Introductory Chapter: A Brief Survey of the Functional Roles of the Hippocampus

1. Introduction

Two views of hippocampal function have dominated the literature for the past half-century, each of which has experimental support. One view asserts that the hippocampus is primarily involved in some forms of memory, particularly episodic and long-term declarative memories (i.e., those that can be verbalized). This view was originally based upon the outcome of a surgery in the 1950s, when Scoville and Milner surgically resected a patient’s hippocampus to relieve epileptic seizures [1]; the hippocampus is critical for these forms of memory, as confirmed in subsequent human and animal studies.

A second view of hippocampal function is that it is involved in navigation by cognitively mapping our surroundings. This view followed the discovery of hippocampal place cells in rats [2]. The intensity of these cells’ activity depended on the animal’s location within a baited maze; their relevance to behavior was demonstrated through deficits in navigation following hippocampal lesions [3, 4]. The human hippocampus is similarly involved in navigation [5, 6, 7].

These two views of hippocampal function are not mutually exclusive; memory of the spatial location of stimuli is essential for navigation, and spatial locations provide contextual information that is embedded into memories. Whether these properties of the hippocampus represent different functions or different facets of the same function has been debated [8, 9, 10, 11].

With the advent of in vivo neuroimaging techniques, the hippocampus has been implicated in additional cognitive functions, with hippocampal dysfunction observed in a variety of neurological disorders. This chapter provides brief survey of these findings.

2. Learning and memory

A hippocampal role in learning and memory was identified in the mid-twentieth century from lesion studies. Later in the century, neuroimaging methods were developed to examine differential activity between tasks that differed in memory or other cognitive function, including methods to identify neural activity during individual trials [12]. Regional increases in hippocampal activity were observed during learning and recall, and greater activity was observed during learning trials when the presented stimulus was later recalled successfully [13, 14]. The development of connectivity methods additionally allowed the influence of the hippocampus on other brain regions to be characterized during different types of memory, both during memory acquisition (learning) and recall.

2.1 Learning (memory acquisition)

Different types of memory have been identified based on the conditions in which they occur and the duration of time they may be recalled. Activity in the hippocampus has been observed for many of them; however, the hippocampus is recognized as essential or intimately involved in the acquisition of three of these: episodic, spatial, and motor memory.

2.1.1 Episodic memory

Episodic memory involves the formation and recall of a one-time unique event in one’s experiences. The hippocampus is essential for the formation of new episodic memories [15]; however, the hippocampus and prefrontal cortex are jointly involved in the formation as well as recall of episodic memory, with bidirectional flow of information between them [16, 17].

In episodic memory formation, the anterior parahippocampal gyrus (entorhinal and perirhinal cortices) encodes a single item, whereas the hippocampus encodes the relation between stimuli; relevant contextual information is selectively activated in the parahippocampal cortex [18]. A similar pattern of activation is found during episodic memory retrieval.

2.1.2 Spatial memory in navigation

Consistent with its proposed function as a cognitive spatial map [2, 19], hippocampal activity during virtual navigation experiments has been correlated with spatial cues [20, 21, 22]. The hippocampal map of space is primarily allocentric [6, 23, 24, 25, 26, 27], although other frameworks have also been reported [28, 29]. The hippocampal allocentric map interacts with brain regions that use an egocentric framework. Navigational strategies specify from memory the locations of sensory reference points, suggesting the hippocampal system organizes relational experiences in memory [30]. Functional interactions between the hippocampus and prefrontal cortex occur during goal-directed navigation [31].

2.1.3 Motor learning and memory

The hippocampus is involved in motor learning [32, 33, 34] and motor memory consolidation [35]. Connectivity analysis shows the hippocampus primarily influencing the contralateral somatosensory cortex during motor learning, differing from the pattern observed during paced repetitive movements in the absence of motor learning [36].

2.2 Memory recall

Hippocampal properties are consistent with its role in memory recall. Pattern separation and pattern completion are two such properties, localized in different regions of the hippocampus.

Pattern separation transforms similar sensory representations or memories into highly dissimilar representations, distinct from each other; this transformation occurs in the hippocampus, whose pattern of activity differs from that of its inputs [37]. Activity associated with pattern separation is most pronounced in the posterior hippocampus [38], particularly in the CA3 and dentate gyrus regions [39, 40, 41, 42]. By contrast, pattern completion reflects expectations about what distinct stimuli are likely to appear based on prior experience. The anterior hippocampus is preferentially involved in pattern completion [38]. The CA3 region supports processes involved in spatial pattern completion (as well as pattern separation), spatial pattern association, novelty detection, and short-term memory [40]. Pattern completion in the hippocampus has been linked to predictive coding in the visual cortex [43].

Some hippocampal neurons fire at successive moments during temporally structured experiences, thus representing the flow of time during specific memories; these have been dubbed 'time cells'. Time cell properties parallel those of hippocampal place cells, providing an additional dimension to be integrated with spatial mapping [44]. The CA1 region supports processes associated with temporal pattern completion, temporal pattern association and intermediate-term memory [40].

Recollection as a form of memory recall is distinct from familiarity. Studies of humans, monkeys, and rats using multiple techniques suggest that the hippocampus is critical for recollection but not familiarity [45]. Recollection can be triggered by a cue that shares one or more elements with the original memory, so by using a cue, the chronology of memory recall can be studied. Pattern completion in the hippocampus begins 500 ms after cue onset, triggering the reinstatement of the target memory in neocortex between 500 and 1500 ms; this gives rise to the subjective feeling of recollection [46]. This process engages temporal dynamics, including the reversal of perceptual processing streams and clocking by theta rhythms.

3. Context and cognition

Hippocampal properties include sensitivity to temporal and spatial relationships [47, 48, 49], which play a role in scene perception and reconstruction [50]. Some interpret these properties as contextual elements required for memory recall [9, 44, 47]; others suggest a more fundamental perceptual role, which may consequently be incorporated into memories [51, 52]. As evident from the examples below, differences between these viewpoints are often nuanced.

According to one viewpoint [53], space and time break up experiences into specific contexts; these features help organize multimodal inputs. If relevant, additional dimensions (such as emotions) can also be incorporated into an event-defined context. Conceiving of hippocampal representations as constrained by task demands, this viewpoint attempts to unify disparate findings on hippocampal representations of space, time, and other dimensions on its core function.

Another theory describes a prefrontal-hippocampal comparator for voluntary action [54, 55]. Action plans are elaborated by the prefrontal cortex, and serve to guide goal-directed behavior. The prefrontal cortex initiates its plan by transmitting an “efference copy” (corollary discharge) to the CA1 region of the hippocampus, which stores it in working memory. This efference copy includes the expected outcomes of the action plan, including the personal and subjective experience of the intended behavior, when, and in what context. The CA1 region of the hippocampus compares the response intention with the actual outcome through cortical interactions mediated through the hippocampal theta rhythm; the theta power serves as a prediction error signal during hippocampal dependent tasks. When a mismatch occurs, an error signal in the hippocampus is transmitted to the prefrontal cortex, the action plan is reformulated, and working memory is updated. When the expected and actual outcomes match, the hippocampus transmits a signal to strengthen or consolidate the action plan in prefrontal cortex.

The hippocampus and the ventromedial prefrontal cortex interact when making decisions, integrating episodic memory via the hippocampus with value-based decision-making via the ventromedial prefrontal cortex [56]. The anterior parts of the hippocampus in humans (the ventral hippocampus in rodents) may also contribute to approach-avoidance conflict decision-making [57]. Such a scenario arises when a goal stimulus is simultaneously associated with reward and punishment.

The hippocampus has been suggested to play a critical role in behavioral flexibility. Cognition and social behaviors often require flexible use of information that can result from the formation, recombination, and reconstruction of relational memory representations. By filling this function, the hippocampus may play an instrumental role in abilities as diverse as decision-making, character judgments, establishing and maintaining social bonds, empathy, social discourse, navigation, exploration, creativity, imagination, memory, and language use [58].

3.1 Cognitive deficits associated with hippocampal dysfunction

During the progression of Alzheimer’s, changes are observed in hippocampal size [59, 60], function [61], and connectivity [62, 63]. Degenerative processes result in the accretion of plaques and tangles; their presence indicates the local loss of neuronal function. Plaques and tangles first appear in the entorhinal cortex, followed shortly thereafter in the hippocampus itself [64, 65, 66].

In schizophrenia, connections between the hippocampus and prefrontal regions are dysfunctional, consistent with a dysconnection syndrome [67].

Parkinson’s, at least in some cases, may also involve the hippocampus. A gene that contributes to familial and juvenile Parkinsonism disrupts hippocampal synaptic transmission in vitro [68]; if the hippocampus plays a role in cognitive control [69], this could result in motor dysfunction. The hippocampus has also been implicated in the cognitive dysfunction observed in some Parkinson’s patients [70].

Cognitive effects of concussions may also arise, at least in part, from damage to the hippocampal system [71, 72]. During concussions, blunt force to the skull typically generates torsional forces that damage the brain. The greatest torsional forces appear in the interior of the skull, including the corpus callosum and nearby structures such as the hippocampus [73, 74, 75]. These forces stretch nerve fibers in the region, resulting in necrosis.

Alterations in hippocampus size or function have also been noted in other neurological conditions, including depression [76, 77], ADHD [78, 79], and PTSD [80, 81].

3.2 Neurogenesis and environmental enrichment

With the proliferation and differentiation of adult neural stem cells, new neurons are generated throughout adulthood in the subgranular zone of the dentate gyrus in the hippocampus [82]. Adult hippocampal neurogenesis is thought to play a major role in hippocampus-dependent functions. By integrating new neurons with the structural plasticity of mature neurons, adult neurogenesis may maintain hippocampal plasticity in its circuits [83]. Adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation [84] as well as spatial learning [85]. Exercise has been suggested to increase the production of neurons, whereas environment enrichment increases the likelihood of their survival through cortical restructuring [85]. This restructuring results from a transient increase in cell activity and structural plasticity, which leads to improved cognition [86].

4. Executive function (cognitive control)

As more information about hippocampal activity has accrued, other roles for the hippocampus have also been suggested, including a role in cognitive control [28, 29, 69, 87]. Cognitive control refers to processes that organize different thoughts, separate currently-relevant and irrelevant information, and coordinate thoughts and actions. One report reviewed place cell studies that used experimental manipulations to dissociate the environment into two or more spatial frames of locations, typically to test notions of pattern separation. The ensemble discharge in the hippocampus self-organized into multiple, transiently-organized representations of space; separate representations of frame-specific positions alternated on timescales from 25 ms to several seconds. The dynamic, functional grouping of discharge predicted the animal’s behavioral needs, which suggested a hippocampal role in cognitive control [28].

A broader role in cognitive control, perhaps in conjunction with the prefrontal cortex, has been suggested based on a consistent pattern showing increased hippocampal connectivity with whichever cortical areas are required for task performance [69]. During a volitional movement task, for example, the specificity of this connectivity was pronounced, with hippocampal connectivity linked spatiotemporally to the representation of the moving finger [87].

5. Consciousness

The hippocampus has been suggested to play a role in conscious perception by integrating information that identifies an object with its spatiotemporal location, embedded within an emotional context [88, 89, 90]. In this view, the hippocampus acts via the medial prefrontal cortex, influencing prefrontal top-down attentional control of sensory processing and thus event memory formation. Citing specific functional deficits in the hippocampus and its neurochemical connections with prefrontal cortex, the authors suggest that weakly-related sensory representations within the hippocampus underlie hallucinations in schizophrenia [88].

Recently, the hippocampus has been proposed to play a central role in all features associated with the normal alert state of consciousness [91]. This state is defined by cognitive characteristics associated with consciousness in a neurologically-intact individual who is awake and alert; this includes sensory perceptions, learning, memory, attention, language, thoughts, emotional responsiveness, decision-making, and motor control. Using evidence from connectivity analyses, Burman demonstrates hippocampal influences on relevant cortical areas involved in all these cognitive processes. Details of his model (and some of his findings) reflect the joint influence from homotopic regions of the left and right hippocampus, the consistent finding that hippocampal connectivity increases in regions that execute a task, and its influence on other regions (especially prefrontal cortex and the precuneus) that support task performance. By recalling memories of self-experiences across periods of sleep and earlier periods of one’s life, the hippocampus is also noted to show characteristics consistent with the conscious sense of self.

6. Hippocampus: one function or many?

The hippocampus has been implicated in many cognitive functions and disorders. One question that arises is whether the hippocampus is functionally diverse, perhaps with different regions specialized for different functions, or whether the various functions ascribed to the hippocampus may all result from its known role in memory. Tasks that are not intended to involve memory almost invariably require a mnemonic component; even a repetitive tapping task that avoids motor learning [36] requires a subject to remember what behavior is required. Hippocampal properties that do not reflect the traditional relationship to memory or learning, such as sensitivity to time or spatial relationships, may reflect contextual elements that are essential for memory [9, 44, 49, 51]. If all properties of the hippocampus are consistent with the requirements for creating and recalling memories, however, the functionality of the hippocampus extends beyond our traditional view of memory, as the hippocampus is involved in decision-making, navigation, intentional movements, language, and many other cognitive functions.

Improvements in experimental methods have helped elucidate the hippocampal role in such diverse functions. Effective connectivity analysis, for example, examines the directional influence of one brain area on another; using this tool, hippocampal influences are observed to be selective for those brain areas relevant for task behavior. Depending on the task, the hippocampus inversely influences activity in sensorimotor cortex for motor tasks, the ventral occipital color region for tasks requiring attention to color (Stroop task and a conjunction task requiring attention to both color and shape), auditory association cortex when presented with annoying sounds, the temporal phonology region when making a rhyming judgment, and the temporal semantic region when making semantic judgments [69]. These influences do not reflect the activation of a specific memory, and thus is inconsistent with a direct role in recall; rather, they reflect the collective influence of memories through the hippocampus on processing in sensory and motor areas of the brain.

Similarly, the hippocampus shows bidirectional interactions with prefrontal cortex during tasks that require planning and memory recall [5, 92, 93]. The hippocampus coordinates brain functions associated with cognitive functions through theta waves and cross-frequency coupling [94, 95, 96, 97, 98, 99, 100, 101]. Hippocampal functionality often appears to be mediated, directly or indirectly, through other brain regions.

Involvement of the hippocampus in diverse cognitive processes thus results from extensive interactions with other brain regions depending on the task at hand. Although the functional properties of the hippocampus may be described in relationship to memory, the functionality of the hippocampus goes far beyond.

7. Conclusion

The hippocampus is best known for its essential role in episodic, declarative long-term memories, yet a survey of findings indicates a much broader role in cognition. Hippocampal influences on other brain regions are extensive, but appear to be specific to the cognitive requirements of the task at hand.