Brain Rhythms: Towards a Coherent Picture of Ensemble Development in Learning

SummaryA recent study suggests that coherence of 20–40 Hz brain oscillations in the hippocampus and upstream lateral entorhinal cortex may support encoding of task-relevant information during associative learning. Coordination of local hippocampal circuits in this frequency range could be important for encoding new information

Temporal Encoding of Place Sequences by Hippocampal Cell Assemblies

SummaryBoth episodic memory and spatial navigation require temporal encoding of the relationships between events or locations. In a linear maze, ordered spatial distances between sequential locations were represented by the temporal relations of hippocampal place cell pairs within cycles of theta oscillation in a compressed manner. Such correlations could arise due to spike “phase precession” of independent neurons driven by common theta pacemaker or as a result of temporal coordination among specific hippocampal cell assemblies. We found that temporal correlation between place cell pairs was stronger than predicted by a pacemaker drive of independent neurons, indicating a critical role for synaptic interactions and precise timing within and across cell assemblies in place sequence representation. CA1 and CA3 ensembles, identifying spatial locations, were active preferentially on opposite phases of theta cycles. These observations suggest that interleaving CA3 neuronal sequences bind CA1 assemblies representing overlapping past, present, and future locations into single episodes

The role of medial entorhinal cortex activity in hippocampal CA1 spatiotemporally correlated sequence generation and object selectivity for memory function

The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval

The Cognitive Architecture of Spatial Navigation: Hippocampal and Striatal Contributions

Spatial navigation can serve as a model system in cognitive neuroscience, in which specific neural representations, learning rules, and control strategies can be inferred from the vast experimental literature that exists across many species, including humans. Here, we review this literature, focusing on the contributions of hippocampal and striatal systems, and attempt to outline a minimal cognitive architecture that is consistent with the experimental literature and that synthesizes previous related computational modeling. The resulting architecture includes striatal reinforcement learning based on egocentric representations of sensory states and actions, incidental Hebbian association of sensory information with allocentric state representations in the hippocampus, and arbitration of the outputs of both systems based on confidence/uncertainty in medial prefrontal cortex. We discuss the relationship between this architecture and learning in model-free and model-based systems, episodic memory, imagery, and planning, including some open questions and directions for further experiments

The Ontogeny of Hippocampus-Dependent Memories

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as "autobiographical" or "episodic" memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories. However, the ability to acquire and store such memories relies on molecular pathways and network-based activity dynamics different from the adult system, which mature with age. The mechanisms underlying the formation of hippocampus-dependent memories during infancy, and the role that experience exerts in promoting the maturation of the hippocampus-dependent memory system, remain to be understood. In this review, we discuss recent advances in our understanding of the ontogeny and the biological correlates of hippocampus-dependent memories

Cortical-hippocampal processing: prefrontal-hippocampal contributions to the spatiotemporal relationship of events

The hippocampus and prefrontal cortex play distinct roles in the generation and retrieval of episodic memory. The hippocampus is crucial for binding inputs across behavioral timescales, whereas the prefrontal cortex is found to influence retrieval. Spiking of hippocampal principal neurons contains environmental information, including information about the presence of specific objects and their spatial or temporal position relative to environmental and behavioral cues. Neural activity in the prefrontal cortex is found to map behavioral sequences that share commonalities in sensory input, movement, and reward valence. Here I conducted a series of four experiments to test the hypothesis that external inputs from cortex update cell assemblies that are organized within the hippocampus. I propose that cortical inputs coordinate with CA3 to rapidly integrate information at fine timescales. Extracellular tetrode recordings of neurons in the orbitofrontal cortex were performed in rats during a task where object valences were dictated by the spatial context in which they were located. Orbitofrontal ensembles, during object sampling, were found to organize all measured task elements in inverse rank relative to the rank previously observed in the hippocampus, whereby orbitofrontal ensembles displayed greater differentiation for object valence and its contextual identity than spatial position. Using the same task, a follow-up experiment assessed coordination between prefrontal and hippocampal networks by simultaneously recording medial prefrontal and hippocampal activity. The circuit was found to coordinate at theta frequencies, whereby hippocampal theta engaged prefrontal signals during contextual sampling, and the order of engagement reversed during object sampling. Two additional experiments investigated hippocampal temporal representations. First, hippocampal patterns were found to represent conjunctions of time and odor during a head-fixed delayed match-to-sample task. Lastly, I assessed the dependence of hippocampal firing patterns on intrinsic connectivity during the delay period versus active navigation of spatial routes, as rats performed a delayed-alternation T-maze. Stimulation of the ventral hippocampal commissure induced remapping of hippocampal activity during the delay period selectively. Despite temporal reorganization, different hippocampal populations emerged to predict temporal position. These results show hippocampal representations are guided by stable cortical signals, but also, coordination between cortical and intrinsic circuitry stabilizes flexible CA1 temporal representations

Novel Space Alters Theta and Gamma Synchrony Across the Longitudinal Axis of the Hippocampus.

Hippocampal theta (6–10 Hz) and gamma (25–50 Hz and 65–100 Hz) local field potentials (LFPs) reflect the dynamic synchronization evoked by inputs impinging upon hippocampal neurons. Novel experience is known to engage hippocampal physiology and promote successful encoding. Does novelty synchronize or desynchronize theta and/or gamma frequency inputs across the septotemporal (long) axis of the hippocampus (HPC)? The present study tested the hypothesis that a novel spatial environment would alter theta power and coherence across the long axis. We compared theta and gamma LFP signals at individual (power) and millimeter distant electrode pairs (coherence) within the dentate gyrus (DG) and CA1 region while rats navigated a runway (1) in a familiar environment, (2) with a modified path in the same environment and (3) in a novel space. Locomotion in novel space was related to increases in theta and gamma power at most CA1 and DG sites. The increase in theta and gamma power was concurrent with an increase in theta and gamma coherence across the long axis of CA1; however, there was a significant decrease in theta coherence across the long axis of the DG. These findings illustrate significant shifts in the synchrony of entorhinal, CA3 and/or neuromodulatory afferents conveying novel spatial information to the dendritic fields of CA1 and DG targets across the long axis of the HPC. This shift suggests that the entire theta/gamma-related input to the CA1 network, and likely output, receives and conveys a more coherent message in response to novel sensory experience. Such may contribute to the successful encoding of novel sensory experience

Rhythmic Action Synchronizes Memory Replay During Reinforcement Learning

Our cognitive abilities - learning from the past, sensing the current environment, planning into the future, executing an action, and infusing value into an experience - all rely on precisely timed and widespread electrical communications across neural networks. The brain’s hippocampal formation receives multimodal input, forges episodic associations, and predicts future state. Oscillating electrical bursts originating from the hippocampus, termed ‘sharp-wave ripples’ (SWR), often contain patterns of previously expressed neural spike sequences, and are necessary for certain forms of learning and memory. The discharge of SWR-replay resonates in remote parts of the brain and displays specific characteristics depending on a subject’s state of awareness and sensory context. In the sleep state, when motoric repertoire is limited, waves of breathing synchronize neural activity in several regions of the brain, including SWRs of the hippocampus. During active sensation of the awake state, cyclic licking dynamically entrains taste-reward networks in subcortical and cortical areas throughout learning. However, the neural correlates linking oromotor movements in the active learning state to the memory system of the hippocampal formation have not yet been established. Given the recurrence of SWR-replay during rhythmic ingestion of reinforcement learning and the hierarchical coupling of orofacial behaviors, we hypothesized that repeated licking could provide the oscillatory framework to synchronize memory reactivation during active learning. We approach this question with new technology development to track licking events at a reward port (P-event) during behavior on a spatial alternation task. Additionally, we developed a modular brain implant to simultaneously record from hippocampal area CA1 and medial entorhinal cortex (MEC) - interconnected brain regions that are crucial to episodic memory processing. Along with the co-modulation of individual neurons by licking and SWRs, we provide the first evidence that SWRs detected in dorsal CA1 synchronize with the phase of P-event cycle during learning. Furthermore, we confirmed that SWRs occurring during licking bouts contain neural reactivation of active navigation and trigger enhanced ripple-frequency power in downstream MEC. These results connect movement with memory and may assist in addressing abnormal ingestion behaviors that negatively affect mental or physical healt

성공기억에서의 해마의 특징적 뇌 기전

학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 뇌인지과학과, 2020. 8. 정천기.One of the most intriguing of the human brain's complex functions is the ability to store information provided by experience and to retrieve much of it at will. This capability of memory processing is critical to humans survival – that is, humans guide their actions based on a given stimulus (e.g., item) in an environment, and can do so even when the stimulus is no longer present owing to the memory of the stimulus. A fundamental question of memory is why some experiences are remembered whereas others are forgotten. Since Scoville and Milners characterization of patient H.M., who demonstrated severe recognition memory deficits following damage to the medial temporal lobe (MTL), the hippocampus has been extensively studied as one of the key neural substrates for memory. In line with this, several experiments have been conducted on exploring the roles of the hippocampus in various ways. One is confirming the causality of the hippocampus in the memory process using direct electrical stimulation to the hippocampal region. The other is investigating the neural correlates of hippocampus using intracranial electroencephalography (iEEG) field potential and single neurons action potential known as spike recorded directly from the hippocampus. The present thesis is focused on providing direct electrophysiological evidence of human hippocampus in episodic memory that may help fill the gap that remained in the field for several years. Here, I will show how direct hippocampal stimulation affect human behavior and present characterized neural correlates of successful memory in the hippocampus. In the first study, building on the previous findings on the hippocampus, I sought to address whether the hippocampus would show functional causality with memory tasks and elicit different neural characteristics depending on memory tasks applied. I found hippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. These results of the task-specific memory modulation suggest that the associative task elicited stronger theta oscillations than the single-item task. In the second study, I tested whether successful memory formation relies on the hippocampal neuronal activity that engaged preceding an event. I found that hippocampal pre-stimulus spiking activity (elicited by a cue presented just before a word) predicted subsequent memory. Stimulus activity during encoding (during-stimulus) also showed a trend of predicting subsequent memory but was simply a continuation of pre-stimulus activity. These findings indicate that successful memory formation in human is predicted by a pre-stimulus activity and suggests that the preparatory mobilization of neural processes before encoding benefits episodic memory performance. Throughout the study, the current finding suggests the possibility that the intervals of poor memory encoding can be identified even before the stimulus presented and may be rescued with targeted stimulation to the hippocampus even before the stimulus presented.인간의 복잡한 뇌 기능 중 흥미로운 하나는 경험에 의거하여 정보를 저장하고 의지에 따라 저장된 정보를 재인하는 기억 능력 이다. 인간은 주어진 자극에 기반하여 행동을 정하며 심지어 자극이 없는 상황에서도 자극에 대한 기억을 바탕으로 행동을 결정하기 때문에 기억 능력은 생존에 있어 매우 결정적이며, 이러한 기억과 관련된 가장 기본적인 질문은 기억의 저장 메커니즘, 즉, 어떤 기억은 저장이 되고 어떤 기억은 잊혀지는 가일 것이다. 스코빌과 밀너가 처음 보고한 기억상실증 환자 H.M.은 측두영역의 손상을 입은 후 심각한 인지 기억 능력의 장애를 보였고, 이후 사람 뇌의 해마 영역은 기억을 관장하는 뇌의 중요한 영역 중 하나로 널리 연구되었다. 해마가 기억에 미치는 영향과 역할에 대해서는 다양한 방법으로 실험이 진행되어 왔다. 그 중의 하나는 뇌에 직접적인 전기자극을 가해 기억 과정 중 해마의 역할을 확인하는 방법인데, 이는 뇌전증 환자의 모델을 통해 사람의 뇌에 접근이 가능해지면서 이루어져 왔다. 두 번째 방법은 전기생리학적 방법을 통하는 것인데 세포 외 활동 전위인 스파이크를 통해 성공기억에서의 뉴런의 활동성을 밝히는 것이다. 이 논문은 이 분야에서 오랫동안 논란이 되었고 부족했던 성공 기억에 관련된 해마의 역할과 기전을 물리적 자극 및 신경세포의 신호를 측정해서 전기생리학적 특성을 제시하는데 초점을 맞추고 있다. 논문에서 본 저자는 사람의 성공기억형성과 재인에 대해 뇌 자극과 단위세포활동을 보고할 것이다. 해마와 기억의 인과관계 및 기억 과정 중의 해마의 뇌 기전과 관련된 기존의 실험적, 행동적 발견들에 근거하여 본 저자는 (ㄱ) 해마에 직접적인 전기 자극을 주고 기억 수행능력의 차이 및 기억 과제에 따른 해마의 신경 기전을 밝히고, (ㄴ) 성공 기억이 형성되는 과정에서 나타나는 신경세포의 발화 패턴의 특성을 살펴보았다. 본 연구를 통해 저자는 향후 기억의 형성 과정에서, 자극이 제시되는 구간뿐 만 아니라 자극이 주어지기 전 단계에서도 해마를 타깃 하여 전기 자극을 줌으로써 기억 실패로 이어질 수 있는 자극을 성공 기억으로 저장할 수 있도록 유도할 수 있을 것이라 기대한다.SECTION 1. INTRODUCTION 1 CHAPTER 1: Human Memory System 1 1.1. The hippocampus and memory 2 1.2. The structure of the hippocampus 3 CHAPTER 2: Human Memory Research: how to see a memory 4 2.1 Clinical rationale for invasive recordings with intracranial electrodes 4 2.2. Human intracranial EEG 6 2.3. Single unit activity recording and spike sorting in human 7 2.4. Direct brain stimulation study 9 CHAPTER 3: Human Memory Research: hippocampal activity for understanding successful memory formation 11 3.1. Functional role of human intracranial oscillatory activity in successful memory mechanism 11 3.1.1. Theta Oscillations 11 3.1.2. Gamma oscillations 13 3.2. Brain stimulation for memory enhancement 14 3.3. Single unit activity study in memory 15 CHAPTER 4: Purpose of the Present Study 17 SECTION 2. EXPERIMENTAL STUDY 19 CHAPTER 5: The importance of the hippocampal oscillatory activity for successful memory: direct brain stimulation study 19 5.1. Abstract 20 5.2. Introduction 22 5.3. Materials and Methods 25 5.3.1. Patients 25 5.3.2. Electrode localization 25 5.3.3. Memory task 29 5.3.4. Brain stimulation 30 5.3.5. Neuropsychological memory test 31 5.3.6. Analysis of memory performance and electrophysiological data 32 5.4. Results 37 5.4.1. Hippocampal stimulation improves associative memory but impairs item memory 37 5.4.2. Stimulation-induced memory enhancement is reflected in increased theta power during retrieval 38 5.4.3. Associative memory elicits higher theta power than item memory during encoding 42 5.4.4. Successful memory encoding elicits higher theta power in both memory task 44 5.4.5. Stimulation-mediated memory effect is greater in subject with poorer baseline cognitive function 46 5.5. Discussion 48 5.5.1. Summary 48 5.5.2. Task-dependent effects of hippocampal stimulation on memory 49 5.5.3. Theta activity as a neural signature for memory enhancement 51 5.5.4. Clinical implications 52 5.5.5. Limitations 54 5.5.6. Conclusion 55 CHAPTER 6: Hippocampal pre-stimulus activity predicts later memory success 57 6.1. Abstract 58 6.2. Introduction 59 6.3. Materials and Methods 62 6.3.1. Patients 62 6.3.2. Electrodes 63 6.3.3. Task and Stimuli 64 6.3.4. Electrophysiological recordings and Spike sorting 65 6.3.5. Analysis of iEEG field potentials 66 6.4. Results 68 6.4.1. Behavioral results 68 6.4.2. Spiking properties of hippocampal neurons 68 6.4.3. Hippocampal pre-stimulus activity correlates with successful memory 70 6.4.4. Hippocampal pre-stimulus spiking activity correlates with high gamma field potentials 74 6.5. Discussion 78 6.5.1. Summary 78 6.5.2. Comparison with previous findings 78 6.5.3. Possible mechanism underlying pre-stimulus activity 79 6.5.4. Conclusion 82 SECTION 3. GENERAL CONCLUSION 83 CHAPTER 7: General Conclusion and Perspective 83 Bibliography 84 Abstract in Korean (국문초록) 93Docto