Spatial Memory Encoding Research Articles

Spatial memory encoding is associated with the anterior and posterior hippocampus: An fMRI activation likelihood estimation meta-analysis.

It has been hypothesized that differential processing occurs along the longitudinal (anterior-posterior) axis of the hippocampus. One hypothesis is that spatial memory (during both encoding and retrieval) is associated with the posterior hippocampus. An alternative hypothesis is that memory encoding (either spatial or nonspatial) is associated with the anterior hippocampus and memory retrieval is associated with the posterior hippocampus. Of importance, during spatial memory encoding, the spatial-posterior hypothesis predicts posterior hippocampal involvement, whereas the encoding-retrieval hypothesis predicts anterior hippocampal involvement. To distinguish between these hypotheses, we conducted a coordinate-based fMRI activation likelihood estimation (ALE) meta-analysis of 26 studies (with a total of 435 participants) that reported hippocampal activity during spatial memory encoding and/or spatial memory retrieval. Both spatial memory encoding and spatial memory retrieval produced extensive activity along the longitudinal axis of the hippocampus as well as the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex. Critically, the contrast of spatial memory encoding and spatial memory retrieval produced activations in both the anterior hippocampus and the posterior hippocampus. That spatial memory encoding produced activity in both the anterior and posterior hippocampus can be taken to reject strict forms of the spatial-posterior hypothesis, which stipulates that all forms of spatial memory produce activity in the posterior hippocampus, and the encoding-retrieval hypothesis, which stipulates that all forms of encoding versus retrieval produce activity in only the anterior hippocampus. Our results indicate that spatial memory encoding can involve the anterior hippocampus and the posterior hippocampus.

Theta-phase locking of single neurons during human spatial memory.

The precise timing of single-neuron activity in relation to local field potentials may support various cognitive functions. Extensive research in rodents, along with some evidence in humans, suggests that single-neuron activity at specific phases of theta oscillations plays a crucial role in memory processes. Our fundamental understanding of such theta-phase locking in humans and its dependency on basic electrophysiological properties of the local field potential is still limited, however. Here, using single-neuron recordings in epilepsy patients performing a spatial memory task, we thus aimed at improving our understanding of factors modulating theta-phase locking in the human brain. Combining a generalized-phase approach for frequency-adaptive theta-phase estimation with time-resolved spectral parameterization, our results show that theta-phase locking is a strong and prevalent phenomenon across human medial temporal lobe regions, both during spatial memory encoding and retrieval. Neuronal theta-phase locking increased during periods of elevated theta power, when clear theta oscillations were present, and when aperiodic activity exhibited steeper slopes. Theta-phase locking was similarly strong during successful and unsuccessful memory, and most neurons activated at similar theta phases between encoding and retrieval. Some neurons changed their preferred theta phases between encoding and retrieval, in line with the idea that different memory processes are separated within the theta cycle. Together, these results help disentangle how different properties of local field potentials and memory states influence theta-phase locking of human single neurons. This contributes to a better understanding of how interactions between single neurons and local field potentials may support human spatial memory.

Paradoxical boosting of weak and strong spatial memories by hippocampal dopamine uncaging.

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 minutes created a short-term memory (weak) that cannot be retrieved one day later, whereas 10 minutes exploration created a long-term memory (strong) that can be retrieved one day later. Remarkably, hippocampal dopamine elevation during the encoding of weak object location memories (OLMs) allowed their retrieval one day 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 hours. 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.Significance statement Increased levels of dopamine have been related to cognitive enhancement. Hippocampal dopamine elevation caused by novelty exposure has been proposed as a strategy to enhance memory based on the observation that surprising events create flashbulb memories that are remembered for long time. However, hyperdopaminergic levels could also underlie maladaptive memories, such as non-desired preservation of traumatic experiences. Our experiments show that dopamine elevation in the dorsal hippocampus during the encoding of spatial memories has paradoxical effects, while the enhancement of weak memories allows their retrieval, the dopaminergic modulation of strong memories limits the ability to modify preexisting spatial memories by changes in the environment. We conclude that cognitive enhancement through dopamine boosting must consider diverse aspects of memory formation.

Cholinergic modulation of rearing in rats performing a spatial memory task.

Spatial memory encoding depends in part on cholinergic modulation. How acetylcholine supports spatial memory encoding is not well understood. Prior studies indicate that acetylcholine release is correlated with exploration, including epochs of rearing onto hind legs. Here, to test whether elevated cholinergic tone increases the probability of rearing, we tracked rearing frequency and duration while optogenetically modulating the activity of choline acetyltransferase containing (i.e., acetylcholine producing) neurons of the medial septum in rats performing a spatial working memory task (n= 17 rats). The cholinergic neurons were optogenetically inhibited using halorhodopsin for the duration that rats occupied two of the four open arms during the study phase of an 8-arm radial arm maze win-shift task. Comparing rats' behaviour in the two arm types showed that rearing frequency was not changed, but the average duration of rearing epochs became significantly longer. This effect on rearing was observed during optogenetic inhibition but not during sham inhibition or in rats that received infusions of a fluorescent reporter virus (i.e., without halorhodopsin; n= 6 rats). Optogenetic inhibition of cholinergic neurons during the pretrial waiting phase had no significant effect on rearing, indicating a context-specificity of the observed effects. These results are significant in that they indicate that cholinergic neuron activity in the medial septum is correlated with rearing not because it motivates an exploratory state but because it contributes to the processing of information acquired while rearing.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model

BackgroundAlzheimer’s disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.MethodsCircuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression.ResultsWe identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons.ConclusionWe report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Standardized extract of Ginkgo biloba treatment and novelty on the weak encoding of spatial recognition memory in rats.

Long-term memory (LTM) formation is dependent on neurochemical changes that guarantee that a recently formed memory (short-term memory [STM]) remains in the specific neural circuitry via the consolidation process. The persistence of recognition memory has been evidenced by using behavioral tagging in young adult rats, but it has not been effective on aging. Here, we investigated the effects of treatment with a standardized extract of Ginkgo biloba (EGb) associated with novelty on the consolidation of object location memory (OLM) and its persistence after weak training of spatial object preference in young adult and aged rats. The object location task used in this study included two habituation sessions, training sessions associated or not associated with EGb treatment and contextual novelty, and short-term or long-term retention testing sessions. Altogether, our data showed that treatment with EGb associated with novelty close to the time of encoding resulted in STM that lasted for 1 h and persisted for 24 h for both young adult and aged rats. In aged rats, the cooperative mechanisms induced robust long-term OLM. Our findings support and extend our knowledge about recognition memory in aged rats and the modulating effects of EGb treatment and contextual novelty on the persistence of memory.

Reward expectation extinction restructures and degrades CA1 spatial maps through loss of a dopaminergic reward proximity signal

Hippocampal place cells support reward-related spatial memories by forming a cognitive map that over-represents reward locations. The strength of these memories is modulated by the extent of reward expectation during encoding. However, the circuit mechanisms underlying this modulation are unclear. Here we find that when reward expectation is extinguished in mice, they remain engaged with their environment, yet place cell over-representation of rewards vanishes, place field remapping throughout the environment increases, and place field trial-to-trial reliability decreases. Interestingly, Ventral Tegmental Area (VTA) dopaminergic axons in CA1 exhibit a ramping reward-proximity signal that depends on reward expectation and inhibiting VTA dopaminergic neurons largely replicates the effects of extinguishing reward expectation. We conclude that changing reward expectation restructures CA1 cognitive maps and determines map reliability by modulating the dopaminergic VTA-CA1 reward-proximity signal. Thus, internal states of high reward expectation enhance encoding of spatial memories by reinforcing hippocampal cognitive maps associated with reward.

Early life GABAA blockade alters the synaptic plasticity and cognitive functions in male and female rats

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adults, has a critical contribution to balanced excitatory-inhibitory networks in the brain. Alteration in depolarizing action of GABA during early life is connected to a wide variety of neurodevelopmental disorders. Additionally, the effects of postnatal GABA blockade on neuronal synaptic plasticity are not known and therefore, we set out to determine whether postnatal exposure to bicuculline, a competitive antagonist of GABAA receptors, affects electrophysiologic changes in hippocampal CA1 neurons later on. To this end, male and female Wistar rats received vehicle or bicuculline (300 μg/kg) on postnatal days (PNDs) 7, 9 and 11, and then underwent different behavioral and electrophysiological examinations in adulthood. Postnatal exposure to bicuculline did not affect basic synaptic transmission but led to a pronounced decrease in paired-pulse facilitation (PPF) in CA1 pyramidal neurons. Bicuculline treatment also attenuated the long-term potentiation (LTP) and long-term depression (LTD) of CA1 neurons accompanied by decreased theta-burst responses in male and female adult rats. These electrophysiology findings together with the reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex reliably explain the disturbance in spatial reference and working memories of bicuculline-treated animals. This study suggests that postnatal GABAA blockade deteriorates short- and long-term synaptic plasticity of hippocampal CA1 neurons and related encoding of spatial memory in adulthood.

Inhibitory projections connecting the dentate gyri in the two hemispheres support spatial and contextual memory.

The dentate gyrus (DG) receives substantial input from the homologous brain area of the contralateral hemisphere. This input is by and large excitatory. Viral-tracing experiments provided anatomical evidence for the existence of GABAergic connectivity between the two DGs, but the function of these projections has remained elusive. Combining electrophysiological and optogenetic approaches, we demonstrate that somatostatin-expressing contralateral DG (SOM+ cDG)-projecting neurons preferentially engage dendrite-targeting interneurons over principal neurons. Single-unit recordings from freely moving mice reveal that optogenetic stimulation of SOM+ cDG projections modulates the activity of GABAergic neurons and principal neurons over multiple timescales. Importantly, we demonstrate that optogenetic silencing of SOM+ cDG projections during spatial memory encoding, but not during memory retrieval, results in compromised DG-dependent memory. Moreover, optogenetic stimulation of SOM+ cDG projections is sufficient to disrupt contextual memory recall. Collectively, our findings reveal that SOM+ long-range projections mediate inter-DG inhibition and contribute to learning and memory.

Volume of the posterior hippocampus mediates age-related differences in spatial context memory and is correlated with increased activity in lateral frontal, parietal and occipital regions in healthy aging

Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19–76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition.

Adult neural stem cells and schizophrenia.

Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.

Cholinergic Regulation of Hippocampal Theta Rhythm.

Cholinergic regulation of hippocampal theta rhythm has been proposed as one of the central mechanisms underlying hippocampal functions including spatial memory encoding. However, cholinergic transmission has been traditionally associated with atropine-sensitive type II hippocampal theta oscillations that occur during alert immobility or in urethane-anesthetized animals. The role of cholinergic regulation of type I theta oscillations in behaving animals is much less clear. Recent studies strongly suggest that both cholinergic muscarinic and nicotinic receptors do actively regulate type I hippocampal theta oscillations and thus provide the cholinergic mechanism for theta-associated hippocampal learning. Septal cholinergic activation can regulate hippocampal circuit and theta expression either through direct septohippocampal cholinergic projections, or through septal glutamatergic and GABAergic neurons, that can precisely entrain hippocampal theta rhythmicity.

Optogenetic stimulation of CA3 pyramidal neurons restores synaptic deficits to improve spatial short-term memory in APP/PS1 mice.

The hippocampal CA3 region, that is involved in the encoding and retrieval of spatial memory, is found to be synaptically impaired in the early-onset of Alzheimer's disease (AD). It is reported optogenetic manipulation of DG or CA1 can rescue the memory impairment of APP/PS1 mice, however, how CA3 region contributes to AD-related deficits in cognitive function is still unknown. Our work shows optogenetic stimulation of CA3 pyramidal neurons (PNs) significantly restores the impaired spatial short-term memory of APP/PS1 mice. This enhances the anatomical synaptic density/strength and synaptic plasticity as well as activates astrocytes. Chemogenetic inhibiting the activity of CA3 astrocytes reverses the effect of optogenetic stimulation of CA3 PNs that leads to reduced anatomical synaptic density/strength, decreased synaptic protein and AMPA receptors GluA3/4, thus disrupting the cognitive restoration of APP/PS1 mice. These results reveal the molecular mechanism of optogenetic activation of CA3 PNs on restoration of the spatial short-term memory of APP/PS1 mice and unveil a potential strategy of manipulating CA3 for AD treatment.

Hyperactivity of Ventral Hippocampal Mossy Cells Degrades Dorsal Hippocampal Mnemonic Function via Longitudinal Projections

The anterior hippocampus in early psychosis or schizophrenia is hyperactive compared to controls. In rodent models, the ventral hippocampus (vHPC), analogous to the human anterior HPC, is also hyperactive. How anterior HPC hyperactivity influences intrahippocampal function across the structure’s longitudinal axis is unknown, an important question to understand why cognitive deficits in schizophrenia involve both anterior and posterior HPC function. We hypothesized that hyperactivity of ventral HPC mossy cells (MCs), which send longitudinal projections within the HPC, disrupts spatial memory encoding, a dorsal HPC (dHPC)-dependent function.

Functional connectivity with the anterior and posterior hippocampus during spatial memory

Evidence of differential connectivity and activity patterns across the long-axis of the hippocampus has led to many hypotheses about functional specialization of the anterior and posterior hippocampus, including a hypothesis linking the anterior hippocampus to memory encoding and the posterior hippocampus to memory retrieval. The hippocampal encoding/retrieval and network (HERNET) model of memory predicts that encoding should engage the anterior hippocampus and the attention network, whereas retrieval should engage the posterior hippocampus and the default network. In a previous fMRI study that employed multivoxel pattern analysis, we found that the patterns of activity in the anterior hippocampus predicted the quadrant of spatial memory encoding. In the current fMRI study, we investigated whether the spatial memory encoding activity in the anterior hippocampus and retrieval activity in the posterior hippocampus had a higher degree of connectivity to the attention network or the default network. During the study phase, abstract shapes were presented in each quadrant of the visual field and participants were instructed to remember each shape's location while maintaining central fixation. During the test phase, the same shapes were presented in the center of the screen and participants identified the previous location of each shape. Generalized psychophysiological interaction analyses were conducted between the anatomically defined anterior and posterior hippocampus and the rest of the brain. This revealed preferential connectivity between the anterior hippocampus and regions of the attention network during encoding and between the posterior hippocampus and regions of the default network during retrieval. In addition, there were location-specific patterns of connectivity with the anterior hippocampus and posterior hippocampus during encoding and retrieval of right visual field items. These results suggest that the anterior and posterior hippocampus interact with regions of the attention network and default network during spatial memory encoding and retrieval, respectively, and support the HERNET model of memory.

Synaptic Mechanisms Underlying the Network State-Dependent Recruitment of VIP-Expressing Interneurons in the CA1 Hippocampus.

Disinhibition is a widespread circuit mechanism for information selection and transfer. In the hippocampus, disinhibition of principal cells is provided by the interneuron-specific interneurons that express the vasoactive intestinal polypeptide (VIP-IS) and innervate selectively inhibitory interneurons. By combining optophysiological experiments with computational models, we determined the impact of synaptic inputs onto the network state-dependent recruitment of VIP-IS cells. We found that VIP-IS cells fire spikes in response to both the Schaffer collateral and the temporoammonic pathway activation. Moreover, by integrating their intrinsic and synaptic properties into computational models, we predicted recruitment of these cells between the rising phase and peak of theta oscillation and during ripples. Two-photon Ca2+-imaging in awake mice supported in part the theoretical predictions, revealing a significant speed modulation of VIP-IS cells and their preferential albeit delayed recruitment during theta-run epochs, with estimated firing at the rising phase and peak of the theta cycle. However, it also uncovered that VIP-IS cells are not activated during ripples. Thus, given the preferential theta-modulated firing of VIP-IS cells in awake hippocampus, we postulate that these cells may be important for information gating during spatial navigation and memory encoding.

The anterior hippocampus is associated with spatial memory encoding

There are many hypotheses regarding specialization of the anterior versus posterior hippocampus including memory encoding versus retrieval and other cognitive processes versus spatial memory. In the present functional magnetic resonance imaging study, we distinguished between the hypothesis linking encoding to the anterior hippocampus and the hypothesis linking spatial memory to the posterior hippocampus by evaluating whether spatial memory encoding involved the anterior hippocampus or the posterior hippocampus. During encoding, participants viewed abstract shapes in each of four visual field quadrants while instructed to maintain central fixation. During retrieval, old shapes were presented at fixation and participants identified the previous quadrant of each shape. A general linear model analysis did not reveal encoding activations in the anterior or posterior hippocampus. These results motivated a multi-voxel pattern analysis to assess whether there were distinct patterns of activity associated with encoding shapes in each quadrant within the anterior or posterior hippocampus. For each participant, patterns of activity associated with each quadrant were split by run (i.e., odd runs versus even runs) and the patterns in half the data were used to classify patterns in the other half of the data. Classification accuracy for items at encoding, collapsed over subsequent accuracy, was significantly above chance in the anterior but not posterior hippocampus. The present findings indicate that spatial memory encoding is associated with patterns of activity in the anterior hippocampus.

Encoding of spatial working memory in virtual reality in the primate prefrontal cortex

Encoding of spatial working memory in virtual reality in the primate prefrontal cortex

Functional implication of retinoic acid-responsive subpopulation of dentate granule cells in encoding of reward-associated spatial memory

Functional implication of retinoic acid-responsive subpopulation of dentate granule cells in encoding of reward-associated spatial memory

P2‐243: IMPAIRMENTS IN NEURAL CORRELATES OF CONTEXTUAL MEMORY IN A MOUSE MODEL OF AMYLOIDOPATHY

One of the brain areas affected earliest in Alzheimer's disease is the medial entorhinal cortex (MEC), which plays a key role in the neural encoding of spatial information via a variety of functional subclasses of neurons. The activity of many of these cell types is strongly modulated by theta frequency (6-12 Hz) oscillations, the power and frequency of which increase with the speed at which the animal is moving. Theta oscillations evoke nested gamma oscillations, resulting in a theta-gamma phase-amplitude coupling (PAC) that increases with running speed in the hippocampus. Previous work suggests that the running speed-theta frequency relationship is steeper in familiar environments than in novel ones, suggesting a neural correlate of contextual spatial memory. 6 months old male J20 and wild-type (WT) mice were surgically implanted with recording probes in the dorsal MEC. Following a recovery period, mice were placed in an open arena (either circular or square, of equal area) and encouraged to explore it for 15 minutes twice a day, for 4 days. On the fifth day all mice were then placed in a novel arena. During these exploration periods, mice were tethered to a multi-channel recording system and the local field potentials in the MEC acquired. As the environment became more familiar, the slope of theta frequency vs running speed increased in WT mice. However, in J20 mice no changes were observed. Equivalent effects were observed in the gamma frequency and power vs running speed relationships, whereby the slope increased with familiarity in WT mice, unlike J20 mice which showed no significant changes. Theta-gamma PAC rose with running speed in WT mice but not in J20 mice, where the overall PAC was reduced. These results provide evidence of a significant disruption to the neuronal network mechanism underlying spatial contextual memory and speed encoding in a mouse model of amyloidopathy.