Associative Recognition Memory Research Articles

Increased flexibility of CA3 memory representations following environmental enrichment

Environmental enrichment (EE) improves memory, particularly the ability to discriminate similar past experiences.1,2,3,4,5,6 The hippocampus supports this ability via pattern separation, the encoding of similar events using dissimilar memory representations.7 This is carried out in the dentate gyrus (DG) and CA3 subfields.8,9,10,11,12 Upregulation of adult neurogenesis in the DG improves memory through enhanced pattern separation.1,2,3,4,5,6,11,13,14,15,16 Adult-born granule cells (abGCs) in DG are suggested to contribute to pattern separation by driving inhibition in regions such as CA3,13,14,15,16,17,18 leading to sparser, nonoverlapping representations of similar events (although a role for abGCs in driving excitation in the hippocampus has also been reported16). Place cells in the hippocampus contribute to pattern separation by remapping to spatial and contextual alterations to the environment.19,20,21,22,23,24,25,26,27 How spatial responses in CA3 are affected by EE and input from increased numbers of abGCs in DG is, however, unknown. Here, we investigate the neural mechanisms facilitating improved memory following EE using associative recognition memory tasks that model the automatic and integrative nature of episodic memory. We find that EE-dependent improvements in difficult discriminations are related to increased neurogenesis and sparser memory representations across the hippocampus. Additionally, we report for the first time that EE changes how CA3 place cells discriminate similar contexts. CA3 place cells of enriched rats show greater spatial tuning, increased firing rates, and enhanced remapping to contextual changes. These findings point to more precise and flexible CA3 memory representations in enriched rats, which provides a putative mechanism for EE-dependent improvements in fine memory discrimination.

Face masks degrade our ability to remember face-name associations more than predicted by judgments of learning

ABSTRACT In response to the COVID-19 pandemic, face masks became required attire. Face masks obstruct the bottom portion of faces, restricting face processing. The present study examined the influence face masks have on memory predictions and memory performance for new face-name associations. Participants studied face-name pairs presented for 8 s (Experiment 1) or 10 s (Experiment 2). Half of the face-name pairs included a face mask obstructing the nose and mouth of the pictured face, counterbalanced across participants. Participants provided item-by-item judgements of learning (JOLs) and completed subsequent cued recall and associative recognition memory tests. Both experiments demonstrated that face masks impaired memory for newly-learned names, however, the magnitude of the mask impact was under-predicted by JOLs. The presence of a face mask negatively influenced memory performance to a greater degree than participants’ JOLs predicted. Results have implications for name learning during pandemics, as well as in settings where face masks are common (e.g., medical field).

Schema-congruency supports the formation of unitized representations: Evidence from event-related potentials

The main goal of the present study was to investigate whether schema-based encoding of novel word pairs (i.e., novel compound words) supports the formation of unitized representations and thus, associative familiarity-based recognition. We report two experiments that both comprise an incidental learning task, in which novel noun-noun compound words were presented in semantically congruent contexts, enabling schema-supported processing of both constituents, contrasted with a schema-neutral condition. In Experiment 1, the effects of schema congruency on memory performance were larger for associative memory performance than for item memory performance in a memory test in which intact, recombined, and new compound words had to be discriminated. This supports the view that schema congruency boosts associative memory by promoting unitization. When contrasting event-related potentials (ERPs) for hits with correct rejections or associative misses, an N400 attenuation effect (520–676 ms) indicating absolute familiarity was present in the congruent condition, but not in the neutral condition. In line with this, a direct comparison of ERPs on hits across conditions revealed more positive waveforms in the congruent than in the neutral condition. This suggests that absolute familiarity contributes to associative recognition memory when schema-supported processing is established. In Experiment 2, we tested whether schema congruency enables the formation of semantically overlapping representations. Therefore, we included semantically similar lure compound words in the test phase and compared false alarm rates to these lures across conditions. In line with our hypothesis, we found higher false alarm rates in the congruent as compared to the neutral condition. In conclusion, we provide converging evidence for the view that schema congruency enables the formation of unitized representations and supports familiarity-based memory retrieval.

Extracellular vesicles from hiPSC-NSCs can prevent peripheral inflammation-induced cognitive dysfunction with inflammasome inhibition and improved neurogenesis in the hippocampus

Extracellular vesicles (EVs) released by human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) are enriched with miRNAs and proteins capable of mediating robust antiinflammatory activity. The lack of tumorigenic and immunogenic properties and ability to permeate the entire brain to incorporate into microglia following intranasal (IN) administrations makes them an attractive biologic for curtailing chronic neuroinflammation in neurodegenerative disorders. We tested the hypothesis that IN administrations of hiPSC-NSC-EVs can alleviate chronic neuroinflammation and cognitive impairments induced by the peripheral lipopolysaccharide (LPS) challenge. Adult male, C57BL/6J mice received intraperitoneal injections of LPS (0.75 mg/kg) for seven consecutive days. Then, the mice received either vehicle (VEH) or hiPSC-NSC-EVs (~ 10 × 109 EVs/administration, thrice over 6 days). A month later, mice in all groups were investigated for cognitive function with behavioral tests and euthanized for histological and biochemical studies. Mice receiving VEH after LPS displayed deficits in associative recognition memory, temporal pattern processing, and pattern separation. Such impairments were associated with an increased incidence of activated microglia presenting NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasomes, elevated levels of NLRP3 inflammasome mediators and end products, and decreased neurogenesis in the hippocampus. In contrast, the various cognitive measures in mice receiving hiPSC-NSC-EVs after LPS were closer to naive mice. Significantly, these mice displayed diminished microglial activation, NLRP3 inflammasomes, proinflammatory cytokines, and a level of neurogenesis matching age-matched naïve controls. Thus, IN administrations of hiPSC-NSC-EVs are an efficacious approach to reducing chronic neuroinflammation-induced cognitive impairments.

Object-place-context learning impairment correlates with spatial learning impairment in aged Long-Evans rats.

The hippocampal formation is vulnerable to the process of normal aging. In humans, the extent of this age-related deterioration varies among individuals. Long-Evans rats replicate these individual differences as they age, and therefore they serve as a valuable model system to study aging in the absence of neurodegenerative diseases. In the Morris water maze, aged memory-unimpaired (AU) rats navigate to remembered goal locations as effectively as young rats and demonstrate minimal alterations in physiological markers of synaptic plasticity, whereas aged memory-impaired (AI) rats show impairments in both spatial navigation skills and cellular and molecular markers of plasticity. The present study investigates whether another cognitive domain is affected similarly to navigation in aged Long-Evans rats. We tested the ability of young, AU, and AI animals to recognize novel object-place-context (OPC) configurations and found that performance on the novel OPC recognition paradigm was significantly correlated with performance on the Morris water maze. In the first OPC test, young and AU rats, but not AI rats, successfully recognized and preferentially explored objects in novel OPC configurations. In a second test with new OPC configurations, all age groups showed similar OPC associative recognition memory. The results demonstrated similarities in the behavioral expression of associative, episodic-like memory between young and AU rats and revealed age-related, individual differences in functional decline in both navigation and episodic-like memory abilities.

Limiting the reliance on navigation assistance with navigation instructions containing emotionally salient narratives for confident wayfinding

We live in a world that is increasingly dependent on technology, including for orientation in both familiar and unfamiliar space, which contributes to a long-term erosion of innate spatial navigation skills. In this study, we examined whether modified navigation instructions can make pedestrians less reliant on navigation aids to solve wayfinding tasks. In contrast to standard instructions, the modified instructions make decision-relevant landmarks at intersections emotionally salient and connected through narrative, and thus more memorable. The results of our online VR study with seventy adults revealed that, after navigating an unfamiliar route using modified navigation instructions, people made significantly fewer references to the navigation aid without compromising the accuracy of navigation compared to standard instructions. Narrative-based navigation instructions improved memory for the order in which relevant features in the environment were encountered along the traversed route, but not landmark recognition memory or memory for landmark-direction associations. Our findings highlight the benefits of using human-centred technologies that – as opposed to current navigation systems – promote the encoding and memorability of spatial information during navigation, and have the potential to train human spatial navigation abilities in the long term as a countermeasure toward GPS cognitive deskilling of population.

Perilesional and contralesional brain activations related to associative encoding of unfamiliar face-names pairs in adults with left chronic stroke with or without ischemic infarct on left inferior frontal gyrus

The study of an Ischemic stroke infarction allows verifying how the lesion produces alterations in the neuronal networks resulting in cognitive deficits. It also allows the verification of adaptive and maladaptive cerebral reorganization related to the injury. In our previous fMRI study, we found that patients without ischemic vascular lesions in left inferior frontal gyrus showed an efficient compensation mechanism during the associative encoding of face name pairs, by the increased activation of ventrolateral and dorsolateral areas of contralesional hemisphere associated with better memory performance. While patients with ischemic vascular lesions on left inferior frontal gyrus (IFG) demonstrated worse memory performance and no signs of compensation mechanism. The present study explores more of these findings by analyzing perilesional and contralesional activations related to unfamiliar face name associative encoding in adults with chronic ischemic stroke, with or without left IFG lesion, compared to healthy controls. The main results showed that stroke survivors without lesions in IFG demonstrated increased activation in perilesional and contralesional prefrontal regions associated with better associative memory recognition, which are indicative of adaptive compensatory mechanisms. However, they also showed a negative correlation between the activation of right anterior prefrontal and inferior parietal regions and the associative memory performance, which may indicate the presence of maladaptive interhemispheric disinhibition. On the other hand, stroke survivors with IFG lesions demonstrated negative correlations in activations of the ipsilesional inferior parietal cortex and positive correlations in activations of the left middle frontal gyrus and left precentral cortex, which demonstrate the simultaneous occurrence of adaptive and maladaptive brain reorganization mechanisms in this group. However, the increase in perilesional prefrontal regions, associated with bilateral activation of the hippocampus and amygdala, was not enough to compensate for the inefficiency of associative memory performance. Finally, the differences in activation observed in stroke survivors reflect their clinical heterogeneity and demonstrate that adaptive or maladaptive compensatory mechanisms can coexist in the same group of patients. Furthermore, they reinforce the importance of the left IFG in the associative encoding of unfamiliar face name pairs and may suggest a deficit in associative memory related to injury in this region.

Episodic memory through a social and emotional lens.

Negative emotion enhances item memory but may reduce associative memory. Social information may also enhance memory, yet how social and emotional cues combine to affect memory for focal and surrounding details is unknown. Gender differences may also exist, but whether women and men encode and remember negative and social information differently is unclear. This study examines how social information contributes to or interacts with emotion to influence item and associative memory, and whether gender plays a role in how social and/or emotional information is recognized. Discovery and replication samples (N = 706) were recruited. Stimuli included (1) images with varying social and emotional content categorized into four conditions: negative social, negative nonsocial, neutral social, neutral nonsocial and (2) neutral images of objects paired with target stimuli to assess associative memory. Participants viewed the image pairings (Encoding). Twenty-four hours later, item and associative recognition memory were tested. Item recognition memory was better for negative vs. neutral and social vs. nonsocial images. By contrast, associative recognition memory was worse for negative vs. neutral, but better for social vs. nonsocial images. Finally, women demonstrated similar item memory performance compared to men but better associative recognition memory performance overall compared to men. Emotional and social cues impart distinct effects on how we form holistic episodic memories, highlighting the importance of considering these critical factors when striving to understand how and what we remember. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

I remember better with me: self-referential enhancement in associative recognition memory

I remember better with me: self-referential enhancement in associative recognition memory

White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood–brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

Dissecting Differential Complex Behavioral Responses to Simulated Space Radiation Exposures.

This study has established the impact that space radiation exposure has on the capability of rats to successfully negotiate behavioral tasks of increasing complexity. Rats previously exposed to a low dose (10 cGy) of either 4He ions or a cocktail of 6 ions that simulates the galactic cosmic ray spectrum (GCRSim) were screened initially on an attentional set shifting (ATSET) task that provides a measure of executive function. Rats that exhibited superior ATSET performance were then selected for follow up behavioral assessments designed to evaluate how the cohort of "good performers" would fare when presented with a novel behavioral paradigm termed the Associative Recognition Memory and Interference Touchscreen (ARMIT) task. Central to this approach was to discriminate if/how adaptive problem solving would be impacted by changing the options of associative cues presented over several learning sessions to obtain a reward under time constraints using this newly designed touch screen-based task. Data from these studies indicated that when faced with an increased cognitive load, possibly due to interference from prior associative recognition memories, rats exhibited impairments in their capability to negotiate task dynamics and efficiently engage abstract reasoning. Interestingly, while exposure to the GCRSim adversely impacted problem-solving capabilities, single ion exposure did not, pointing to the nuances of space radiation exposure on CNS functionality. Since the selected behavioral paradigms exhibit strong cross-species correlates, data suggest that rodents succumb to increased task rigor as observed in humans, and make similar mistakes when challenged with the interference of overlapping associative memories. Furthermore, data clearly points to the limitations of over-reliance on a single cognitive endpoint that may underestimate global neurocognitive risk due to space radiation exposure.

Sleep and memory consolidation in temporal lobe epilepsy

Objectives . Work in our lab and others have found that individuals with temporal-lobe epilepsy show Accelerated Long-Term Forgetting, a situation characterized by normal memory at short intervals (15–30 mins, which is typical of clinical assessments) but a rapid rate of forgetting relative to controls over hours and days afterward. These findings suggest disruption to a process involving hippocampal-neocortical interaction enabling ‘consolidation’ of memory traces in the neocortex over time. Indeed, we have reported that functional connectivity between the affected hippocampus and temporal neocortex is positively associated with recall after 72 hours (Audrain & McAndrews, Cortex 2018). Here, we investigated how slow-wave sleep (SWS) might moderate these effects. Methods . We examined associative recognition memory in 19 patients with temporal lobe epilepsy on the Epilepsy Monitoring Unit at the Toronto Western Hospital. Critically, we focused on forgetting over a period of 6 hours to 16 hours as a function of duration of SWS overnight and frequency of frontotemporal interictal epileptic discharges (IEDs) during the same period. We also compared behavioral forgetting rates against age-matched healthy controls. Results . While there was no significant difference between patients and controls in forgetting rates over that interval, most controls showed a facilitative impact whereas there was considerable variability amongst the patient group. In patients, there was a significant relationship between duration of SWS and forgetting (r = 0.60), such that greater SWS was associated with greater forgetting, which is opposite to the typical facilitative effect of SWS on retention in controls. We hypothesized that IEDs might mediate this effect, as they might serve as disruptive signals to consolidation processes during sleep and are more abundant during SWS. However, while IEDs did correlate with forgetting (r = 0.42), this did not prove to be a significant independent mediator. Conclusions . The counter-intuitive effects of SWS on memory retention in individuals with temporal lobe epilepsy found here replicates one previous study. We consider the possibility that hippocampal IEDs, not captured adequately by scalp recordings, may play a significant role and we plan to investigate this in a subsequent study. Funding . Natural Sciences and Engineering Research Council of Canada.

Long-term associative memory in rats: Effects of familiarization period in object-place-context recognition test.

Spontaneous recognition tests, which utilize rodents' innate tendency to explore novelty, can evaluate not only simple non-associative recognition memory but also more complex associative memory in animals. In the present study, we investigated whether the length of the object familiarization period (sample phase) improved subsequent novelty discrimination in the spontaneous object, place, and object-place-context (OPC) recognition tests in rats. In the OPC recognition test, rats showed a significant novelty preference only when the familiarization period was 30 min but not when it was 5 min or 15 min. In addition, repeated 30-min familiarization periods extended the significant novelty preference to 72 hours. However, the rats exhibited a successful discrimination between the stayed and replaced objects under 15 min and 30 min familiarization period conditions in the place recognition test and between the novel and familiar objects under all conditions of 5, 15 and 30 min in the object recognition test. Our results suggest that the extension of the familiarization period improves performance in the spontaneous recognition paradigms, and a longer familiarization period is necessary for long-term associative recognition memory than for non-associative memory.

Melatonin improves brain function in a model of chronic Gulf War Illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus

Persistent cognitive and mood dysfunction is the primary CNS symptom in veterans afflicted with Gulf War Illness (GWI). This study investigated the efficacy of melatonin (MEL) for improving cognitive and mood function with antioxidant, antiinflammatory, and pro-cognitive effects in a rat model of chronic GWI. Six months after exposure to GWI-related chemicals and stress, rats were treated with vehicle or MEL (5, 10, 20, 40, and 80 mg/kg) for eight weeks. Behavioral tests revealed cognitive and mood dysfunction in GWI rats receiving vehicle, which were associated with elevated oxidative stress, reduced NRF2, catalase and mitochondrial complex proteins, astrocyte hypertrophy, activated microglia with NLRP3 inflammasomes, elevated proinflammatory cytokines, waned neurogenesis, and synapse loss in the hippocampus. MEL at 10 mg/kg alleviated simple and associative recognition memory dysfunction and anhedonia, along with reduced oxidative stress, enhanced glutathione and complex III, and reduced NLRP3 inflammasomes, IL-18, TNF-α, and IFN-γ. MEL at 20 mg/kg also normalized NRF2 and catalase and increased microglial ramification. MEL at 40 mg/kg, in addition, reduced astrocyte hypertrophy, activated microglia, NF-kB-NLRP3-caspase-1 signaling, IL-1β, MCP-1, and MIP-1α. Moreover, MEL at 80 mg/kg activated the BDNF-ERK-CREB signaling pathway, enhanced neurogenesis and diminished synapse loss in the hippocampus, and improved a more complex hippocampus-dependent cognitive function. Thus, MEL therapy is efficacious for improving cognitive and mood function in a rat model of chronic GWI, and MEL's effect was dose-dependent. The study provides the first evidence of MEL's promise for alleviating neuroinflammation and cognitive and mood impairments in veterans with chronic GWI.

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Plasticity in Prefrontal Cortex Induced by Coordinated Synaptic Transmission Arising from Reuniens/Rhomboid Nuclei and Hippocampus.

The nucleus reuniens and rhomboid nuclei of the thalamus (ReRh) are reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of ReRh is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation, and working memory. Although anatomical and electrophysiological evidence suggests ReRh makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether ReRh and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that ReRh and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that ReRh, but not HPC, undergoes marked short-term plasticity during theta frequency transmission, and that HPC, but not ReRh, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by ReRh (but not pairing ReRh followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC–ReRh–mPFC encoding.

Associative recognition memory for identity, spatial and temporal relations in healthy aging

ABSTRACT The ability to generate associative representations and to retrieve them from long-term episodic memory generally declines in healthy aging. However, it is unclear whether healthy aging has differential effects on associative memory for identity, spatial configuration, and temporal order relationships. In the current study, we assessed how healthy aging impacts on associative memory for identity, spatial, or temporal relationships between pairs of visual objects via discrimination of intact and rearranged pairs. Accuracy and response time performance of healthy older adults (aged 65–80) were compared with young adults (ages 19–30). Age-related declines in associative memory were observed equally for all types of associations, but these declines differed by associative status: aging most strongly affected ability to discriminate rearranged pairs. These results suggest that associative memory for identity, spatial, and temporal relationships are equally affected by healthy aging, and may all depend on a shared set of basic associative mechanisms.

Levels of Processing Affect Perceptual Features in Visual Associative Memory

The levels of processing (LOP) account has inspired thousands of studies with verbal material. The few studies investigating levels of processing with nonverbal stimuli used images with nameable objects that, like meaningful words, lend themselves to semantic processing. Thus, nothing is known about the effects of different levels of processing on basic visual perceptual features, such as color. Across four experiments, we tested 187 participants to investigate whether the LOP framework also applies to basic perceptual features in visual associative memory. For Experiments 1 and 2, we developed a paradigm to investigate recognition memory for associations of basic visual features. Participants had to memorize object–color associations (Experiment 1) and fractal–color associations (Experiment 2, to suppress verbalization). In Experiments 3 and 4, we extended our account to cued recall. All experiments revealed reliable LOP effects for basic perceptual features in visual associative memory. Our findings demonstrate that the LOP account is more universal than the current literature suggests.

Oscillations around memory

Neuroscience Hippocampal oscillations in the theta range have been hypothesized to play a central role in organizing neuronal ensembles to link together item and contextual representations. Experimental evidence in rodents shows the importance of theta oscillations for associative memory. However, the role of hippocampal theta oscillations in human memory is not as well understood. Kota et al. administered an associative recognition memory task to epilepsy patients who happened to have electroencephalogram electrodes implanted for other medical reasons. Theta oscillatory power increase in the 2- to 5-Hz range and phase reset in the hippocampus reflected processes supporting recollection, rather than familiarity, during encoding and retrieval. These observations link theta-range activity to associative memory encoding and retrieval in humans. J. Neurosci. 40 , 9507 (2020).

Hippocampal Theta Oscillations Support Successful Associative Memory Formation.

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2-5 Hz and 5-9 Hz theta oscillations, by which power increases in 2-5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2-5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5-9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.SIGNIFICANCE STATEMENT Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2-5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.