, we developed a new chemogenetic strategy which specifically modulates the mitochondrial G-protein signaling and we observed its contribution in brain mitochondrial activity and cognitive functions. Specific chemogenetic activation of mitochondrial G- protein signaling results in increased mitochondrial respiration which in turns rescues THC-induced amnesic effect.Overall, the results of this Thesis indicate the mechanisms linking the diversity of cellular and subcellular CB1 receptors in higher brain functions, including learning and memory and provide the basis for the development of more selective and precise therapeutic strategies for cognitive disorders.
Exploration of a novel environment has been shown to promote memory formation in healthy adults. Studies in animals have suggested that such novelty-induced memory boosts are mediated by hippocampal dopamine. The dopaminergic system is known to develop and deteriorate over the lifespan, but so far, the effects of novelty on memory across the lifespan have not yet been investigated. In the current study, we had children, adolescents, younger, and older adults (n = 439) explore novel and previously familiarized virtual environments to pinpoint the effects of spatial novelty on declarative memory in humans across different age groups. After exploration, words were presented while participants performed a deep or shallow encoding task. Incidental memory was quantified in a surprise test. Results showed that participants in the deep encoding condition remembered more words than those in the shallow condition, while novelty did not influence this effect. Interestingly, however, children, adolescents and younger adults benefitted from exploring a novel compared to a familiar environment as evidenced by better word recall, while these effects were absent in older adults. Our findings suggest that the beneficial effects of novelty on memory follow the deterioration of neural pathways involved in novelty-related processes across the lifespan.
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.
The experience of novelty can enhance memory for information that occurs close in time, even if not directly related to the experience – a phenomenon called “behavioural tagging”. For example, an animal exposed to a novel spatial environment shows improved memory for other information presented previously. This has been linked to neurochemical modulations induced by novelty, which affect consolidation of memories for experiences that were encoded around the same time. Neurophysiological research in animals has shown that novelty benefits weakly-encoded but not strongly-encoded information. However, a benefit that is selective to weak memories seems difficult to reconcile with studies in humans that have reported that novelty improves recollection, but not familiarity. One possibility is that the novelty increases activity in hippocampus, which is also associated with processes that enable recollection. This is consistent with another prediction of behavioural tagging theory, namely that novelty only enhances consolidation of information that converges on the same neuronal population. However, no study has directly explored the relationship between encoding strength and retrieval quality (recollection versus familiarity). We examined the effects of exposure to a novel immersive virtual reality environment on memory for words presented immediately beforehand, under either deep or shallow encoding tasks, and by testing both recall memory immediately, and recognition memory with remember/know instructions the next day. However, Bayes Factors showed no evidence to support the behavioural tagging predictions: that novelty would improve memory, particularly for shallowly-encoded words, and this improvement would differentially affect familiarity versus recollection.
A series of brief, high-frequency trains of electrical stimulation delivered to the perforant-path results in long-term potentiation (LTP) of the dentate gyrus as measured by average evoked potentials (EPs). Similar increases in dentate evoked potentials have been reported after natural learning. Previous studies of this behavioral LTP have not adequately controlled for ongoing behavior at the time of recording, even though motor activity also influences the amplitude of EPs. Chronically implanted rats were trained in both a radial-arm maze and an avoidance task using a crossover design. EPs in the dentate gyrus following perforant-path stimulation were recorded daily under 3 different behavioral conditions: immobility, movement, and freely behaving. After completion of both tasks, animals were given tetanizing stimulation of the perforant path. Results indicated strong improvements in the performance of both tasks. Tetanization induced significant LTP, which was still present at the end of 5 d. Significant differences were found between EPs collected during immobility and movement throughout the experiment. No evidence of behavioral LTP was observed, and the EPs remained consistent with baseline measures. These data show the necessity of controlling for ongoing behavior at the time of recording in electrophysiological studies of learning. The data also indicate that the phenomenon of behavioral LTP, as assessed by hippocampal EPs, is not universal to all learning experiences.
As an alternative approach to the study of hippocampal function in relation to behavior, the averaged evoked potentials (AEPs) evoked by electrical stimulation of the Schaffer collaterals (SCH), the alveus and the contralateral hippocampus were recorded at various depths in the hippocampal CA1 region of freely moving rats with chronically implanted electrodes. Significant correlations between AEPs, behavior and EEG were found. At one end of the continuum of AEPs were those recorded during large irregular activity (LIA), an EEG pattern associated with slow-wave sleep or awake-immobility. These AEPs had large early peak and low-amplitude late peaks. At the order end of the continuum, during high frequency theta EEG associated with behaviors such as walking, postural change or phasic paradoxical sleep. AEPs had a smaller early peak, increased later peak(s) and appeared oscillatory. The evoked population spike, a synchronous postsynaptic firing of CA1 neurons, was smaller during behaviors associated with theta than during those associated with LIA. It is postulated that a recurrent inhibitory circuit within the hippocampus can account for the change of the AEPs with EEG and behavior and with stimulus intensity. During theta EEG, the negative feedback may increase such that the evoked population excitatory postsynaptic potential and the evoked population spike decrease and ascillatory response is more readily elecited. The excitability state of hippocampal CA1 may be described by the negative feedback gain in this model.
Activity of single units of the noradrenergic nucleus locus coeruleus was recorded in rats during active exploration of a novel environment. Novelty was controlled by the placement of objects in given holes in a hole board. The basic protocol included a habituation session in which the holes were empty and an object session in which a novel object was placed in one of the two holes. During the habituation session, when the whole environment was unfamiliar, there was a phasic response the first time the rat visited any hole, which habituated after one visit. During the second session, when one of the holes contained an object, the cell fired when the rat encountered the novel object. There was no response to empty holes in this session. The neuronal response was markedly diminished or entirely absent on the second and subsequent visits to object-containing holes, indicative of rapid habituation. In some rats it was possible to run a second object session, when a new object was introduced into a previously empty hole. Visits to this hole elicited a robust response, which again habituated after one single visit. The results show that the responses of locus coeruleus to novelty or change, which has been demonstrated in formal learning situations, occurs in freely behaving rats while they are learning about a new environment. Moreover, the response to novelty and change in the environment is short-lived, rapidly habituating after one or two encounters with the stimulus.
The present investigation had two aims: (1) to study responses of dopamine neurons to stimuli with attentional and motivational significance during several steps of learning a behavioral task, and (2) to study the activity of dopamine neurons during the performance of cognitive tasks known to be impaired after lesions of these neurons. Monkeys that had previously learned a simple reaction time task were trained to perform a spatial delayed response task via two intermediate tasks. During the learning of each new task, a total of 25% of 76 dopamine neurons showed phasic responses to the delivery of primary liquid reward, whereas only 9% of 163 neurons responded to this event once task performance was established. This produced an average population response during but not after learning of each task. Reward responses during learning were significantly more numerous and pronounced in area A10, as compared to areas A8 and A9. Dopamine neurons also showed phasic responses to the two conditioned stimuli. These were the instruction cue, which was the first stimulus in each trial and indicated the target of the upcoming arm movement (58% of 76 neurons during and 44% of 163 neurons after learning), and the trigger stimulus, which was a conditioned incentive stimulus predicting reward and eliciting a saccadic eye movement and an arm reaching movement (38% of neurons during and 40% after learning). None of the dopamine neurons showed sustained activity in the delay between the instruction and trigger stimuli that would resemble the activity of neurons in dopamine terminal areas, such as the striatum and frontal cortex. Thus, dopamine neurons respond phasically to alerting external stimuli with behavioral significance whose detection is crucial for learning and performing delayed response tasks. The lack of sustained activity suggests that dopamine neurons do not encode representational processes, such as working memory, expectation of external stimuli or reward, or preparation of movement. Rather, dopamine neurons are involved with transient changes of impulse activity in basic attentional and motivational processes underlying learning and cognitive behavior.
Attempts to correlate behavioral learning with cellular changes, such as increased synaptic efficacy, have often relied on
increased extracellular potentials as an index of enhanced synaptic strength. A recent example is the enlarged excitatory
field potentials in the dentate gyrus of rats that are learning spatial relations by exploration. The altered hippocampal
field potentials do not reflect learning-specific cellular changes but result from a concomitant rise in brain temperature
that is caused by the associated muscular effort. Enhanced dentate field excitatory potentials followed both passive and active
heating and were linearly related to the brain temperature. These temperature-related effects may mask any learning-induced
changes in field potential.
Recent evidence showing that basal forebrain cholinergic neurons with projections to the frontal cortex and hippocampus are activated by behaviorally salient stimuli suggests that these neurons are involved in arousal and/or attentional processes. We sought in the present experiments to test this hypothesis by examining whether unconditioned stimuli (a tone and flashing light) that normally increase cortical nad hippocampal acetylcholine (ACh) release would fail to do so after habituation (i.e., repeated presentation with no programmed consequences). In addition, the extent to which presentation of these stimuli would continue to increase ACh release when they had previously been paired with an aversive stimulus was investigated. Three experimental groups were used: habituation, novel stimuli, and conditioned fear. Subjects in each of these groups were placed in a training apparatus for twelve 200 min sessions. While the habituation group received extensive exposure to the tone and light during the training sessions, subjects in the novel stimuli group were placed in the apparatus but were never exposed to the tone or light during these sessions. The conditioned fear group was treated identically to the habituation group, with the addition that the tone and light were paired with footshock. On completion of these training schedules, all animals were implanted with microdialysis probes in the frontal cortex and hippocampus. Two days later, they were placed in the apparatus and the tone and light were presented to all subjects during microdialysis. In the novel stimuli group, the tone and light (unconditioned stimuli) produced significant increases in frontal cortical and hippocampal ACh release. Similarly, in the conditioned fear group, presentation of the tone and light (conditioned stimuli) also significantly increased ACh release in frontal cortex and hippocampus. In contrast, in the habituation group the tone and light failed to significantly enhance ACh release in either structure. During the test session, the tone and light elicited a variety of arousal- and fear-related behaviors in the novel stimuli and conditioned fear groups. In contrast, subjects in the habituation group generally failed to respond to these stimuli. These data indicate that cortically and hippocampally projecting basal forebrain cholinergic neurons are activated by conditioned and unconditioned stimuli that produce arousal in rats (novelty or conditioned fear). In contrast, presentation of these stimuli to habituated animals fails to enhance ACh release. These findings are consistent with a growing body of information indicating that ACh release in the cortex and hippocampus is reliably activated by behaviorally relevant stimuli. They also provide strong support for the hypothesis that cholinergic neurons in the basal forebrain are involved in arousal and/or attentional processes.
Trains of action potentials in hippocampal pyramidal neurons are followed by a prolonged afterhyperpolarization (AHP) lasting several seconds, which is attributable to the activation of a slow calcium-activated potassium current ((sI)AHP). Here we examine the location of (sI)AHP on CA1 pyramidal neurons by comparing it with two GABAergic inhibitory postsynaptic currents (IPSCs) with known somatic and dendritic locations. Whole-cell patch-clamp recordings were made for CA1 pyramidal neurons in acute hippocampal slices. Stepping the membrane potential at the peak of (sI)AHP produced a relaxation ("switchoff") of the AHP current with a time constant of 7.4 +/- 0.4 msec (mean +/- SEM). The switchoff time constants for somatic and dendritic GABAA IPSCs were 3.5 +/- 0.5 msec and 8.8 +/- 0.3 msec, respectively. This data, together with cable modeling, indicates that active (sI)AHP channels are distributed over the proximal dendrites within approximately 200 micrometers of the soma. Excitatory postsynaptic potentials (EPSPs) evoked in stratum (s.) radiatum had their amplitudes shunted more by the AHP than did EPSPs evoked in s. oriens, suggesting that active AHP channels are restricted to the apical dendritic tree. Blockade of the AHP during a tetanus, which in control conditions elicited a decremental short-term potentiation (STP), converted STP to long-term potentiation (LTP). Thus, activation of the AHP increases the threshold for induction of LTP. These results suggest that in addition to its established role in spike frequency adaptation, the AHP works as an adjustable gain control, variably hyperpolarizing and shunting synaptic potentials arising in the apical dendrites.
The role of the mesolimbic dopaminergic system in the reinforcement of learning suggests that dopamine should be able to modulate activity-dependent synaptic plasticity. We have examined the effect of D1/D5 agonists on early long-term potentiation (LTP) (40 min) in the CA1 region of hippocampal slices. D1/D5 agonists (+)bromo-APB, 6-chloro-PB, and dihydrexidine increased the magnitude of LTP in a synapse-specific manner (by approximately 10, 15, and 20%, respectively). This D1/D5 effect was mimicked by a low dose (10 microM) of the adenylyl cyclase activator forskolin. The D1/D5 antagonist (+)SCH 23390 reduced early LTP. In catecholamine-depleted slices, LTP was smaller by approximately 20-25% and could not be decreased further by D1/D5 antagonist. Under these conditions, D1/D5 agonist 6-chloro-PB and forskolin produced a larger enhancement of LTP (20-25%), restoring it to the control level. At the same dose, dideoxyforskolin did not affect early LTP. The D1/D5 agonist effect was completely blocked by the D1/D5 antagonist (+)SCH 23390. These results indicate that dopamine produces a synapse-specific enhancement of early LTP through D1/D5 receptors and cAMP.
The induction of activity-dependent persistent increases in synaptic efficacy, such as long-term potentiation (LTP), is inhibited by behavioural stress. The question arises whether stress also affects the ability to induce persistent decreases in synaptic efficacy, such as long-term depression (LTD). We now report that the induction of stable homosynaptic LTD in the CA1 area of the hippocampus of awake adult rats is facilitated, rather than inhibited, by exposure to mild naturalistic stress. The same stress blocked the induction of LTP. The effects of such stress were short lasting: acclimatization to, or removal from, the conditions that facilitated LTD induction led to a rapid loss of the ability to elicit this form of plasticity. The time window in which LTD could be reliably elicited was prolonged by inducing anaesthesia immediately after the stress. These data reveal that even brief exposure to mild stress can produce a striking shift in the susceptibility to synaptic plasticity in the awake animal.
Experience-dependent long-lasting increases in excitatory synaptic transmission in the hippocampus are believed to underlie certain types of memory. Whereas stimulation of hippocampal pathways in freely moving rats can readily elicit a long-term potentiation (LTP) of transmission that may last for weeks, previous studies have failed to detect persistent increases in synaptic efficacy after hippocampus-mediated learning. As changes in synaptic efficacy are contingent on the history of plasticity at the synapses, we have examined the effect of experience-dependent hippocampal activation on transmission after the induction of LTP. We show that exploration of a new, non-stressful environment rapidly induces a complete and persistent reversal of the expression of high-frequency stimulation-induced early-phase LTP in the CA1 area of the hippocampus, without affecting baseline transmission in a control pathway. LTP expression is not affected by exploration of familiar environments. We found that spatial exploration affected LTP within a defined time window because neither the induction of LTP nor the maintenance of long-established LTP was blocked. The discovery of a novelty-induced reversal of LTP expression provides strong evidence that extensive long-lasting decreases in synaptic efficacy may act in tandem with enhancements at selected synapses to allow the detection and storage of new information by the hippocampus.
To study the physiological and molecular mechanisms of age-related memory loss, we assessed spatial memory in C57BL/B6 mice from different age cohorts and then measured in vitro the late phase of hippocampal long-term potentiation (L-LTP). Most young mice acquired the spatial task, whereas only a minority of aged mice did. Aged mice not only made significantly more errors but also exhibited greater individual differences. Slices from the hippocampus of aged mice exhibited significantly reduced L-LTP, and this was significantly and negatively correlated with errors in memory. Because L-LTP depends on cAMP activation, we examined whether drugs that enhanced cAMP would attenuate the L-LTP and memory defects. Both dopamine D1/D5 receptor agonists, which are positively coupled to adenylyl cyclase, and a cAMP phosphodiesterase inhibitor ameliorated the physiological as well as the memory defects, consistent with the idea that a cAMP-protein kinase A-dependent signaling pathway is defective in age-related spatial memory loss.
Homosynaptic long-term depression (LTD) consists of a persistent nonpathological decrease in synaptic transmission, which is induced by low-frequency stimulation. In vivo, low-frequency stimulation (1 Hz, 900 pulses) induces LTD in Wistar but not Hooded Lister rats. In this study, we investigated the influence of behavioral learning and behavioral state on the expression of LTD in both rat strains. Recordings were taken from freely moving animals that had undergone chronic implantation of a recording electrode in the hippocampal CA1 region and a bipolar stimulating electrode in the ipsilateral Schaffer collateral-commissural pathway. Exposure of the rat strains to stress induced a significant elevation in serum corticosterone levels but did not facilitate LTD expression. However, LFS given during exploration of a novel environment resulted in LTD expression in Hooded Lister, and LTD enhancement in Wistar, rats. Reexposure to the same environment did not result in new expression of LTD. Behavioral comparison between the first and second environmental exposure confirmed that the animals had habituated to the novel environment. These observations strongly implicate an association between novelty acquisition and LTD.
While it has previously been assumed that mesolimbic dopamine neurons carry a reward signal, recent data from single-unit, microdialysis and voltammetry studies suggest that these neurons respond to a large category of salient and arousing events, including appetitive, aversive, high intensity, and novel stimuli. Elevations in dopamine release within mesolimbic, mesocortical and nigrostriatal target sites coincide with arousal, and the increase in dopamine activity within target sites modulates a number of behavioral functions. However, because dopamine neurons respond to a category of salient events that extend beyond that of reward stimuli, dopamine levels are not likely to code for the reward value of encountered events. The paper (i) examines evidence showing that dopamine neurons respond to salient and arousing change in environmental conditions, regardless of the motivational valence of that change, and (ii) asks how this might shape our thinking about the role of dopamine systems in goal-directed behavior.
Long-term potentiation (LTP) has several different phases, and there is general agreement that the late phase of LTP requires the activation of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). In contrast, several studies indicate that the early LTP is not affected by interfering with the cAMP pathway. We have further tested the role of the cAMP pathway in early LTP using several types of inhibitors. Bath application of the PKA inhibitor H89 suppressed the early LTP induced by a single tetanus. Similarly, the LTP induced by a pairing protocol was decreased by postsynaptic intracellular perfusion of the peptide PKA inhibitor PKI(6-22) amide. The decrease of LTP produced by these inhibitors was evident immediately after induction. These results indicate that PKA is important in early LTP, that its locus of action is postsynaptic, and that it does not act merely by enhancing the depolarization required for LTP induction. The failure of some other inhibitors of the cAMP pathway to affect the early phase of LTP might be attributable to the saturation of some step in the cAMP pathway during a tetanus. In agreement with this hypothesis we found that application of the AC inhibitor SQ 22536 by itself did not affect the early phase of LTP, but did produce a reduction if the cAMP pathway was already attenuated by the PKA inhibitor H89. Our analysis of the results of genetic modifications of the cAMP pathway, especially the work on AC knock-outs, indicates that the genetic data are generally consistent with the pharmacological results showing the importance of this pathway in early LTP.
Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.
Associative learning is thought to depend on detecting mismatches between actual and expected experiences. With functional magnetic resonance imaging (FMRI), we studied brain activity during different types of mismatch in a paradigm where contrasting-colored lights signaled the delivery of painful heat, nonpainful warmth, or no stimulation. When painful heat stimulation was unexpected, there was increased FMRI signal intensity in areas of the hippocampus, superior frontal gyrus, cerebellum, and superior parietal gyrus that was not found with mismatch between expectation and delivery of nonpainful warmth stimulation. When painful heat stimulation was unexpectedly omitted, the FMRI signal intensity decreased in the left superior parietal gyrus and increased in the other regions. These contrasting activation patterns correspond to two different mismatch concepts in theories of associative learning (Rescorla-Wagner, temporal difference vs. Pearce-Hall, Mackintosh). Searching for interventions to specifically modulate activation of these brain regions therefore offers an approach to identifying new treatments for chronic pain, which often has a substantial associative learning component.
Interactions between noradrenergic and cholinergic receptor signaling may be important in some forms of learning. To investigate whether noradrenergic and cholinergic receptor interactions regulate forms of synaptic plasticity thought to be involved in memory formation, we examined the effects of concurrent beta-adrenergic and cholinergic receptor activation on the induction of long-term potentiation (LTP) in the hippocampal CA1 region. Low concentrations of the beta-adrenergic receptor agonist isoproterenol (ISO) and the cholinergic receptor agonist carbachol had no effect on the induction of LTP by a brief train of 5 Hz stimulation when applied individually but dramatically facilitated LTP induction when coapplied. Although carbachol did not enhance ISO-induced increases in cAMP, coapplication of ISO and carbachol synergistically activated p42 mitogen-activated protein kinase (p42 MAPK). This suggests that concurrent beta-adrenergic and cholinergic receptor activation enhances LTP induction by activating MAPK and not by additive or synergistic effects on adenylyl cyclase. Consistent with this, blocking MAPK activation with MEK inhibitors suppressed the facilitation of LTP induction produced by concurrent beta-adrenergic and cholinergic receptor activation. Although MEK inhibitors also suppressed the induction of LTP by a stronger 5 Hz stimulation protocol that induced LTP in the absence of ISO and carbachol, they had no effect on LTP induced by high-frequency synaptic stimulation or low-frequency synaptic stimulation paired with postsynaptic depolarization. Our results indicate that MAPK activation has an important, modulatory role in the induction of LTP and suggest that coactivation of noradrenergic and cholinergic receptors regulates LTP induction via convergent effects on MAPK.
The Alzheimer's disease-related beta-amyloid precursor protein (beta-APP) is metabolized to a number of potentially amyloidogenic peptides that are believed to be pathogenic. Application of relatively low concentrations of the soluble forms of these peptides has previously been shown to block high-frequency stimulation-induced long-term potentiation (LTP) of glutamatergic transmission in the hippocampus. The present experiments examined how these peptides affect low-frequency stimulation-induced long-term depression (LTD) and the reversal of LTP (depotentiation). We discovered that beta-amyloid peptide (Abeta1-42) and the Abeta-containing C -terminus of beta-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus. The LTD was frequency- and NMDA receptor-dependent. Thus, although low-frequency stimulation alone was ineffective, after intracerebroventricular injection of Abeta1-42, it induced an LTD that was blocked by d-(-)-2-amino-5-phosphonopentanoic acid. Furthermore, an NMDA receptor-dependent depotentiation was induced in a time-dependent manner, being evoked by injection of CT 10 min, but not 1 hr, after LTP induction. These use- and time-dependent effects of the amyloidogenic peptides on synaptic plasticity promote long-lasting reductions in synaptic strength and oppose activity-dependent strengthening of transmission in the hippocampus. This will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.
Cocaine administration evokes cardiovascular responses that are variable in rats such that the pressor response is attributable to either a large increase in systemic vascular resistance and a decrease in cardiac output (vascular responders) or a smaller increase in systemic vascular resistance and no change or an increase in cardiac output (mixed responders). This study was designed to determine the role of central corticotropin releasing factor (CRF) and adrenergic receptors in mediating specific hemodynamic response patterns. Rats were instrumented for ascending aortic blood flow determination (cardiac output) using a pulsed Doppler system, arterial pressure measurement and for intravenous and intracerebroventricular (icv) administration of drugs. After characterizing the hemodynamic response pattern in individual rats to cocaine (5 mg/kg, i.v., 4-6 trials), selective receptor antagonists were administered icv 10 min before cocaine (5 mg/kg, i.v.). Pretreatment with the CRF antagonist alpha-helical CRF(9-41) (10 microg/5 microl, icv) prevented the decrease in cardiac output in vascular responders without altering hemodynamic responses to cocaine in mixed responders. Astressin (5 microg/5 microl, icv) exerted a similar effect in vascular responders. The alpha(2) receptor antagonist, yohimbine (3 microg/microl, icv) also prevented the decrease in cardiac output in vascular responders. Lower doses of alpha-helical CRF(9-41) (1 and 3 microg) were ineffective whereas higher doses of either CRF antagonist were lethal within 24 h. In contrast, propranolol (3 or 30 microg, icv) pretreatment enhanced the cocaine-induced decrease in cardiac output and increase in systemic vascular resistance noted in vascular responders and resulted in a decrease in cardiac output in mixed responders. We conclude that CRF and adrenoceptors in the CNS play an important role in determining the hemodynamic response pattern to cocaine. Furthermore, central beta-adrenoceptors may be responsible for the reported effects of intravenous propranolol on cocaine-induced responses.
The basolateral amygdala (BLA) can influence distinct learning and memory formation. Hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation, can be modulated by stimulation of the BLA in its induction and early maintenance. However, it is not known how the late maintenance of LTP beyond its initial phases might be affected. Behavioral stimuli have been shown to result in a reinforcement of a transient early-LTP into a lasting potentiation. Here we show that BLA stimulation mimics the behavioral effects on early-LTP in freely moving rats when the BLA is activated within a time window of 30 min before or after tetanization of the perforant path. The reinforcement of LTP was blocked by inhibitors of muscarinergic and beta-adrenergic but not dopaminergic receptors and was dependent on translation. Through these heterosynaptic associative interactions, hippocampal sensory information can be stabilized by amygdaloidal influences.
N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity in the mammalian hippocampus is essential for learning and memory. Although computational models and anatomical studies have emphasized functional differences among hippocampal subregions, subregional specificity of NMDA receptor function is largely unknown. Here we present evidence that NMDA receptors in CA3 are required in a situation in which spatial representation needs to be reorganized, whereas the NMDA receptors in CA1 and/or the dentate gyrus are more involved in acquiring memory that needs to be retrieved after a delay period exceeding a short-term range. Our data, with data from CA1-specific knockout mice, suggest the possibility of heterogeneous mnemonic function of NMDA receptors in different subregions of the hippocampus.
One of the molecular events associated with contextual long-term memory (LTM) formation is the induction of cyclic AMP response element (CRE)-mediated transcription¹. Here we report that activation of NMDA receptors and of extracellular signal–regulated kinase (ERK) were necessary for stimulation of CRE-mediated transcription during contextual fear conditioning. In addition, we found that inhibition of CRE-regulated transcription during learning blocked LTM, which indicates that this transcriptional activity is critical for memory formation.
Long-term potentiation (LTP) is widely regarded as a memory mechanism, but it is not known whether it can last long enough to underlie very long-term memory. We report that high-frequency stimulation (HFS) paradigms applied to the rat dentate gyrus can elicit stable LTP lasting months and up to at least 1 year. The induction of stable LTP was sensitive to stimulation variables on the day of HFS and was associated with phosphorylation of cAMP response element-binding protein. The maintenance of stable LTP was also experience-dependent, because it was reversed when animals were exposed repeatedly to an enriched environment beginning 14 d post-HFS. However, stable LTP eventually consolidated over time and became resistant to reversal, because exposure to enriched environments 90 d post-HFS failed to influence stable LTP maintenance. Thus, LTP can be shown to meet one of the principal criteria for a very long-term memory storage mechanism. However, under naturalistic environmental conditions, LTP may normally be retained in the hippocampus for only short periods of time.
Activity of single units of the noradrenergic nucleus locus coeruleus was recorded in rats during active exploration of a novel environment. Novelty was controlled by the placement of objects in given holes in a hole board. The basic protocol included a habituation session in which the holes were empty and an object session in which a novel object was placed in one of the two holes. During the habituation session, when the whole environment was unfamiliar, there was a phasic response the first time the rat visited any hole, which habituated after one visit. During the second session, when one of the holes contained an object, the cell fired when the rat encountered the novel object. There was no response to empty holes in this session. The neuronal response was markedly diminished or entirely absent on the second and subsequent visits to object-containing holes, indicative of rapid habituation. In some rats it was possible to run a second object session, when a new object was introduced into a previously empty hole. Visits to this hole elicited a robust response, which again habituated after one single visit. The results show that the responses of locus coeruleus to novelty or change, which has been demonstrated in formal learning situations, occurs in freely behaving rats while they are learning about a new environment. Moreover, the response to novelty and change in the environment is short-lived, rapidly habituating after one or two encounters with the stimulus.
The fact that medial temporal lobe structures, including the hippocampus, are critical for declarative memory is firmly established by now. The understanding of the role that these structures play in declarative memory, however, despite great efforts spent in the quest, has eluded investigators so far. Given the existing scenario, novel ideas that hold the promise of clarifying matters should be eagerly sought. One such idea was recently proposed by Vargha-Khadem and her colleagues on the basis of their study of three young people suffering from anterograde amnesia caused by early-onset hippocampal pathology. The idea is that the hippocampus is necessary for remembering ongoing life's experiences (episodic memory), but not necessary for the acquisition of factual knowledge (semantic memory). We discuss the reasons why this novel proposal makes good sense and why it and its ramifications should be vigorously pursued. We review and compare declarative and episodic theories of amnesia, and argue that the findings reported by Vargha-Khadem and her colleagues fit well into an episodic theory that retains components already publicized, and adds new ones suggested by the Vargha-Khadem et al. study. Existing components of this theory include the idea that acquisition of factual knowledge can occur independently of episodic memory, and the idea that in anterograde amnesia it is quite possible for episodic memory to be more severely impaired than semantic memory. We suggest a realignment of organization of memory such that declarative memory is defined in terms of features and properties that are common to both episodic and semantic memory. The organization of memory thus modified gives greater precision to the Vargha-Khadem et al. neuroanatomical model in which declarative memory depends on perihippocampal cortical regions but not on the hippocampus, whereas episodic memory, which is separate from declarative memory, depends on the hippocampus.
The effect of the dopamine system on the induction of long-term potentiation (LTP) in the dentate gyrus was studied in anesthetized rats. A subthreshold tetanic train (seven pulses at 100 Hz) given to the perforant pathway, which usually fails to elicit LTP, potentiated a slope of field excitatory postsynaptic potentiation (fEPSP) measured from the hilus of the dentate gyrus when a precursor for catecholamine, L-3,4-dihydroxyphenylalanine (L-DOPA), was administered orally to rats. The increase in the fEPSP slope persisted for at least 60 min. Intraventricular injection of a specific dopamine D1/D5 agonist, SKF38393, mimicked the effect of L-DOPA, suggesting an involvement of D1/D5 receptors in the induction of dentate gyrus LTP. Consistent with this, intraventricular administration of the D1/D5 antagonist SCH23390 resulted in complete inhibition of LTP induction by a longer tetanus (100 pulses at 100 Hz), which usually elicits a robust LTP. Thus, D1/D5 receptor activation appears to modulate LTP induction in vivo.
Hippocampal principal neurons—‘place cells’–exhibit location-specific firing. Recent work addresses the link between place cell activity and hippocampal memory function. New tasks that challenge spatial memory allow recording from single neurons, as well as ensembles of neurons, during memory computations, and insights into the cellular mechanisms of spatial memory are beginning to emerge.
Certain kinds of learning may be related to potentiation of transmission at specific hippocampal synapses. We investigated whether transmission across the perforant-path/granule-cell synapses of the dentate gyrus is facilitated when rats are learning about novel objects in an open field during exploration. Such studies are complicated by the sensitivity of hippocampal field potentials to brain temperature change. To control for this, we have recorded both brain temperature and field potentials and compared potentials sampled during exploration with potentials taken at corresponding brain temperature in a passive warming situation, with the animals at rest. Relative to these reference potentials, both the f-EPSP slope and the population spike were elevated while the rats explored. The potentiation reached its maximum within < 5 sec after the exploration began. During the first 2 min, the f-EPSP slope was enhanced by 6.5% relative to the control values. The potentiation then decayed, reaching the reference values after 20-30 min of exploration. Significant potentiation required exploration above a certain minimum intensity. Control experiments showed that the changes were neither mimicked by arousal in response to aversive stimuli nor by motor activity. It is suggested that the facilitated transmission across the perforant-path/dentate synapses may be involved in learning during exploration.
The effect of dopaminergic D1 receptor blockade on the expression of long-term potentiation (LTP) was investigated in the rat hippocampal CA1 region in vitro by extracellular recordings (by measuring the population spike amplitude and the field EPSP). The presence of the very selective D1 receptor blocker SCH 23390 at a concentration of 0.1 microM during tetanization with 3 trains of 100 impulses (100 Hz) resulted in a prevention of late LTP stages (greater than 1-2 h). When SCH 23390 was added to the bath medium immediately after tetanization, an influence on established LTP could not be observed during the first 3 h investigated.
Review of the normally occurring neuronal patterns of the hippocampus suggests that the two principal cell types of the hippocampus, the pyramidal neurons and granule cells, are maximally active during different behaviors. Granule cells reach their highest discharge rates during theta-concurrent exploratory activities, while population synchrony of pyramidal cells is maximum during immobility, consummatory behaviors, and slow wave sleep associated with field sharp waves. Sharp waves reflect the summed postsynaptic depolarization of large numbers of pyramidal cells in the CA1 and subiculum as a consequence of synchronous discharge of bursting CA3 pyramidal neurons. The trigger for the population burst in the CA3 region is the temporary release from subcortical tonic inhibition.
1. The after‐effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro‐electrodes in rabbits anaesthetized with urethane.
2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant path volleys was potentiated for periods ranging from 30 min to 10 hr after one or more conditioning trains at 10–20/sec for 10–15 sec, or 100/sec for 3–4 sec.
3. The population response was analysed in terms of three parameters: the amplitude of the population excitatory post‐synaptic potential (e.p.s.p.), signalling the depolarization of the granule cells, and the amplitude and latency of the population spike, signalling the discharge of the granule cells.
4. All three parameters were potentiated in 29% of the experiments; in other experiments in which long term changes occurred, potentiation was confined to one or two of the three parameters. A reduction in the latency of the population spike was the commonest sign of potentiation, occurring in 57% of all experiments. The amplitude of the population e.p.s.p. was increased in 43%, and of the population spike in 40%, of all experiments.
5. During conditioning at 10–20/sec there was massive potentiation of the population spike (‘frequency potentiation’). The spike was suppressed during stimulation at 100/sec. Both frequencies produced long‐term potentiation.
6. The results suggest that two independent mechanisms are responsible for long‐lasting potentiation: ( a ) an increase in the efficiency of synaptic transmission at the perforant path synapses; ( b ) an increase in the excitability of the granule cell population.
Hippocampal long-term potentiation (LTP) is thought to serve as an elementary mechanism for the establishment of certain forms of explicit memory in the mammalian brain. As is the case with behavioral memory, LTP in the CA1 region has stages: a short-term early potentiation lasting 1 to 3 hours, which is independent of protein synthesis, precedes a later, longer lasting stage (L-LTP), which requires protein synthesis. Inhibitors of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) blocked L-LTP, and analogs of cAMP induced a potentiation that blocked naturally induced L-LTP. The action of the cAMP analog was blocked by inhibitors of protein synthesis. Thus, activation of PKA may be a component of the mechanism that generates L-LTP.
The possible modulation by D1 drugs of learning abilities of a population of aged memory-impaired animals was investigated in the present study. The level of D1/[3H]SCH 23390 receptors was first examined by quantitative autoradiography to ascertain if cognitive deficits seen in these animals could be related to alterations in the levels of these receptors. No significant differences in [3H]SCH 23390 binding were observed in any of the brain areas examined between young, and aged memory-unimpaired and aged memory-impaired animals. However, the cognitive deficits of the aged-impaired rats were modulated by D1 drugs. The D1 agonists SKF 38393 and SKF 81297 (3.0 mg/kg, i.p.) significantly reduced the latency period to find a hidden platform in the Morris Water Maze, reflecting improved cognitive functions, while the D1 antagonist SCH 23390 (0.05 mg/kg, i.p.) had no overall significant effect. Moreover, the D1 agonist SKF 38393 increased, whereas the antagonist inhibited, in vivo hippocampal acetylcholine release. Taken together, these results suggest that functional hippocampal acetylcholine-dopamine interactions exist in aged memory-impaired rats. More importantly, the cognitive deficits seen in the aged-impaired rats can be attenuated by stimulations of D1 receptors, hence suggesting an alternative approach to alleviate the cognitive deficits seen in the aged brain.
The hippocampal formation has long been thought to play a role in learning and memory. Previous studies from our laboratory examined the organization of mesencephalic projections to the hippocampal formation in the rat. In order to evaluate the effects on learning and memory of retrograde selective lesions of mesencephalic dopaminergic neurons, following bilateral injection of 6-hydroxydopamine in the dorsal and ventral subiculum and adjacent CA1 field of the hippocampal formation, young adult Sprague-Dawley rats were trained in classical inhibitory avoidance, inhibitory avoidance using a multiple trial (training to criterion) and the standard Morris water maze task (cued and spatial versions). With regard to inhibitory avoidance, retention was examined one, three and 10 days after training. Concerning the Morris water maze task, 6-hydroxydopamine-lesioned and sham-operated rats received four training trials on each of four days. After training sessions, the rats were tested during a 60-s probe trial (free-swim trial) in which the platform was removed from the maze. The loss of mesencephalic dopaminergic neurons in the 6-hydroxydopamine-lesioned rats, compared to sham-operated rats, was verified by tyrosine hydroxylase immunohistochemistry. Although the 6-hydroxydopamine-lesioned rats were indistinguishable from sham-operated rats in performing the inhibitory avoidance and the cued version of the Morris water maze task, in the spatial version of the Morris water maze, lesioned rats, compared to controls, exhibited significant differences in the latency (P < 0.05), quadrant time (P < 0.01) and number of platform crossings (P < 0.05). These results suggest that the rat's ability to acquire spatial learning and memory for place navigation in the Morris water maze is likely to be dependent also on the integrity of mesohippocampal dopaminergic connections.
Current theories on the encoding and storage of information in the brain commonly suppose that a short-term memory is converted into a lasting one; thus, it becomes consolidated over time. Within a finite period after training, such a short-term memory can be reinforced by behavioral and humoral stimuli. We have found that, long-term potentiation (LTP), a likely candidate for a memory-encoding mechanism at the cellular level, displays similar features. LTP in the dentate gyrus of freely moving rats was reinforced after its induction by appetitive and aversive stimuli. The efficacy of these stimuli terminates about 1 h after tetanization, which may reflect the time constants of the mechanisms underlying the consolidation that takes place. The reinforcement by appetitive and aversive stimulation was blocked by the beta-adrenergic antagonist propranolol, implicating norepinephrine in the underlying cellular processes.
Novelty detection is a fundamental capacity of all mammalian nervous systems /64/. The ability to orient to unexpected events is critical for both survival and normal memory function /82/. The mechanisms whereby the brain detects and responds to novelty have become of increasing interest to neuroscientists. A review is provided of human electrophysiological and blood flow data focused on delineating the neural systems engaged by novelty. Electrophysiological recording of event-related potentials (ERPs) has shown that novel stimuli activate a distributed network involving prefrontal and posterior association cortex as well as the hippocampus /4,23,24,32,33,36,86,88/. Activation of this network facilitates subsequent memory for novel events /27/. Neural modeling provides additional support for a prominent role of novelty in normal memory function /43/. Blood flow studies employing PET and fMRI have also begun to define the neural regions activated by novelty. The blood flow data provide converging evidence on the role of the hippocampus and cortical association regions in the processing of novelty /30,66,75,76/. The results of the behavioral, ERP and blood flow research confirm that a distributed neocortical-limbic circuit is activated by stimulus novelty. These distributed circuits maintain a template of the recent past /74/. Deviations from the template activate a neocortical-limbic network facilitating behavioral response to and memory storage of novel events.
We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta-adrenergic receptor antagonist propranolol on the persistence of long-term potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In slices, SCH-23390 but not propranolol reduced the persistence of long-term potentiation in area CA1 without affecting its induction. The drugs exerted reverse effects in the dentate gyrus, although in this case the induction of long-term potentiation was also affected by propranolol. The lack of effect of SCH-23390 on the induction and maintenance of long-term potentiation in the dentate gyrus was confirmed in awake animals. The drug also had little or no effect on the expression of inducible transcription factors. In area CA1 of awake animals, SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming the results in slices. To rule out a differential release of catecholamines induced by our stimulation protocols between brain areas, we compared the effects of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on the persistence of a weakly induced, decremental long-term potentiation in CA1 slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392 facilitated the induction of long-term potentiation. These data demonstrate that there is a double dissociation of the catecholamine modulation of long-term potentiation between CA1 and the dentate gyrus, suggesting that long-term potentiation in these brain areas may be differentially consolidated according to the animal's behavioural state.
Certain kinds of learning may be related to potentiation of transmission at specific hippocampal synapses. We investigated whether transmission across the perforant-path/granule-cell synapses of the dentate gyrus is facilitated when rats are learning about novel objects in an open field during exploration. Such studies are complicated by the sensitivity of hippocampal field potentials to brain temperature change. To control for this, we have recorded both brain temperature and field potentials and compared potentials sampled during exploration with potentials taken at corresponding brain temperature in a passive warming situation, with the animals at rest. Relative to these reference potentials, both the f-EPSP slope and the population spike were elevated while the rats explored. The potentiation reached its maximum within < 5 sec after the exploration began. During the first 2 min, the f-EPSP slope was enhanced by 6.5% relative to the control values. The potentiation then decayed, reaching the reference values after 20-30 min of exploration. Significant potentiation required exploration above a certain minimum intensity. Control experiments showed that the changes were neither mimicked by arousal in response to aversive stimuli nor by motor activity. It is suggested that the facilitated transmission across the perforant-path/dentate synapses may be involved in learning during exploration.
In vivo release of dopamine (DA) and noradrenaline (NA) in mouse medial prefrontal cortex, medial striatum and hippocampus was characterized using in vivo microdialysis. Basal release of NA was similar in these areas, but DA in striatum was 13-30 times higher than in other areas. Unconditioned stimuli (handling, novelty) induced strong increases, except for striatal DA. Striatal NA was more sensitive to handling than NA in other areas.
Hippocampal depotentiation comprises a reversal of tetanization- induced long-term potentiation (LTP) which occurs following low-frequency stimulation. In the CA1 region, it has been reported that agonist activation of D1/D5 dopamine receptors enhances LTP expression and inhibits depotentiation. The role of these receptors in synaptic plasticity in the dentate gyrus (DG) has not been characterized. This study therefore investigated the role of D1/D5 receptors in LTP and depotentiation in the DG of freely moving rats. Male Wistar rats underwent chronic implantation of a recording electrode in the DG granule cell layer, a bipolar stimulating electrode in the medial perforant path and a cannula in the ipsilateral cerebral ventricle (to enable drug administration). The D1/D5 agonist Chloro-PB dose-dependently inhibited depotentation in the DG. This effect was prevented by the D1/D5 antagonist SCH 23390. Neither D1/D5 agonist nor antagonist had an effect on LTP expression or basal synaptic transmission. These results highlight differences between D1/D5 receptor-involvement in LTP and depotentiation in the CA1 region and DG, and indicate that whereas D1/D5 receptor activation may not be a critical factor in LTP induction in the DG, a differential role for these receptors in the expression of depotentiation, in this hippocampal subfield, may exist.
Processing of multimodal sensory information by the morphological subdivisions of the hippocampus and its input and output structures was investigated in unanesthetized rabbits by extracellular recording of neuronal activity. Analysis shows principal differences between CA3 neurons with uniform multimodal, mainly inhibitory, rapidly habituating sensory responses, and CA1‐subicular neurons, substantial parts of which have phasic reactions and patterned on‐responses, depending on the characteristics of the stimuli. These differences result from the organization of the afferent inputs to CA1 and CA3. Analysis of neuronal responses in sources of hippocampal inputs, their electrical stimulation, and chronic disconnection show the greater functional significance of the brain‐stem reticular input for tonic responses characteristic of CA3. This input signal before entering the hippocampus is additionally preprocessed at the MS‐DB relay, where it becomes more uniform and frequency‐modulated in the range of theta‐rhythm. It is shown that the new sensory stimuli produce inhibitory reset, after which synchronized theta‐modulation is triggered. Other stimuli, appearing at the background of the ongoing theta, do not evoke any responses of the hippocampal neurons. Thus, theta‐modulation can be regarded as a mechanism of attention, which prolongs response to a selected stimulus and simultaneously protects its processing against interference.
The cortical input of the hippocampus introduces highly differentiated information analyzed at the highest levels of the neocortex through the intermediary of the entorhinal cortex and presubiculum. However, only CA1‐subiculum receives this information directly; before its entrance into CA3, it is additionally preprocessed at the FD relay, where the secondary simplification of signals occurs. As a result, CA3 receives by its two inputs (MS‐DB and FD) messages just about the presence and level of input signals in each of them, and performs relatively simple functions of determination of match/mismatch of their weights. For this comparator system, the presence of signal only in the reticulo‐septal input is equivalent to quality of novelty. The cortical signal appears with some delay, after its analysis in the neocortex and shaping in the prehippocampal structures; besides, it is gradually increased due to LTP‐like incremental changes in PP and mossy fiber synapses. The CA3 neurons with potentiated synapses of cortical input do not respond to sensory stimuli; that is, the increased efficacy of the cortical signals can be regarded as “familiarity” of a signal, terminating the reactive state of the CA3 neurons. The integrity of both inputs is necessary for gradual habituation of sensory responses in the hippocampus.
The output signals of CA3 following in the precommissural fornix to the output relay‐LS nucleus and to the brain‐stem structures have strong regulatory influence on the level of brain activity (arousal), which is an important condition for processing and registration of information. The primary targets of this output signal are raphe nuclei, which suppress activity of the ascending excitatory RF. In the background state, activity of the CA3 neurons through the intermediary of raphe keeps RF under tonic inhibitory control. Inhibition of the majority of CA3 pyramidal neurons during a novel stimulus action decreases the volume of its output signal to raphe and releases RF from tonic inhibition (increase in level of activity of the forebrain, arousal). When the responses of CA3 neurons habituate, the initial high background activity is reinstated, as well as tonic suppression of RF. Analysis of the second output of CA3 (by Schaffer's collaterals to CA1) shows that activity in this pathway can block access of cortical signals from PP to CA1 neurons by action upon the local system of inhibitory neurons, or by shunting the propagation of signals in apical dendrites. Thus, CA3 can act as a filter controlling the information transmission by CA1; such transmission at any given moment is allowed only in those CA1 neurons which receive SC from CA3 neurons, responding to the sensory stimulus by suppression of their activity. Disconnection of the CA3 output fibers results in disappearance of habituation in all its target structures (raphe, RF, CA1).
The output signal of CA1‐subiculum follows by postcommissural fornix to the chain of structures of the main limbic circuit: mammillary bodies (medial nucleus), anterior thalamic nuclei (mainly antero‐ventral nucleus), and cingulate limbic cortex (mainly posterior area). In each of these links, the signal is additionally processed. Habituation is nearly absent in these structures; instead, strong incremental dynamics are observed. Various types of reaction shaping, often with changes in level and structure of background activity, are observed in them. Within this output circuit, the farther is the output structure from the hippocampus, the more repetitions of stimulus are required for shaping the sensory response. That is why this system is regarded as a chain of integrators, where each one starts to respond only after reaction develops at the previous link, and as a delay line, preventing premature fixation of spurious, irrelevant, low probability signals. The responses in the higher link of this system, the posterior limbic cortex, may be regarded as the ultimate signal for information fixation in the nonprimary areas of the neocortex. In this way, the two morpho‐functional circuits, regulatory (based on CA3) and informational (based on CA1), perform the unified functions of attention and initial stages of memory trace fixation. Hippocampus 2001;11:578–598. © 2001 Wiley‐Liss, Inc.
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 the expectations generated by sequence recall. One possible site for computing mismatch is CA1, since it receives predictions from CA3 and sensory "reality" via the perforant path. Our data suggest that disruption of this comparison would be expected under conditions of dopamine hyperfunction or NMDA hypofunction. Also relevant is the fact that the VTA, which fires in response to novelty, may both depend on hippocampal-dependent novelty detection processes and, in turn, affect hippocampal function. Through large-scale modeling that considers both the processes performed by the hippocampus and the neuromodulatory loops in which the hippocampus is embedded, it is becoming possible to generate working hypotheses that relate synaptic function and malfunction to behavior.
CREB is critical for long-lasting synaptic and behavioral plasticity in invertebrates. Its role in the mammalian hippocampus is less clear. We have interfered with CREB family transcription factors in region CA1 of the dorsal hippocampus. This impairs learning in the Morris water maze, which specifically requires the dorsal hippocampus, but not context conditioning, which does not. The deficit is specific to long-term memory, as shown in an object recognition task. Several forms of late-phase LTP are normal, but forskolin-induced and dopamine-regulated potentiation are disrupted. These experiments represent the first targeting of the dorsal hippocampus in genetically modified mice and confirm a role for CREB in hippocampus-dependent learning. Nevertheless, they suggest that some experimental forms of plasticity bypass the requirement for CREB.
The contribution that components of the hippocampal system in the rat make to the modulation of attention or stimulus processing was assessed using several simple behavioural assays: the orienting response (OR) to a novel stimulus, the subsequent habituation and dishabituation of this OR, and the latent inhibition effect that typically results from repeated exposure to a stimulus. Excitotoxic lesions of components of the hippocampal system produce dissociable effects on the OR, habituation and latent inhibition: lesions of the entorhinal cortex have no effect on the OR or changes in the OR during exposure to a stimulus, but disrupt latent inhibition; lesions of the subiculum disrupt the OR but not latent inhibition; and lesions of the hippocampus disrupt the OR and latent inhibition. These effects have important implications for our understanding of habituation and latent inhibition, and the neural mechanisms involved in attentional modulation.
Different medial temporal lobe structures are involved in memory for different types of novel cues and novel relationships among familiar cues. We measured the behavior of rats with amygdala or hippocampal damage, when confronted with novelty in an incidental learning paradigm. We examined both direct and indirect measures of memory. Following habituation to an environment, proximal objects or distal cues were manipulated in several ways. We found that rats with hippocampal damage exhibited a deficit on direct measures of memory, but performed normally on all indirect measures. Rats with amygdala damage exhibited a deficit on a direct measure, and performed normally on an indirect measure, of memory for proximal object identity. Thus, the hippocampus may be necessary for success on direct measures of memory for distal cues and proximal objects and the relationships among them. Likewise, the amygdala may be necessary for success on some direct measures of memory, such as memory for aspects of proximal object identity. Neither the amygdala nor the hippocampus functions as a generalized novelty detection system. To the extent that we tap implicit and explicit knowledge using this paradigm, we suggest that in the rat, the amygdala and hippocampal systems are necessary for at least some types of explicit knowledge.
Novelty exploration reverses early phase of long-term potentiation in hippocampal CA1 region of freely behaving rats
- S Li
- R Anwyl
- M J Rowan
Li, S., Anwyl, R. & Rowan, M.J. Novelty exploration reverses early phase of long-term potentiation in hippocampal CA1 region of freely behaving rats. Irish J. Med. Sci. 171, 172 (2002).