The hippocampus shows two major "modes" of activity, each associated with a distinct pattern of neural population activity and waves of electrical activity as measured by an electroencephalogram (EEG). These modes are named after the EEG patterns associated with them: theta and large irregular activity (LIA).
The main characteristics described below are for the rat, which is the animal most extensively studied. In the theta mode, the EEG is dominated by large regular waves with a frequency range of 6–9 Hz, and the main groups of hippocampal neurons (pyramidal cells and granule cells) show sparse population activity, which means that in any short time interval, the great majority of cells are silent, while the small remaining fraction fire at relatively high rates, up to 50 spikes in one second for the most active of them.
An active cell typically stays active for half a second to a few seconds. As the rat behaves, the active cells fall silent and new cells become active, but the overall percentage of active cells remains more or less constant. In many situations, cell activity is determined largely by the spatial location of the animal, but other behavioral variables also clearly influence it.
The LIA mode appears during slow-wave (non-dreaming) sleep, and also during states of waking immobility, such as resting or eating.
Because of its densely packed neural layers, the hippocampus generates some of the largest EEG signals of any brain structure. In some situations the EEG is dominated by regular waves at 3–10 Hz, often continuing for many seconds. These reflect subthreshold membrane potentials and strongly modulate the spiking of hippocampal neurons and synchronise across the hippocampus in a travelling wave pattern. This EEG pattern is known as a theta rhythm.
Theta rhythmicity is very obvious in rabbits and rodents, and also clearly present in cats and dogs. Whether theta can be seen in primates is a vexing question. In rats (the animals that have been the most extensively studied), theta is seen mainly in two conditions: first, when an animal is walking or in some other way actively interacting with its surroundings; second, during REM sleep.
The function of theta has not yet been convincingly explained, although numerous theories have been proposed. The most popular hypothesis has been to relate it to learning and memory. For example, the phase with which theta at the time of stimulation of a neuron shapes the effect of that stimulation upon its synapses and therefore may affect learning and memory dependent upon synaptic plasticity. It is well-established that lesions of the medial septum—the central node of the theta system—cause severe disruptions of memory. However, the medium septum is more than just the controller of theta, it is also the main source of cholinergic projections to the hippocampus.
During sleep, or during waking states when an animal is resting or otherwise not engaged with its surroundings, the hippocampal EEG shows a pattern of irregular slow waves, somewhat larger in amplitude than theta waves.
This pattern is occasionally interrupted by large surges called ''sharp waves''. These events are associated with bursts of spike activity, lasting 50–100 msec, in pyramidal cells of CA3 and CA1. They are also associated with short-lasting high-frequency EEG oscillations called "ripples", with frequencies in the range 150–200 Hz in rats.
Sharp waves are most frequent during sleep, when they occur at an average rate around 1 per second (in rats), but in a very irregular temporal pattern. Sharp waves are less frequent during inactive waking states, and are usually smaller. Sharp waves have also been observed in humans and monkeys. In macaques, sharp waves are robust, but do not occur as frequently as in rats. and numerous later studies, reported that when hippocampal place cells have overlapping spatial firing fields (and therefore often fire in near-simultaneity), they tend to show correlated activity during sleep following the behavioral session. This enhancement of correlation, commonly known as ''reactivation'', has been found to occur mainly during sharp waves. It has been proposed that sharp waves are, in fact, reactivations of neural activity patterns that were memorized during behavior, driven by strengthening of synaptic connections within the hippocampus.
This idea forms a key component of the "two-stage memory" theory, advocated by Buzsáki and others, which proposes that memories are stored within the hippocampus during behavior, and then later transferred to the neocortex during sleep: sharp waves are suggested to drive Hebbian synaptic changes in the neocortical targets of hippocampal output pathways.
Since at least the time of Ramon y Cajal, psychologists have speculated that the brain stores memory by altering the strength of connections between neurons that are simultaneously active. This idea was formalized by Donald Hebb in 1948, but for many years thereafter, attempts to find a brain mechanism for such changes came up empty.
In 1973, Tim Bliss and Terje Lømo described a phenomenon in the rabbit hippocampus that appeared to meet Hebb's specifications: a change in synaptic responsiveness induced by brief strong activation and lasting for hours, days, or longer. This phenomenon was soon referred to as ''long-term potentiation'', abbreviated ''LTP''. As a candidate mechanism for memory, LTP has been studied intensively over the following years, and a great deal has been learned about it.
The hippocampus is a particularly favorable site for studying LTP because of its densely packed and sharply defined layers of neurons, but similar types of activity-dependent synaptic change have now been observed in many other brain areas.
The best-studied form of LTP occurs at synapses that terminate on dendritic spines and use the transmitter glutamate. Several of the major pathways within the hippocampus fit this description, and show LTP.
The synaptic changes depend on a special type of glutamate receptor, the NMDA receptor, which has the special property of allowing calcium to enter the postsynaptic spine only when presynaptic activation and postsynaptic depolarization occur at the same time.
Drugs that interfere with NMDA receptors block LTP and also have major effects on some types of memory, especially spatial memory. Transgenic mice, genetically modified in ways that disable the LTP mechanism, also generally show severe memory deficits.) have a severe impact on many types of cognition, but even normal, healthy aging is associated with a gradual decline in some types of memory, including episodic memory and working memory.
Because the hippocampus is thought to play a central role in memory, there has been considerable interest in the possibility that age-related declines could be caused by hippocampal deterioration. Some early studies reported substantial loss of neurons in the hippocampus of elderly people, but later studies using more precise techniques found only minimal differences.
There are also reports that memory tasks tend to produce less hippocampal activation in elderly than in young subjects.
Functional synapses are lost in the dentate gyrus and CA1 region, and NMDA receptor-mediated responses are reduced. These changes may account for deficits in induction and maintenance of long-term potentiation, a form of synaptic plasticity that has been implicated in memory.
There are also age-related declines in hippocampal expression of several genes associated with synaptic plasticity.
Finally, there are differences in the stability of "place cell" representations. In young rats, the arrangement of place fields is usually altered if the rat is moved into a different environment, but remains the same if a rat is returned to an environment it has visited previously.
In aged rats, the place fields frequently fail to "remap" when a rat is moved to a different environment, and also frequently fail to restore the original "map" when the rat is returned to the same environment.
The hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-term stress than most other brain areas. Stress-related steroids affect the hippocampus in at least three ways: first, by reducing the excitability of some hippocampal neurons; second, by inhibiting the genesis of new neurons in the dentate gyrus; third, by causing atrophy of dendrites in pyramidal cells of the CA3 region.
There is evidence that humans who have experienced severe, long-lasting traumatic stress (for example, Holocaust survivors) show atrophy of the hippocampus, more than of other parts of the brain. These effects show up in post-traumatic stress disorder, and they may contribute to the hippocampal atrophy reported in schizophrenia and severe depression.
Hippocampal atrophy is also frequently seen in Cushing's syndrome, a disorder caused by high levels of cortisol in the bloodstream. At least some of these effects appear to be reversible if the stress is discontinued. There is, however, evidence mainly derived from studies using rats that stress shortly after birth can affect hippocampal function in ways that persist throughout life.
The hippocampus is often the focus of epileptic seizures: hippocampal sclerosis is the most commonly visible type of tissue damage in temporal lobe epilepsy. It is not yet clear, though, whether the epilepsy is usually caused by hippocampal abnormalities, or the hippocampus is damaged by cumulative effects of seizures.
In experimental settings where repetitive seizures are artificially induced in animals, hippocampal damage is a frequent result: this may be a consequence of the hippocampus being one of the most electrically excitable parts of the brain. It may also have something to do with the fact that the hippocampus is one of very few brain regions where new neurons continue to be created throughout life.
The causes of schizophrenia are not at all well understood, but numerous abnormalities of brain structure have been reported. The most thoroughly investigated alterations involve the cerebral cortex, but effects on the hippocampus have also been described. Many reports have found reductions in the size of the hippocampus in schizophrenic subjects.
The changes probably result from altered development rather than tissue damage, and show up even in subjects who have never been medicated. Several lines of evidence implicate changes in synaptic organization and connectivity. Others have suggested that hippocampal dysfunction might account for disturbances in long term memory frequently observed in people with schizophrenia.
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