|Gyorgy Buzsaki (2011), Scholarpedia, 6(1):1468.||doi:10.4249/scholarpedia.1468||revision #141265 [link to/cite this article]|
The hippocampus is a part of the forebrain, located in the medial temporal lobe. It is critical for the formation of those kinds of memories, which can be consciously declared. Due to its self-generated network patterns, newly acquired memories are gradually transferred to neocortical stores through the process of memory consolidation. The hippocampus, as the brain’s search engine also allows a fast and efficient search among the deposited memories in the neocortex, which is a process essential for planning the future and generating creative ideas. Most physiological studies on the hippocampus have been performed in rodents and gave rise to the spatial navigation theory. This, however, does not reflect a species difference. Instead, it appears that neural algorithms, perhaps evolved initially for computing first-order (neighborhood) and higher order (e.g., short-cuts, detours) distances in the physical world, are the same as those used for the navigation in cognitive space during recall and planning. Nearly all hippocampal functions are performed in collaboration with several of its partners, of which the most prominent is the entorhinal cortex, and strongly influenced by subcortical neuromodulators.
Hippocampal connections constrain functional operations
The banana-shaped hippocampus can be conceived as an appendage to the neocortex (Fig. 1). By way of its main partner, the entorhinal cortex, it communicates with all parts of the neocortex (Amaral and Lavenex, 2006). Two important principles emerge from such connectivity. First, since the main output target of the hippocampus are the same as its input source, its expected physiological contribution is to modify the connections of its inputs (i.e., circuits in the neocortex). Second, since all parts of the neocortex are represented in the hippocampus in a compressed manner and all neocortical regions can be addressed by the hippocampal-entorhinal output, hippocampal operations in different species largely reflect the nature of neocortical operations. With the large expansion of the neocortex during the mammalian evolution, the relatively small representation of associational areas in the ventral quadrant of the rodent hippocampus has become enlarged in primates (uncus and body; Fig. 1). A consequence of this anatomical organization is that insights about the global function of the hippocampus depend on the portion of the hippocampus being investigated and the species. Studying the physiological pattern of the dorsal hippocampus of the rat (corresponding largely to the tail of the primate hippocampus) gave rise to the cognitive map theory (O’Keefe and Nadel, 1978). In contrast, human studies involving surgical removal of the uncus and body of the hippocampus in drug treatment-resistant cases of epilepsy, such as the famous patient H. M., lead to the conclusion that the hippocampus is responsible for generating personal (autobiographical) or episodic memories (Scoville and Milner, 1957). These conceptual differences therefore should not be viewed as different functions from the viewpoint of the hippocampus (since hippocampal operations remain largely the same across all species and in all parts of the hippocampus). Instead, one may hypothesize that the neural algorithms that evolved initially for the computation of first-order (neighborhood) and higher order (e.g., short-cuts, detours) distances in the physical world are fundamentally the same as those used for navigation in cognitive space and for the computation of relationships among perceived, conceived or imagined items. Making a map requires exploration of the environment by self-referenced (egocentric) dead-reckoning type of navigation, (i.e., the same method as used by Christopher Columbus to discover the New World). Similarly, generation of semantic (i.e., self-independent or allocentric) knowledge requires prior self-referenced episodic experience. For these reasons, it has been hypothesized that the mechanisms underlying dead reckoning navigation and episodic memory ('navigation in cognitive space') are the same. Similarly, the mechanisms that support the cognitive map and semantic knowledge are also identical (Buzsáki, 2006).
Information in the multisynaptic feedforward loops of the entorhinal-hippocampal system is propelled mainly unidirectionally (Fig. 2). An important feature of this complex circuit is that recurrent excitatory networks are interposed between layers with largely parallel organization. The most extensive recurrent system in the brain is formed by the extensive collaterals of the CA3 neurons. Entorhinal layer 2 and layer 5 axon collaterals are also extensive. The advantage of this alternating pattern type of organization is that in successive layers the neuronal representations can be iteratively segregated (at parallel stages) and integrated (at recursive stages). These operations require time for computation before the results of local processing can be transmitted forward to the next computational stage. The speed of layer-to-layer transfer is controlled by the complex system of inhibitory interneurons. Such control dynamics, often in the form of network oscillations, provide time for local computation and enable the hippocampal system to communicate effectively with various domains of the neocortex in discrete temporal windows. The relatively simple cortical circuitry of the hippocampus has inspired many connectionist theories.
Network patterns of the hippocampus
Three major network patterns characterize the temporal dynamics of the hippocampal system: theta oscillations (4–10 Hz), sharp waves and associated ripples (140–200 Hz), and gamma (30–130 Hz) oscillations. These patterns also define states of the hippocampus. The theta state is associated with exploratory (preparatory) movement and REM sleep, while intermittent sharp waves mark immobility, consummatory behaviors, and slow-wave sleep (Fig. 4; MOVIE). These two competing states also largely determine the main direction of information flow, with neocortico-hippocampal transfer taking place mainly during theta oscillations and hippocampo-neocortical transfer during sharp waves. These two states also affect the regularity of gamma oscillations and switching between the states is largely determined by the subcortical neuromodulatory inputs to the hippocampal system.
Gamma frequency oscillations are present in all brain structures where fast inhibition is provided by soma-targeting interneurons (Whittington et al., 1995; Wang and Buzsáki, 1996; Bartos et al.; neural inhibition by Jonas and Buzsáki, 2007). In the simplest case, an interconnected network of basket interneurons can generate sustained gamma oscillations, provided that their depolarization and spiking are secured by some means (such as subcortical neurotransmitters). In the intact brain, gamma oscillations are mainly generated by the interaction between principal cells and interneurons. In both scenarios, the frequency of oscillations is mainly determined by the time course of GABAA receptor–mediated inhibition. Neurons that discharge within the time period of a gamma cycle (10–30 msec) define a cell assembly (Harris et al., 2003). Because the membrane time constant of pyramidal neurons in vivo is also within this temporal range, recruiting neurons into this assembly time window is the most effective mechanism for discharging the downstream postsynaptic neuron(s) on which the assembly members converge (Buzsáki, 2010). Although gamma oscillations can emerge in each hippocampal region, they can be coordinated across regions by either excitatory connections or by long-range interneurons.
The LFP theta oscillation is the result of coherent membrane potential oscillations across neurons in all hippocampal subregions (Buzsáki, 2002). Theta currents derive from multiple sources, including synaptic currents, intrinsic currents of neurons, dendritic Ca2+ spikes, resonance and other voltage-dependent membrane oscillations. The theta rhythm modulation of perisomatic interneurons provides an outward current in somatic layers. The theta rhythm phase therefore biases the power of gamma oscillations, the results of which is a theta-nested gamma burst. Excitatory afferents form active sinks (inward current) at confined dendritic domains of the cytoarchitecturally organized layers of all regions. Since each layer-specific input is complemented by one or more families of interneurons with similar axonal projections, such layer-specific inhibitory dipoles can compete with the excitatory inputs. The resulting rich consortium of theta generators in hippocampal and parahippocampal regions is coordinated by the medial septum and a network of long-range interneurons (Freund and Buzsáki, 1996; Klausberger and Somogyi, 2008). Although theta oscillations are generally coherent throughout the hippocampal system, the momentary power, coherence and phase of theta oscillators can fluctuate significantly in different regions and layers as a function of overt and covert behaviors.
When subcortical modulatory inputs decrease in tone, as it happens in the absence of ambulatory movement and during sleep, theta oscillations are replaced by intermittently occurring, large-amplitude field potentials, or sharp waves (SPWs). SPWs are initiated by the self-organized population bursts of the CA3 pyramidal cells (Buzsáki et al., 1983). The CA3-induced depolarization of CA1 pyramidal cell apical dendrites is reflected by an extracellular negative wave, that is, the SPW, which is most prominent in stratum radiatum. SPWs are associated with fast-field oscillations (140–200 Hz), or ripples, confined to the CA1 pyramidal cell layer (O’Keefe and Nadel, 1978; Buzsáki et al., 1992; fast oscillations by Traub, 2006). In the time window of SPWs, 50,000–100,000 neurons discharge synchronously in the CA3–CA1–subicular complex–entorhinal axis of the rat. The population burst is characterized by a three- to five-fold gain of network excitability in the CA1 region, preparing local circuits for synaptic plasticity and, at the same time, exerting a powerful effect on cortical targets.
Hippocampal place cells and episode cells
A striking and reliable correlate of firing patterns of hippocampal pyramidal cells is the spatial location of the rat in a given environment, for which reason these cells are known as place cells, discovered by John O'Keefe. (Fig. 6; courtesy of D. Robbe; O’Keefe and Nadel, 1978; Moser et al., 2008). From a physiological perspective, place cells are speed-dependent oscillators, since their oscillation frequency is determined by the animal’s traveling velocity. Every place cell oscillates faster than the ongoing LFP theta, i.e., the extracellular field, which is largely generated by the coherent membrane potential fluctuations of the contributing place cells.
The paradox of how a slower population theta is generated by place cells, each of which oscillates faster than the population mean, can be explained as follows. The activity of place cells is modulated by a Gaussian function of the animal's position and by the theta frequency oscillation (Fig. 5; Burgess et al., 2007; Geisler et al., 2010). The place fields of sequentially active place cells can overlap and their temporal relationships are governed by a compression rule: within the theta cycle, the spike timing sequence of neurons predicts the upcoming sequence of locations in the path of the rat, with larger time lags representing larger distances (O’Keefe and Recce, 1993; Skaggs et al., 1996; Dragoi and Buzsáki, 2006). Because of the time lags between the spikes of the transiently oscillating neurons, the oscillation frequency of their population output, also reflected by the local LFP, is slower than the mean of the oscillating frequencies of the constituent neurons. The tripartite relationship between LFP theta frequency \(f_\theta\ ,\) the oscillation frequency of single neurons \(f_0\) and the distance-related, theta time-scale temporal lags of spikes (time compressed sequences) has important consequences on the assembly organization of hippocampal neurons. First, the difference in oscillation frequency between the population (\(f_\theta\)) and active single neurons generates an interference pattern, known as phase precession of place cells (O’Keefe and Recce, 1993) so that the distance traveled from the beginning of the place field can be instantly inferred from the theta phase of place cell spikes (Fig. 5). Second, the slope of the phase precession defines the size of the place field. Third, the field size (i.e., the lifetime of activity) is inversely related to the oscillation frequency of the neuron. In sum, neurons which oscillate faster have smaller place fields and display steeper phase-precession slopes, as it is the case in the septal portion of the hippocampus, compared to neurons in more caudal (temporal) parts, which oscillate slower, have larger place fields and less steep phase-precession slopes (Maurer et al., 2005). The dynamic local adjustment of these interdependent parameters is responsible for the globally coherent theta oscillation in the hippocampal system (Geisler et al., 2010).
The bidirectional dynamic relationship between single neurons and their population product has important functional consequences. First, despite the variable running speed of the rat, place cells continue to represent the same positions and distances in a given environment. Second, the duration of the theta cycle (120–150 msec in the rat) sets a natural upper limit of distance coding by theta-scale time lags (~50 cm for neurons in the dorsal hippocampus). The behavioral consequence of this constraint is that objects and locations > 50 cm ahead of the rat are initially less distinguishable, but as the animal approaches, they are progressively better resolved by the interleaved cell assemblies. Third, the number of cell assemblies that can nest in a given theta period (5 to 9, as reflected by the number of gamma cycles/theta; Bragin et al., 1995), determines the spatial resolution of distance representation. A consequence of the limited number of theta-nested assemblies is that distance resolution scales with the size of the environment; temporal lags that represent fine spatial resolution in small enclosures correspond to coarser distance representations in larger environments.
Although our current understanding of the dynamics of hippocampal networks derives largely from experiments carried out in spatial tasks, it is important to recognize that the above physiological mechanisms do not necessarily reflect the imposition of environmental stimuli on hippocampal neurons (Eichenbaum and Cohen, 1993; McNaughton et al., 1996). In fact, all of the above-described patterns can emerge by internal mechanisms, without a reliance on external cues or reafferent body signals (Pastalkova et al., 2008; Gelbard-Sagiv et al., 2008). Conceptualizing locations as discrete items, the temporal compression mechanism can limit the attention span and the register capacity of the memory buffer of the gamma-nested theta-cycle to 5 to 9 items (Lisman and Idiart, 1995). Due to the compression mechanism, the spatiotemporal resolution of an episodic recall is high for the conditions/context that surround a recalled event, whereas the relationships among items representing the far past or far future, relative to the recalled event, are progressively less resolved. However, as the content of the recall moves forward in perceived time, subsequent events gain high contextual resolution. The compression dynamic can also allow that not only adjacent but more distant assemblies are linked, as long as they consistently co-occur in the same theta cycles. These higher order connections, in turn, can provide a substrate for alternative combinations of different assembly sequences, mechanisms necessary e.g., for solving detour and transitive inference problems (Muller et al., 1996) and for higher-order associations of items in episodic memory (Polyn and Kahana, 2008).
Consolidation and transfer of hippocampal memories
Learning an episode typically requires only a single exposure. After an experience, the memory trace either disappears or consolidates into a long-term form. It has been hypothesized that the theta-SPW switch supports a two-stage memory mechanism with a rapid acquisition stage during theta oscillations, followed by repeated reactivation of acquired information during post-experience SPWs (Buzsáki, 1989).
SPWs represent the most synchronous assembly pattern in the mammalian brain, characterized by a three- to five-fold gain of network excitability, creating short time windows for efficient transfer of hippocampal information to the neocortex. Both place cell sequences and the distances between the place fields experienced during exploration are reflected in the temporal structure of neuronal sequences during SPW (Fig. 7; Wilson and McNaughton, 1994; Lee and Wilson, 2002; Dupret et al., 2010), and their selective elimination after learning interferes with memory consolidation (Girardeau et al., 2009). In the waking animal, SPW-related sequences can be replayed in either a forward manner, typically prior to initiating a journey, or in a reverse order after reaching the goal (Foster et al., 2006; Diba and Buzsáki, 2007). This bidirectional re-enactment of temporal sequences may also contribute to the establishment of higher-order associations in episodic memory. Generating windows of high excitability states for teaching the neocortex comes with a price. A slight perturbation of the balance between inhibition and excitation can lead to interictal spikes and seizures. The highly excitable SPWs explain why the hippocampus is the most seizure-prone structure in the brain. Impairment of any of the multiple temporal dynamics can underlie diseases such as schizophrenia and Alzheimer's disease.
Other functions and implications
This overview is meant to be a progress report of our current knowledge of hippocampal dynamics, embedded in a hypothetical framework. I recognize that not all observations fit this framework and acknowledge the many other or related viewpoints, advanced by outstanding colleagues. Hippocampus-like structures are also present in reptiles and birds, and potentially serve navigation functions (http://en.wikipedia.org/wiki/Evolution_of_the_Hippocampus). Granule cells are the specialty neuron of the hippocampus, not present in the neocortex. Granule cells are generated postnatally (Bayer and Altman, 1974; Gage, 2000) and involved in a multitude of functions (Scharfmann, 2007). Revealing the physiological roles of granule cells is, therefore, a key step for understanding hippocampal computation. Furthermore, while this entry focuses on hippocampal-neocortical interactions, the hippocampus also exerts a critical effect on its downstream targets, such as the hypothalamus and basal ganglia, mostly by way of the subiculum.
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