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Systems neuroscience has increasingly moved beyond localizationist views of brain function toward circuit-level models in which cognition emerges from dynamic interactions among distributed brain regions. This chapter traces that transition through the study of hippocampal function, beginning with clinical evidence from medial temporal lobe amnesia and the discovery of hippocampal place cells, which contributed to the development of the cognitive map framework. Subsequent research demonstrated that hippocampal representations are far more dynamic and context-dependent than initially proposed, incorporating information about trajectories, behavioral states, and temporal sequences. Oscillatory coordination during theta and sharp-wave ripple states, together with ensemble reactivation during experience and sleep, further illustrates how hippocampal networks organize and integrate information.A central theme is that hippocampal function cannot be understood in isolation but is embedded within broader neural networks, particularly interactions with the medial prefrontal cortex. Communication between these regions is enhanced during spatial working memory and is associated with successful behavioral performance. The nucleus reuniens of the ventral midline thalamus is highlighted as a key regulator of hippocampal–prefrontal communication, coordinating activity across these regions and supporting network synchrony. Finally, translational research in fetal alcohol spectrum disorders demonstrates how disruption of hippocampal–prefrontal–thalamic circuitry, with particular vulnerability of the nucleus reuniens, is associated with impairments in spatial working memory and executive function. Together, these findings illustrate how circuit-level dysfunction can provide a mechanistic link between alterations in neural communication and cognitive deficits.
Department of Psychological and Brain Sciences, University of Delaware, Newark, USA
*Address all correspondence to: amygriff@udel.edu
1. Introduction
Over the last couple of decades, behavioral and systems neuroscience has increasingly emphasized circuit- and network-level models of brain function, moving beyond earlier approaches that emphasized the role of individual brain regions in isolation. This shift has been driven in part by advances in neural recording techniques, including high-density single-unit recordings in animal models and high-resolution functional MRI in humans, which together have enabled the measurement of activity across distributed brain systems.
In this chapter, we focus on one such distributed circuit – the hippocampus, the midline thalamic nucleus reuniens (RE), and the medial prefrontal cortex (mPFC) – which provides a useful model for understanding how interactions among brain regions support complex cognition. This circuit has been implicated in coordinating memory retrieval with executive processes to support memory-guided decision making.
2. An abbreviated history of the role of the hippocampus in cognition
The hippocampus has a long history of being linked to two major cognitive domains: spatial cognition and memory, often framed as competing accounts in the literature. Rather than viewing these as mutually exclusive explanations, a more current perspective holds that both capture important aspects of hippocampal function within a broader distributed system. Spatial navigation and memory are complex cognitive operations that depend on interactions among multiple brain regions, rather than a single structure operating in isolation. Early lesion studies provided critical evidence that the hippocampus, particularly its dorsal region, is necessary for intact performance on spatial memory tasks [1, 2], but they could not fully specify its role within the wider circuit. Thus, while hippocampal damage impairs memory for spatial contexts and related behaviors, this does not imply that the hippocampus alone “stores” spatial or episodic representations. Instead, these findings are more accurately interpreted as evidence that the hippocampus is a core component of a larger circuit required for spatial memory, such that disrupting the circuit compromises performance.
2.1 From place cells to LTP: The hippocampus in spatial memory
The 1970s marked a pivotal decade in systems neuroscience, characterized by two major discoveries that reshaped the understanding of hippocampal function in cognition. Prior to this period, much of what was known about the hippocampus came from studies of human patients, most notably patient H.M. (Henry Molaison), who exhibited profound anterograde amnesia following bilateral medial temporal lobe resection [3–5].
First, in 1971, O’Keefe and Dostrovsky reported that they had discovered that hippocampal neurons discharge preferentially when a rat occupies a specific location in an environment [6]. These neurons were later termed “place cells.” Building on this discovery, O’Keefe and Nadel [7] proposed that the hippocampus constructs a cognitive map of the environment, providing a spatial framework for organizing memory and guiding behavior. This work also initiated a surge of experimental research on hippocampal function and, in parallel, drove major advances in in vivo electrophysiological recording techniques [8], developments that continue to shape the field today [9, 10].
Just a few years later, Bliss and Lømo [11, 12] discovered that high-frequency stimulation of the perforant path – a projection from the entorhinal cortex to the dentate gyrus – produced a persistent increase in the amplitude of the field excitatory postsynaptic potential (fEPSP), lasting at least six hours. This phenomenon, termed long-term potentiation (LTP), was particularly significant because it provided a physiological mechanism consistent with activity-dependent synaptic strengthening, a key candidate process underlying memory formation.
Place cells and LTP established two essential components of hippocampal function: structured neural representations of space and a cellular mechanism for synaptic modification. Yet cognition does not emerge from representation or plasticity alone. For memory to guide behavior, neural activity must be coordinated across time and across distributed brain regions. Understanding how the brain solves this coordination problem requires moving beyond single-neuron and synaptic mechanisms to consider population-level dynamics. This motivates a focus on neural oscillations as a mechanism for organizing communication within and between hippocampal–prefrontal circuits.
2.2 Theta, ripples, and everything in between: The role of hippocampal oscillations
One of the most prominent oscillations in the hippocampus is the theta rhythm. This 8–12 Hz oscillation has been implicated in a wide range of behaviors, but is most consistently associated with exploratory behavior and rapid eye movement (REM) sleep [13]. While a comprehensive review of hippocampal theta is beyond the scope of this chapter, a key concept is that theta, along with other slow oscillations, is thought to provide a mechanism through which distributed brain regions can coordinate activity over distance.
At the level of single neurons, action potentials reflect the output of a local circuit, whereas network oscillations reflect the interaction between intrinsic cellular properties and convergent synaptic inputs. For a coherent oscillation to emerge, synaptic currents must be temporally coordinated across populations of neurons. In this sense, large-scale, low-frequency oscillations reflect the synchronized influence of multiple afferent systems. In the hippocampus, theta is strongly shaped by inputs from the medial septum, which provides rhythmic modulation of inhibitory interneurons, as well as from the entorhinal cortex, which integrates multimodal sensory information, including self-motion signals (e.g., vestibular and proprioceptive input) and external sensory inputs from visual, somatosensory, auditory, olfactory, and gustatory cortices.
Importantly, this framework is supported by causal evidence indicating that theta-frequency activity is not merely correlated with spatial working memory performance but can actively influence it. Work in my lab demonstrated that optogenetic inhibition of the medial septum impairs spatial working memory [14]. Using viral-mediated expression of light-sensitive opsins, we selectively targeted medial septal neurons and transiently suppressed their activity with light during task performance. This approach allowed us to reversibly manipulate septal output with millisecond precision while animals performed a delayed spatial alternation task, providing a direct test of the causal role of septal activity in memory. In contrast, optogenetic stimulation of the medial septum at theta frequency enhances performance on a delayed spatial alternation task, particularly under conditions of high memory demand [15]. Remarkably, stimulation delivered at the endogenous theta frequency improved performance, whereas stimulation at non-theta frequencies did not produce the same behavioral benefit, underscoring the importance of temporal coordination rather than simply increasing neural activity. Concurrently recorded hippocampal local field potentials confirmed that septal inhibition disrupted hippocampal theta oscillations, whereas theta-frequency stimulation enhanced theta synchrony, linking the physiological effects of septal modulation directly to behavioral performance. These findings indicate that septal drive can regulate hippocampal theta dynamics in a manner that improves behavioral performance, providing direct evidence that theta-frequency coordination plays a functional role in spatial working memory.
Together, these results support a model in which theta oscillations serve as a dynamically regulated temporal framework that can be modulated by input structures such as the medial septum to optimize memory-guided behavior.
At the opposite end of the frequency spectrum are hippocampal sharp-wave ripples (SWRs), brief high-frequency oscillations that occur synchronously in CA1 and reflect coordinated bursts originating in CA3 [16]. During these events, CA1 pyramidal neurons fire strongly, and SWRs are thought to support the offline reactivation and transfer of hippocampal representations to distributed cortical targets. Consistent with this idea, hippocampal ensembles have been shown to replay sequences of neuronal activity during SWRs that recapitulate the order of firing observed during prior exploratory behavior [17–19].
These oscillatory patterns highlight a key principle of hippocampal function: neural activity is organized into temporally structured events that coordinate communication within and between brain regions. However, this raises an additional question: what is the content of the information being transmitted within these oscillatory time windows? In other words, how does hippocampal activity represent not only where an animal is, but also where it is going? Addressing this question requires moving from population-level dynamics to task-dependent modulation of single-cell firing, which leads to the phenomenon of trajectory coding in hippocampal neurons.
2.3 Hippocampal trajectory coding
How can the hippocampus represent both the spatial layout of an environment and the specific experiences that occur within it? A landmark study addressing this question was conducted by Emma Wood while she was training in Howard Eichenbaum’s laboratory. Wood et al. [20] recorded hippocampal CA1 neurons while rats performed a continuous spatial alternation task in a modified T-maze. In this task, rats began each trial from a common start location, traversed a shared central stem, and then chose either the left or right goal arm to obtain a food reward. To receive a reward on subsequent trials, animals were required to alternate between the two goal arms, creating distinct trial types despite identical movement through the central portion of the maze. This design allowed investigators to determine whether hippocampal neurons encoded only an animal’s current location or also incorporated information about the animal’s recent experience and upcoming behavioral choice. A key feature of this task is that animals must alternate visits to the left and right goal arms to obtain a reward. As a result, rats traverse the same central stem of the maze on both left-bound and right-bound trials. If hippocampal neurons encode only spatial location, then firing rates on the stem should be similar regardless of the animal’s intended destination. In contrast, if hippocampal activity incorporates information about the animal’s current goal or recent experience, neuronal firing should differ between left-bound and right-bound trajectories.
Consistent with the latter hypothesis, a substantial proportion of CA1 neurons exhibited trajectory-dependent firing, discharging differently on the central stem depending on whether the rat was about to turn left or right. These neurons became affectionately known as “splitter cells” within the Eichenbaum laboratory and beyond [20]. Similar trajectory-dependent firing has since been observed by multiple laboratories using a variety of maze configurations, including plus mazes, in which rats approach the same intersection before turning in different directions [21]; standard and continuous T-mazes [22, 23]; and W-mazes, which require animals to navigate overlapping trajectories while alternating between multiple reward locations [24]. Across these diverse maze configurations, neurons consistently distinguished between overlapping paths according to the animal’s experience or intended destination rather than spatial location alone.
Why was the discovery of trajectory coding so influential? At the time, the finding challenged a prevailing view that hippocampal neurons primarily represented an animal’s current location within space. The demonstration that neurons could distinguish between identical spatial locations based on an animal’s past experience or future behavioral goal suggested that hippocampal representations contain more than spatial coordinates alone. Instead, hippocampal activity appears to integrate information about location with information relevant to memory and behavior. Notably, these findings predated the discovery of grid cells in the entorhinal cortex [25], which would later provide evidence that spatial representations are distributed across a broader network. Trajectory coding, therefore, helped shift the field toward the idea that hippocampal representations are shaped not only by where an animal is, but also by where it has been and where it intends to go.
3. The prefrontal cortex communicates with the hippocampus
Trajectory coding also raised an important question: how are these memory-relevant representations used to guide behavior? Encoding an animal’s past experiences, current location, and future goals is only useful if that information can influence ongoing decisions. Tasks such as continuous alternation require animals not only to remember where they have been but also to use that information to select an appropriate future action. Such behaviors are unlikely to be supported by the hippocampus in isolation. Rather, they require interactions between brain systems specialized for memory and those involved in executive control, behavioral flexibility, and decision making.
The mPFC has long been implicated in many of these executive functions, including working memory, behavioral planning, and the selection of actions based on past experience [26, 27]. As evidence accumulated that hippocampal representations contain information relevant to memory-guided behavior, attention increasingly shifted toward understanding how the hippocampus communicates with the prefrontal cortex.
By the early 2000s, growing evidence that hippocampal representations contain information relevant to memory-guided behavior led researchers to investigate how the hippocampus interacts with the mPFC during cognitive tasks. This period marked a surge of interest in hippocampal–prefrontal communication and the mechanisms by which these regions coordinate activity [26].
An influential theoretical framework for understanding these long-range interactions was proposed by Fries [28], who articulated the “communication-through-coherence” hypothesis. In this model, neuronal communication between distributed brain regions is dynamically regulated by oscillatory synchronization, such that effective communication occurs when neuronal populations are aligned in their phase of excitability. Rather than viewing oscillations as byproducts of neural activity, this framework proposes that rhythmic synchronization serves a functional role in selectively routing information between brain regions.
Within this context, coherence in specific frequency bands, such as theta in the hippocampal–prefrontal system, can be understood as a mechanism for temporally aligning periods of high excitability across connected networks. This alignment increases the likelihood that spikes generated in one region will effectively influence downstream targets in another, thereby providing a biophysical mechanism for selective communication. The communication-through-coherence framework has therefore been highly influential in shaping how large-scale brain rhythms are interpreted, particularly in studies of memory-guided behavior and interregional coordination.
Early electrophysiological work provided some of the first direct evidence that hippocampal activity is temporally coordinated with activity in the mPFC during behavior. Siapas et al. [29] demonstrated that spikes in prefrontal cortical neurons are systematically modulated by the phase of hippocampal theta oscillations, indicating that hippocampal network activity can structure the timing of prefrontal spiking even across anatomically distinct regions. This finding provided an important early demonstration that long-range coordination between the hippocampus and prefrontal cortex is organized at the level of oscillatory phase relationships.
Building on this framework, subsequent work from multiple groups showed that hippocampal–prefrontal synchrony is not only present but also dynamically modulated by behavioral demands and predictive of performance. A landmark contribution came from the laboratory of Jones and Wilson, in which they similarly found that mPFC neuronal activity is entrained to the hippocampal theta rhythm during spatial working memory performance, with significantly stronger hippocampal–prefrontal theta synchrony during correct than during error trials [30]. Benchenane et al. [31] reported that theta-band coupling between hippocampus and mPFC is stronger during correct trials in spatial working memory tasks, whereas weaker coordination is associated with errors, suggesting that effective communication between these regions is necessary for accurate decision making. Together, these findings provided converging evidence that oscillatory synchrony reflects a behaviorally relevant mechanism for coordinating information flow across distributed memory circuits, rather than a byproduct of arousal or movement.
Mechanistically, work from the Hasselmo laboratory further refined this view by showing that behaviorally responsive mPFC neurons dynamically switch between hippocampal theta-phase–entrained and non-phasic firing depending on task demands and behavioral context, providing evidence that prefrontal–hippocampal communication is flexibly coordinated through theta synchrony during memory-guided behavior [32, 33]. This striking observation suggests that hippocampal output can exert a selective influence on the timing of prefrontal spiking, rather than simply imposing a global oscillatory drive on the mPFC. Such selective entrainment offers a plausible mechanism by which information represented in hippocampal ensembles – such as spatial context, trajectories, or task-relevant memories – can be routed into prefrontal circuits. In this way, theta-coordinated hippocampal–prefrontal interactions provide a temporal framework through which memory representations can shape prefrontal computations involved in planning, decision making, and behavioral flexibility.
One contribution that my lab made to this research field was comparing hippocampal–prefrontal oscillatory synchrony across two tasks, one that requires spatial working memory and one that does not. We had previously developed a task that we called a visual–tactile conditional discrimination. In this task, rats are trained to visit the right or left goal arm of a T-maze depending on the texture and appearance of the floor inserts placed in the maze (Figure 1). For example, they learn to turn left if the floor is black mesh and right if the floor is smooth wood. Importantly, this task is independent of the hippocampus; dorsal hippocampal inactivation with muscimol did not disrupt choice accuracy in this task, whereas inactivation of the dorsal striatum impaired task performance [34].
Figure 1.
Schematic of the conditional discrimination task. Wooden or mesh floor inserts were used to guide choice behavior. Rats were randomly assigned to one of two insert–reward contingencies. Blue arrows indicate the correct trajectory, and red arrows indicate the incorrect trajectory. Top: Wood-left/mesh-right contingency, in which the left arm is correct when the wood insert is present. Bottom: Wood-right/mesh-left contingency, in which the left arm is correct when the mesh insert is present. The delay zone is indicated by the arrow at the bottom of the maze. Green dots indicate that food reward is available in the reward zone.
The critical experiment was to compare hippocampal–prefrontal oscillatory synchrony across the two tasks. Synchrony was assessed using both hippocampal–prefrontal theta coherence and the degree to which mPFC neurons were phase-locked to the hippocampal theta rhythm. If hippocampal–prefrontal interactions play a specific role in memory-guided decision making, synchrony should be enhanced during spatial alternation relative to conditional discrimination, despite the fact that both tasks require locomotion, reward seeking, and decision making. This design, therefore, allowed us to isolate the contribution of memory demands to hippocampal–prefrontal communication.
Consistent with this hypothesis, we found that hippocampal–prefrontal oscillatory synchrony was significantly stronger during spatial alternation than during visual–tactile conditional discrimination [35]. Both hippocampal–prefrontal theta coherence and the phase locking of mPFC neurons to the hippocampal theta rhythm were enhanced during performance of the spatial working memory task. These findings suggested that hippocampal–prefrontal synchrony is not simply a byproduct of task engagement. Rather, coordinated activity between the hippocampus and mPFC appears to be particularly important when memories must be used to guide ongoing decisions.
While these studies demonstrated a strong relationship between hippocampal–prefrontal synchrony and memory-guided behavior, they left open an important question: does synchrony simply correlate with successful performance, or can it actively influence behavioral outcomes? To address this question, Stout and colleagues developed a brain–machine interface that continuously monitored hippocampal–prefrontal theta coherence in real time and initiated trials when synchrony was either relatively high or low [36]. Remarkably, trials initiated during periods of strong hippocampal–prefrontal theta synchrony were associated with a higher probability of correct choices (Figure 2). Together, these findings suggest that synchronized brain rhythms are not merely epiphenomenal correlates of cognition but may help establish network states that bias behavior toward successful outcomes.
Figure 2.
High medial prefrontal cortex (mPFC)–hippocampal theta coherence enhances spatial working memory performance. (a) Experimental design showing electrode placements in the dorsal hippocampus and mPFC and the closed-loop task in which trials were initiated during periods of high or low mPFC–hippocampal theta coherence or at randomly timed control intervals. (b) Representative local field potential recordings from the mPFC and hippocampus during high- and low-coherence states. (c) Time-frequency coherograms illustrating elevated theta (6–10 Hz) coherence preceding trials triggered during high-coherence states. (d) Behavioral performance improved when trials were initiated during periods of high mPFC–hippocampal theta coherence compared with yoked and random-delay control trials, demonstrating that naturally occurring increases in interregional theta synchrony facilitate working memory performance. Adapted from a study by Stout et al. [36].
These results further strengthened the emerging view that cognitive functions such as spatial working memory arise from interactions among distributed brain regions. The findings also raised an important mechanistic question: how is communication between the hippocampus and mPFC coordinated? While direct projections exist from the hippocampus to the mPFC, the growing evidence for bidirectional functional interactions suggested that additional circuit elements may contribute to this communication. Increasingly, attention turned to the nucleus RE of the ventral midline thalamus, a structure ideally positioned to influence information flow between the hippocampus and the prefrontal cortex.
4. The nucleus RE orchestrates hippocampal–prefrontal synchrony during spatial working memory
The discovery that hippocampal and medial prefrontal cortical activity becomes synchronized during memory-guided behavior naturally raised the question of how these regions communicate. Anatomically, the nucleus RE of the ventral midline thalamus is uniquely positioned to support such communication. The RE receives inputs from the mPFC and other limbic structures and sends dense projections to both the hippocampus and mPFC. Importantly, a subset of RE neurons projects to both structures, providing a potential substrate for coordinating activity across the hippocampal–prefrontal network [27–29].
Interest in the role of RE in cognition increased substantially following anatomical studies demonstrating its strategic connectivity within limbic circuits. Early behavioral studies revealed that damage to the ventral midline thalamus impaired performance on tasks requiring flexible memory use, particularly when successful behavior depended on interactions between the hippocampus and prefrontal cortex [30, 31]. These findings suggested that RE might contribute to cognition not through independent information processing, but by facilitating communication among distributed brain regions.
Causal evidence for the role of the RE in hippocampal–prefrontal interactions has come from a series of lesion studies. Work by Dolleman-van der Weel et al. demonstrated that damage to the RE produces robust impairments in spatial working memory tasks, particularly those requiring flexible use of recent spatial information to guide future choices. These deficits are most clearly observed in delayed alternation paradigms, in which animals must maintain and update information across brief delay periods to select the correct response. Importantly, the behavioral consequences of RE lesions closely resemble those observed following disruption of hippocampal–prefrontal communication, suggesting that the RE is not simply a parallel contributor to memory processes, but rather a critical node required for coordinating activity between these regions. Consistent with this interpretation, lesion-induced impairments are most pronounced under conditions that place high demands on the integration of hippocampal representations with prefrontal executive control. Together, these findings support the idea that the RE is necessary for the functional coupling of the hippocampus and mPFC during spatial working memory [37].
One of the strongest areas of evidence implicating RE in cognition comes from studies of spatial working memory. Spatial alternation tasks require animals to remember recent choices and use that information to guide future decisions, making them highly dependent on interactions between the hippocampus and mPFC. Consistent with a role in coordinating these interactions, reversible inactivation of RE reliably impairs performance on delayed alternation and other spatial working memory tasks [32–35]. Importantly, these impairments often resemble those produced by disrupting hippocampal–prefrontal communication itself, supporting the idea that RE is a critical component of this circuit.
A key step in clarifying the functional role of the RE in hippocampal–prefrontal interactions came from work examining the temporal specificity of its contribution to spatial working memory. Using optogenetic suppression of RE activity in rats performing a delayed non-match-to-position task, my lab demonstrated that transient inhibition of the RE selectively impairs the encoding phase of spatial information, while leaving delay and retrieval phases relatively intact [38]. This phase-specific disruption suggests that the RE is particularly important for the initial formation of hippocampal-dependent representations that are later used to guide decision making.
These findings provide important mechanistic insight into how RE contributes to hippocampal–prefrontal communication. Rather than serving as a uniform relay across all task epochs, RE appears to exert its strongest influence when new spatial information must be integrated into an existing mnemonic framework. This encoding-specific role is consistent with the broader view that RE supports the temporal coordination of hippocampal–prefrontal interactions during moments when task demands require updating internal representations to guide future choices.
Electrophysiological studies have provided insight into the mechanisms underlying these behavioral effects. During spatial working memory tasks, neuronal activity in RE is coordinated with activity in both the hippocampus and mPFC, and RE neurons exhibit task-related firing patterns that reflect ongoing cognitive demands [39]. Furthermore, disrupting RE activity reduces hippocampal–prefrontal theta synchrony, suggesting that RE contributes to the temporal coordination of information transfer between these regions [35]. Inactivation of RE also disrupts trajectory-dependent coding in hippocampal neurons during spatial alternation, indicating that RE influences not only communication between structures but also the content of hippocampal representations themselves [39]. Notably, Stout et al. [36] also reported that interactions between the mPFC and the ventral midline thalamus were elevated during periods of strong hippocampal–prefrontal theta synchrony. Moreover, optogenetic manipulation of the ventral midline thalamus altered hippocampal–prefrontal network synchrony, providing causal evidence that thalamic circuitry can regulate the coordination between hippocampal and prefrontal activity.
Together, these findings support a model in which the RE acts as a hub within the hippocampal–prefrontal network (Figure 3). Rather than serving as a passive relay, the RE appears to coordinate the exchange of information necessary for memory-guided decisions. By regulating communication between hippocampal representations of past experience and prefrontal mechanisms involved in action selection and behavioral flexibility, the RE enables animals to use memory to guide ongoing behavior.
Figure 3.
Proposed role of RE in coordinating hippocampal–prefrontal interactions during memory-guided behavior. RE occupies a central position within the distributed circuit linking the hippocampus and medial prefrontal cortex. Through reciprocal connections with both regions, RE contributes to coordinating information transfer and synchronizing neural activity, particularly in the theta frequency range. Inputs from the medial septum further modulate hippocampal theta oscillations that facilitate communication across the circuit. Dynamic interactions among these regions support spatial working memory, deliberation, flexible navigation, and memory-guided decision making. Dysfunction of this circuit has been implicated in disorders including fetal alcohol spectrum disorders.
Findings from systems neuroscience have important translational implications for understanding neurodevelopmental disorders that impair executive function and memory-guided behavior. Fetal alcohol spectrum disorders (FASD) represent a prominent example in which developmental disruption leads to long-lasting cognitive deficits, particularly in spatial working memory, behavioral flexibility, and decision-making. Rather than arising from isolated regional damage, these impairments increasingly appear to reflect dysfunction within distributed hippocampal–prefrontal–thalamic networks.
A growing body of work from the Klintsova laboratory has provided converging evidence that the thalamic nucleus RE is a particularly vulnerable node in this circuit. Early studies demonstrated that developmental alcohol exposure produces significant neuronal loss and volume reductions in RE, suggesting that this structure may be selectively sensitive to ethanol during critical periods of brain development [40, 41]. Subsequent work further established that these structural alterations are persistent and can be observed following both high- and moderate-dose exposure paradigms, indicating that RE vulnerability is robust across a range of developmental insults [42].
Importantly, this structural vulnerability is accompanied by alterations in circuit organization. In rodent models of third-trimester–equivalent alcohol exposure, prefrontal projections to the thalamus are reorganized, and patterns of hippocampal–prefrontal connectivity are disrupted [42]. These findings suggest that FASD is associated not only with damage to individual brain regions but with altered connectivity within the extended hippocampal–prefrontal system.
At the behavioral level, these circuit disruptions are associated with impairments in tasks requiring executive control and spatial working memory. Animals exposed to developmental alcohol exhibit deficits in deliberative behaviors and reduced flexibility during decision-making, consistent with disrupted integration of hippocampal representations with prefrontal action-selection mechanisms [43]. Given the emerging role of the nucleus RE in coordinating hippocampal–prefrontal communication, damage to this structure may represent a mechanistic link between developmental alcohol exposure and impaired network synchrony.
Together, this body of work supports a circuit-level interpretation of FASD in which cognitive impairments arise from disrupted coordination across the hippocampus, prefrontal cortex, and ventral midline thalamus. Within this framework, the nucleus RE emerges as a particularly important locus of vulnerability, providing a potential mechanistic explanation for how developmental perturbations translate into long-term deficits in memory-guided behavior.
6. Conclusion
Over the past several decades, the study of hippocampal function has undergone a fundamental transformation. Early work, driven by lesion studies and single-region interpretations of behavior, established the hippocampus as critical for memory. The case of patient H.M. provided compelling evidence that damage to the medial temporal lobe produces profound anterograde amnesia, firmly linking the hippocampus to the formation of new declarative memories. Subsequent discoveries in animal models, including the identification of place cells and the development of the cognitive map theory, extended this view by demonstrating that hippocampal neurons encode structured representations of space that can support behavior.
As recording techniques advanced, it became increasingly clear that hippocampal representations are not limited to static spatial coordinates. Trajectory-dependent firing, ensemble reactivation during SWRs, and oscillatory coordination during theta rhythms all revealed that hippocampal activity is dynamically modulated by behavioral context, past experience, and future goals. These findings collectively shifted the field away from viewing the hippocampus as a unitary spatial or mnemonic module and toward understanding it as a system that generates flexible, experience-dependent representations.
A parallel line of work demonstrated that these representations do not operate in isolation. Instead, hippocampal activity is embedded within distributed networks involving the mPFC and other cortical and subcortical regions. Evidence for theta-phase coordination, task-dependent synchrony, and the selective engagement of hippocampal–prefrontal interactions during memory-guided behavior highlighted the importance of interregional communication in cognition. Importantly, these interactions appear to be particularly pronounced when behavior requires the integration of past experience with ongoing decision making.
Within this broader circuit framework, the nucleus RE of the ventral midline thalamus has emerged as a key structure for coordinating hippocampal–prefrontal communication. Anatomically positioned to influence both regions, and functionally implicated in regulating synchrony and supporting spatial working memory, RE provides a mechanistic substrate through which distributed memory systems may be dynamically coupled. Rather than serving as an isolated hub of computation, it appears to shape the conditions under which hippocampal representations can influence prefrontal processes.
Together, these lines of work support a shift in perspective from localizationist accounts of brain function toward a circuit-based view of cognition. Memory-guided behavior emerges not from any single structure, but from the coordinated activity of interacting networks whose dynamics are shaped by oscillatory synchronization, task demands, and anatomical connectivity. Understanding these interactions across the hippocampus, prefrontal cortex, and thalamic midline structures provides a framework for explaining how past experience is transformed into adaptive behavior in the present.
Importantly, this circuit framework also provides a translational lens for understanding neurodevelopmental and neuropsychiatric conditions. In FASD, disruption of hippocampal–prefrontal–thalamic networks – particularly the vulnerability of the nucleus RE – leads to impairments in spatial working memory and executive function. These findings suggest that cognitive deficits may arise not only from dysfunction within individual brain regions, but also from altered coordination across the networks that normally support flexible, memory-guided behavior.
Acknowledgments
This work has been supported by federal and institutional funding over the course of my research program. Key support has come from the National Institute of Mental Health and the National Institute on Alcohol Abuse and Alcoholism, including an R01 focused on hippocampal–thalamo–prefrontal circuitry in a model of fetal alcohol spectrum disorders (R01 AA027269; PI: A. Klintsova; Co-I role) and NIMH-funded work examining hippocampal–prefrontal synchrony in spatial working memory (R01 MH102394; R21 MH117687; PI role). Early support from an NIMH F32 fellowship (F32 MH070184; PI role) and the University of Delaware Research Foundation helped establish the foundational studies linking prefrontal and hippocampal activity to spatial memory processes.
Additional support was provided through participation in the COBRE-funded Delaware Center for Neuroscience Research (P20 GM103653), where I served as Target Investigator on work examining medial prefrontal contributions to behavioral plasticity.
Conflict of Interest
The author declares no conflict of interest.
Notes/thanks/other declarations
I am deeply grateful to the students and trainees who have contributed to this work over the past two decades. This research program has been shaped in fundamental ways by their intellectual curiosity, experimental rigor, and commitment to discovery. To name just a few: Henry Hallock, John Stout, SuHyeong Kim, Zachary Gemzik, Hailey Rosenblum, Meg Donahue, Greg Peters, Dylan Layfield, Arick Wang, Kat Cline, Crystal Shaw, Glenn Watson, Peter Adelman, Adrian Arreola, Eric Myhre, Brett Emanuel, Allison George, Suhaas Adiraju, and Jackson Mace.
I am also deeply grateful to my colleagues and collaborators, whose scientific partnership has been essential to this work: Anna Klintsova, Jaclyn Schwarz, Philip Gable, Joshua Neunuebel, and Manuel Scottdorf.
I am also profoundly indebted to my mentors, both formal and informal, whose guidance helped launch and sustain my scientific career. In particular, I would like to acknowledge Howard Eichenbaum, Michael Hasselmo, and Rebecca Burwell, whose mentorship, insight, and support have been invaluable through both the successes and challenges of this work. I reserve special gratitude for Stephen Berry, who not only trained me as a scientist but also modeled the possibility of building a fulfilling scientific career while maintaining a full and balanced life. His influence has been foundational in shaping how I think about both science and sustainability in academia.
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Written By
Amy Griffin
Submitted: 09 June 2026Reviewed: 20 July 2026Published: 20 August 2026
Open access peer-reviewed chapter - ONLINE FIRST
