Hippocampus
Overview
The hippocampus is a major component of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

s of humans
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 and other vertebrates. It belongs to the limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...

 and plays important roles in the consolidation of information from short-term memory
Short-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...

 to long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

 and spatial navigation
Navigation
Navigation is the process of monitoring and controlling the movement of a craft or vehicle from one place to another. It is also the term of art used for the specialized knowledge used by navigators to perform navigation tasks...

. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is closely associated with the cerebral cortex, and in primates is located in the medial temporal lobe, underneath the cortical surface.
Unanswered Questions
Encyclopedia
The hippocampus is a major component of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

s of humans
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 and other vertebrates. It belongs to the limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...

 and plays important roles in the consolidation of information from short-term memory
Short-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...

 to long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...

 and spatial navigation
Navigation
Navigation is the process of monitoring and controlling the movement of a craft or vehicle from one place to another. It is also the term of art used for the specialized knowledge used by navigators to perform navigation tasks...

. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is closely associated with the cerebral cortex, and in primates is located in the medial temporal lobe, underneath the cortical surface. It contains two main interlocking parts: Ammon's horn and the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...

.

In Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms. Damage to the hippocampus can also result from oxygen starvation
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

 (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

), encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesia
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...

—the inability to form or retain new memories.

In rodents, the hippocampus has been studied extensively as part of a brain system responsible for spatial memory
Spatial memory
In cognitive psychology and neuroscience, spatial memory is the part of memory responsible for recording information about one's environment and its spatial orientation. For example, a person's spatial memory is required in order to navigate around a familiar city, just as a rat's spatial memory is...

 and navigation. Many neurons in the rat and mouse hippocampus respond as place cell
Place cell
Place cells are neurons in the hippocampus that exhibit a high rate of firing whenever an animal is in a specific location in an environment corresponding to the cell's "place field". These neurons are distinct from other neurons with spatial firing properties, such as grid cells, border cells,...

s: that is, they fire bursts of action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s when the animal passes through a specific part of its environment. Hippocampal place cells interact extensively with head direction cells
Head direction cells
Many mammals possess neurons called head direction cells, which are active only when the animal's head points in a specific direction within an environment. These neurons fire at a steady rate Many mammals possess neurons called head direction (HD) cells, which are active only when the animal's...

, whose activity acts as an inertial compass, and with grid cells
Grid cells
A grid cell is a type of neuron that has been found in the brains of rats and mice; and it is likely to exist in other animals including humans...

 in the neighboring entorhinal cortex
Entorhinal cortex
The entorhinal cortex is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex...

.

Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system
Scientific modelling
Scientific modelling is the process of generating abstract, conceptual, graphical and/or mathematical models. Science offers a growing collection of methods, techniques and theory about all kinds of specialized scientific modelling...

 for studying neurophysiology. The form of neural plasticity known as long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...

 (LTP) was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memory is stored in the brain.

Name

The earliest description of the ridge running along the floor of the temporal horn of the lateral ventricle comes from the Venetian anatomist Julius Caesar Aranzi
Julius Caesar Aranzi
Julius Caesar Aranzi was a leading figure in the history of the science of human anatomy.He was born in Bologna, the son of Ottaviano di Jacopo and Maria Maggi...

 (1587), who initially likened it to a seahorse, using the (from , "horse" and , "sea monster") or alternatively to a silkworm. The German anatomist Duvernoy (1729), the first to illustrate the structure, also wavered between "seahorse" and "silkworm." "Ram's horn" was proposed by the Danish anatomist Jacob Winsløw
Jacob B. Winslow
Jacob B. Winsløw, also known as Jacques-Bénigne Winslow, Danish-born anatomist .- Life :Winsløw was born in Denmark, later he became a pupil and successor of Guichard Joseph Duverney, as well as a convert to Catholicism, naturalized in France, and finally became professor of anatomy at the Jardin...

 in 1732; and a decade later his fellow Parisian, the surgeon de Garengeot, used "cornu Ammonis" - horn of (the ancient Egyptian god) Amun
Amun
Amun, reconstructed Egyptian Yamānu , was a god in Egyptian mythology who in the form of Amun-Ra became the focus of the most complex system of theology in Ancient Egypt...

.

Another mythological reference appeared with the term pes hippocampi, which may date back to Diemerbroeck in 1672, introducing a comparison with the shape of the folded back forelimbs and webbed feet of the Classical hippocamp
Hippocamp
The hippocamp or hippocampus , often called a sea-horse in English, is a mythological creature shared by Phoenician and Greek mythology, though the name by which it is recognised is purely Greek; it became part of Etruscan mythology...

us (Greek: ἱππόκαμπος), a sea monster with a horse's forequarters and a fish's tail. The hippocampus was then described as pes hippocampi major, with an adjacent bulge in the occipital horn
Posterior horn of lateral ventricle
The posterior horn of the lateral ventricle passes into the occipital lobe, its direction being backward and lateralward, and then medialward....

, the calcar avis, being named pes hippocampi minor. The renaming of the hippocampus as hippocampus major, and the calcar avis as hippocampus minor, has been attributed to Félix Vicq-d'Azyr
Félix Vicq-d'Azyr
Félix Vicq d'Azyr was a French physician and anatomist, the originator of comparative anatomy and discoverer of the theory of homology in biology.-Biography:Vicq d'Azyr was born in Valognes, Normandy, the son of a physician...

 systematising nomenclature of parts of the brain in 1786. Mayer mistakenly used the term hippopotamus
Hippopotamus
The hippopotamus , or hippo, from the ancient Greek for "river horse" , is a large, mostly herbivorous mammal in sub-Saharan Africa, and one of only two extant species in the family Hippopotamidae After the elephant and rhinoceros, the hippopotamus is the third largest land mammal and the heaviest...

 in 1779, and was followed by some other authors until Karl Friedrich Burdach
Karl Friedrich Burdach
Karl Friedrich Burdach was a German physiologist, born in Leipzig.He was graduated in medicine there in 1800; became professor of physiology in the University of Dorpat in 1811, and four years later took a similar position at the University of Königsberg.He provided in 1822 the name--due the...

 resolved this error in 1829. In 1861 the hippocampus minor became the centre of a dispute over human evolution
Human evolution
Human evolution refers to the evolutionary history of the genus Homo, including the emergence of Homo sapiens as a distinct species and as a unique category of hominids and mammals...

 between Thomas Henry Huxley and Richard Owen
Richard Owen
Sir Richard Owen, FRS KCB was an English biologist, comparative anatomist and palaeontologist.Owen is probably best remembered today for coining the word Dinosauria and for his outspoken opposition to Charles Darwin's theory of evolution by natural selection...

, satirised as the Great Hippocampus Question
Great Hippocampus Question
The Great Hippocampus Question was a 19th century scientific controversy about the anatomy of apes and human uniqueness. The dispute between Thomas Henry Huxley and Richard Owen became central to the scientific debate on human evolution that followed Charles Darwin's publication of On the Origin of...

. The term hippocampus minor fell from use in anatomy textbooks, and was officially removed in the Nomina Anatomica
Nomina Anatomica
In the late nineteenth century some 50,000 terms for various body parts were in use. The same structures were described by different names, depending on the anatomist’s school and national tradition. Vernacular translations of Latin and Greek, as well as various eponymous terms, were barriers to...

 of 1895.

Today, the structure is called the hippocampus rather than hippocampus major, with pes hippocampi often being regarded as synonymous with De Garengeot's "cornu Ammonis", a term which survives in the names of the four main histological
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

 divisions of the hippocampus: CA1, CA2, CA3 and CA4.

Functions

Historically, the earliest widely held hypothesis was that the hippocampus is involved in olfaction
Olfaction
Olfaction is the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates...

. This idea was cast into doubt by a series of anatomical studies that did not find any direct projections to the hippocampus from the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

. However, later work did confirm that the olfactory bulb does project into the ventral part of the lateral entorhinal cortex, and field CA1 in the ventral hippocampus sends axons to the main olfactory bulb, the anterior olfactory nucleus, and to the primary olfactory cortex. There continues to be some interest in hippocampal olfactory responses, particularly the role of the hippocampus in memory for odors, but few people believe today that olfaction is its primary function.

Over the years, three main ideas of hippocampal function have dominated the literature: inhibition, memory, and space. The behavioral inhibition theory (caricatured by O'Keefe and Nadel as "slam on the brakes!") was very popular up to the 1960s. It derived much of its justification from two observations: first, that animals with hippocampal damage tend to be hyperactive; second, that animals with hippocampal damage often have difficulty learning to inhibit responses that they have previously been taught, especially if the response requires remaining quiet as in a passive avoidance test. Jeffrey Gray
Jeffrey Alan Gray
Jeffrey Alan Gray was a British psychologist. He was born in the East End of London. His father was a tailor, but died when Jeffrey was only seven. His mother, who ran a haberdashery, brought him up alone....

 developed this line of thought into a full-fledged theory of the role of the hippocampus in anxiety. The inhibition theory is currently the least popular of the three.

The second major line of thought relates the hippocampus to memory. Although it had historical precursors, this idea derived its main impetus from a famous report by Scoville and Brenda Milner
Brenda Milner
Brenda Milner, is a Canadian neuroscientist who has contributed extensively to the research literature on various topics in the field of clinical neuropsychology. -Biography:...

 describing the results of surgical destruction of the hippocampus (in an attempt to relieve epileptic seizures), in a patient named Henry Gustav Molaison, known until his death in 2008 as H.M.
HM (patient)
Henry Gustav Molaison , famously known as HM or H.M., was an American memory disorder patient who was widely studied from late 1957 until his death...

 The unexpected outcome of the surgery was severe anterograde
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...

 and partial retrograde amnesia
Retrograde amnesia
Retrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....

: H.M. was unable to form new episodic memories after his surgery and could not remember any events that occurred just before his surgery, but retained memories for things that happened years earlier, such as his childhood. This case produced such enormous interest that H.M. reportedly became the most intensively studied medical subject in history. In the ensuing years, other patients with similar levels of hippocampal damage and amnesia (caused by accident or disease) have been studied as well, and thousands of experiments have studied the physiology of activity-driven changes in synaptic connections
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

 in the hippocampus. There is now almost universal agreement that the hippocampus plays some sort of important role in memory; however, the precise nature of this role remains widely debated.

The third important theory of hippocampal function relates the hippocampus to space. The spatial theory was originally championed by O'Keefe and Nadel, who were influenced by E.C. Tolman's
Edward C. Tolman
Edward Chace Tolman was an American psychologist. He was most famous for his studies on behavioral psychology....

 theories about "cognitive map
Cognitive map
Cognitive maps are a type of mental processing composed of a series of psychological transformations by which an individual can acquire, code, store, recall, and decode information about the relative locations and attributes of phenomena in their everyday or metaphorical spatial environment.The...

s" in humans and animals. O'Keefe and his student Dostrovsky in 1971 discovered neurons in the rat hippocampus that appeared to them to show activity related to the rat's location within its environment. Despite skepticism
Skepticism
Skepticism has many definitions, but generally refers to any questioning attitude towards knowledge, facts, or opinions/beliefs stated as facts, or doubt regarding claims that are taken for granted elsewhere...

 from other investigators, O'Keefe and his co-workers, especially Lynn Nadel
Lynn Nadel
Lynn Nadel is the Regents' Professor of Psychology at the University of Arizona. Nadel specializes in memory, and has investigated the role of the hippocampus in memory formation. Together with John O'Keefe, he coauthored the influential 1978 book The Hippocampus as a Cognitive Map, which...

, continued to investigate this question, in a line of work that eventually led to their very influential 1978 book The Hippocampus as a Cognitive Map. As with the memory theory, there is now almost universal agreement that spatial coding plays an important role in hippocampal function, but the details are widely debated.

Role in memory

Psychologists
Psychology
Psychology is the study of the mind and behavior. Its immediate goal is to understand individuals and groups by both establishing general principles and researching specific cases. For many, the ultimate goal of psychology is to benefit society...

 and neuroscientists
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...

 generally agree that the hippocampus has an important role in the formation of new memories
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....

 about experienced events (episodic
Episodic memory
Episodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...

 or autobiographical memory
Autobiographical memory
Autobiographical memory is a memory system consisting of episodes recollected from an individual's life, based on a combination of episodic and semantic memory.-Formation:Conway and Pleydell-Pearce proposed that autobiographical...

). Part of this role is hippocampal involvement in the detection of novel events, places and stimuli. Some researchers view the hippocampus as part of a larger medial temporal lobe memory system responsible for general declarative memory
Declarative memory
Declarative memory is one of two types of long term human memory. It refers to memories which can be consciously recalled such as facts and knowledge. Its counterpart is known as non-declarative or Procedural memory, which refers to unconscious memories such as skills...

 (memories that can be explicitly verbalized—these would include, for example, memory for facts
Semantic memory
Semantic memory refers to the memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences. The conscious recollection of factual information and general knowledge about the world is generally thought to be independent of context and personal relevance...

 in addition to episodic memory).

Due to bilateral symmetry the brain has a hippocampus in both cerebral hemispheres, so every normal brain has two of them. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the other hemisphere, the brain can retain near-normal memory functioning. Severe damage to the hippocampus in both hemispheres results in profound difficulties in forming new memories (anterograde amnesia
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...

), and often also affects memories formed before the damage (retrograde amnesia
Retrograde amnesia
Retrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....

). Although the retrograde effect normally extends some years before the brain damage, in some cases older memories remain—this sparing of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain.

Damage to the hippocampus does not affect some types of memory, such as the ability to learn new motor
Motor skill
A motor skill is a learned sequence of movements that combine to produce a smooth, efficient action in order to master a particular task. The development of motor skill occurs in the motor cortex, the region of the cerebral cortex that controls voluntary muscle groups.- Development of motor skills...

 or cognitive skills (playing a musical instrument, or solving certain types of puzzles, for example). This fact suggests that such abilities depend on different types of memory (procedural memory
Procedural memory
Procedural memory is memory for how to do things. Procedural memory guides the processes we perform and most frequently resides below the level of conscious awareness. When needed, procedural memories are automatically retrieved and utilized for the execution of the integrated procedures involved...

) and different brain regions. Furthermore, amnesic patients frequently show "implicit" memory for experiences even in the absence of conscious knowledge. For example, a patient asked to guess which of two faces they have seen most recently may give the correct answer the majority of the time, in spite of stating that they have never seen either of the faces before. Some researchers distinguish between conscious recollection, which depends on the hippocampus, and familiarity, which depends on portions of the medial temporal cortex.

Role in spatial memory and navigation

Studies conducted on freely moving rats and mice have shown that many hippocampal neurons have "place fields", that is, they fire bursts of action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s when a rat passes through a particular part of the environment. Evidence for place cell
Place cell
Place cells are neurons in the hippocampus that exhibit a high rate of firing whenever an animal is in a specific location in an environment corresponding to the cell's "place field". These neurons are distinct from other neurons with spatial firing properties, such as grid cells, border cells,...

s in primates is limited, perhaps in part because it is difficult to record brain activity from freely moving monkeys. Place-related hippocampal neural activity has been reported in monkeys moving around inside a room while seated in a restraint chair; on the other hand, Edmund Rolls
Edmund Rolls
Professor Edmund T. Rolls is a psychologist and neuroscientist. He has served as Professor of Experimental Psychology at the University of Oxford, Vice President of Corpus Christi College, Oxford and currently serves as an Honorary Fellow in Applied Neuroimaging at the University of Warwick.He has...

 and his colleagues instead described hippocampal cells that fire in relation to the place a monkey is looking at, rather than the place its body is located. In humans, cells with location-specific firing patterns have been reported in a study of patients with drug-resistant epilepsy who were undergoing an invasive procedure to localize the source of their seizures, with a view to surgical resection. The patients had diagnostic electrodes implanted in their hippocampus and then used a computer to move around in a virtual reality
Virtual reality
Virtual reality , also known as virtuality, is a term that applies to computer-simulated environments that can simulate physical presence in places in the real world, as well as in imaginary worlds...

 town.

Place responses in rats and mice have been studied in hundreds of experiments over four decades, yielding a large quantity of information. Place cell responses are shown by pyramidal cell
Pyramidal cell
Pyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...

s in the hippocampus proper, and granule cell
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...

s in the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...

. These constitute the great majority of neurons in the densely packed hippocampal layers. Inhibitory interneuron
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...

s, which make up most of the remaining cell population, frequently show significant place-related variations in firing rate, but much weaker than that shown by pyramidal or granule cells. There is little if any spatial topography in the representation: cells lying next to each other in the hippocampus generally have uncorrelated spatial firing patterns. Place cells are typically almost silent when a rat is moving around outside the place field, but reach sustained rates as high as 40 Hz when the rat is near the center. Neural activity sampled from 30–40 randomly chosen place cells carries enough information to allow a rat's location to be reconstructed with high confidence. The size of place fields varies in a gradient along the length of the hippocampus, with cells at the dorsal end showing the smallest fields, cells near the center showing larger fields, and cells at the ventral tip fields that cover the entire environment. In some cases, the firing rate of rat hippocampal cells depends not only on place but also on the direction a rat is moving, the destination toward which it is traveling, or other task-related variables.

The discovery of place cells in the 1970s led to a theory that the hippocampus might act as a cognitive map—a neural representation of the layout of the environment. Several lines of evidence support the hypothesis. It is a frequent observation that without a fully functional hippocampus, humans may not remember where they have been and how to get where they are going: getting lost is one of the most common symptoms of amnesia. Studies with animals have shown that an intact hippocampus is required for initial learning and long-term retention of some spatial memory
Spatial memory
In cognitive psychology and neuroscience, spatial memory is the part of memory responsible for recording information about one's environment and its spatial orientation. For example, a person's spatial memory is required in order to navigate around a familiar city, just as a rat's spatial memory is...

 tasks, particularly ones that require finding the way to a hidden goal. The "cognitive map hypothesis" has been further advanced by recent discoveries of head direction cells
Head direction cells
Many mammals possess neurons called head direction cells, which are active only when the animal's head points in a specific direction within an environment. These neurons fire at a steady rate Many mammals possess neurons called head direction (HD) cells, which are active only when the animal's...

, grid cells
Grid cells
A grid cell is a type of neuron that has been found in the brains of rats and mice; and it is likely to exist in other animals including humans...

, and border cells
Border cell (brain)
Border cells are entorhinal neurons that are border-sensitive, reacting when a border is present in the proximal environment. Cells with such firing characteristics were predicted by Neil Burgess in 2000, and detected in December 2008, according to a single report by the group of scientists that...

 in several parts of the rodent brain that are strongly connected to the hippocampus.

Brain imaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...

 shows that people have more active hippocampi when correctly navigating, as tested in a computer-simulated "virtual" navigation task. Also, there is evidence that the hippocampus plays a role in finding shortcuts and new routes between familiar places. For example, London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...

's taxi drivers must learn a large number of places and the most direct routes between them (they have to pass a strict test, The Knowledge, before being licensed to drive the famous black cabs
Hackney carriage
A hackney or hackney carriage is a carriage or automobile for hire...

). A study at University College London
University College London
University College London is a public research university located in London, United Kingdom and the oldest and largest constituent college of the federal University of London...

 by Maguire, et al.. (2000) showed that part of the hippocampus is larger in taxi drivers than in the general public, and that more experienced drivers have bigger hippocampi. Whether having a bigger hippocampus helps an individual to become a cab driver, or if finding shortcuts for a living makes an individual's hippocampus grow is yet to be elucidated. However, in that study Maguire, et al.. examined the correlation between size of the grey matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...

 and length of time that had been spent as a taxi driver, and found a positive correlation
Correlation
In statistics, dependence refers to any statistical relationship between two random variables or two sets of data. Correlation refers to any of a broad class of statistical relationships involving dependence....

 between the length of time an individual had spent as a taxi driver and the volume of the right hippocampus. It was found that the total volume of the hippocampus remained constant, from the control group vs. taxi drivers. That is to say that the posterior portion of a taxi driver's hippocampus is indeed increased, but at the expense of the anterior portion. There have been no known detrimental effects reported from this disparity in hippocampal proportions.

Anatomy

Anatomically, the hippocampus is an elaboration of the edge of the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

. The structures that line the edge of the cortex make up the so-called limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...

 (Latin limbus = border): these include the hippocampus, cingulate cortex
Cingulate cortex
The cingulate cortex is a part of the brain situated in the medial aspect of the cortex. It includes the cortex of the cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cingulate sulcus...

, olfactory cortex
Olfactory system
The olfactory system is the sensory system used for olfaction, or the sense of smell. Most mammals and reptiles have two distinct parts to their olfactory system: a main olfactory system and an accessory olfactory system. The main olfactory system detects volatile, airborne substances, while the...

, and amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...

. Paul MacLean once suggested, as part of his triune brain
Triune brain
The triune brain is a model of the evolution of the vertebrate forebrain and behavior proposed by the American physician and neuroscientist Paul D. MacLean. MacLean originally formulated his model in the 1960s and propounded it at length in his 1990 book The Triune Brain in Evolution...

 theory, that the limbic structures comprise the neural basis of emotion. Some neuroscientists no longer believe that the concept of a unified "limbic system" is valid, though. However, the hippocampus is anatomically connected to parts of the brain that are involved with emotional behavior—the septum, the hypothalamic mammillary body, and the anterior nuclear complex in the thalamus so its role as a limbic structure cannot be completely dismissed.

The hippocampus as a whole has the shape of a curved tube, which has been analogized variously to a seahorse, a ram's horn (Cornu Ammonis, hence the subdivisions CA1 through CA4), or a banana. It can be distinguished as a zone where the cortex narrows into a single layer of densely packed pyramidal neurons 3-6 cells deep in rats, which curl into a tight U shape; one edge of the "U," field CA4, is embedded into a backward facing strongly flexed V-shaped cortex, the dentate gyrus. It consists of ventral and dorsal
Anatomical terms of location
Standard anatomical terms of location are designations employed in science that deal with the anatomy of animals to avoid ambiguities that might otherwise arise. They are not language-specific, and thus require no translation...

 portions, both of which share similar composition but are parts of different neural circuits.
This general layout holds across the full range of mammalian species, from hedgehog to human, although the details vary. In the rat, the two hippocampi resemble a pair of bananas, joined at the stems by the hippocampal commissure that crosses the midline under the anterior corpus callosum. In human or monkey brains, the portion of the hippocampus down at the bottom, near the base of the temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....

, is much broader than the part at the top. One of the consequences of this complex geometry is that cross-sections through the hippocampus can show a variety of shapes, depending on the angle and location of the cut.

The entorhinal cortex (EC), located in the parahippocampal gyrus, is considered to be part of the hippocampal region because of its anatomical connections. The EC is strongly and reciprocally connected with many other parts of the cerebral cortex. In addition, the medial septal nucleus, the anterior nuclear complex and nucleus reuniens of the thalamus and the supramammillary nucleus of the hypothalamus, as well as the raphe nuclei and locus coeruleus in the brainstem send axons to the EC. The main output pathway (perforant path, first described by Ramon y Cajal) of EC axons comes from the large stellate pyramidal cells in layer II that "perforate" the subiculum and project densely to the granule cells in the dentate gyrus, apical dendrites of CA3 get a less dense projection, and the apical dendrites of CA1 get a sparse projection. Thus, the perforant path establishes the EC as the main "interface" between the hippocampus and other parts of the cerebral cortex. The dentate granule cell axons (called mossy fibers) pass on the information from the EC on thorny spines that exit from the proximal apical dendrite of CA3 pyramidal cells. Then, CA3 axons exit from the deep part of the cell body, and loop up into the region where the apical dendrites are located, then extend all the way back into the deep layers of the entorhinal cortex—the Shaffer collaterals completing the reciprocal circuit; field CA1 also sends axons back to the EC, but these are more sparse than the CA3 projection. Within the hippocampus, the flow of information from the EC is largely unidirectional, with signals propagating through a series of tightly packed cell layers, first to the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...

, then to the CA3 layer, then to the CA1 layer, then to the subiculum
Subiculum
The subiculum is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper.-Paths:...

, then out of the hippocampus to the EC, mainly due to collateralization of the CA3 axons. Each of these layers also contains complex intrinsic circuitry and extensive longitudinal connections.

Several other connections play important roles in hippocampal function. Beyond the output to the EC, additional output pathways go to other cortical areas including the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...

. A very important large output goes to the lateral septal area
Septal nuclei
The septal area are structures that lie below the rostrum of corpus callosum in front of lamina terminalis , composed of medium-size neurons grouped into medial, lateral, and posterior groups...

 and to the mammillary body of the hypothalamus. The hippocampus receives modulatory input from the serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 systems, and from nucleus reuniens
Nucleus reuniens
The nucleus reuniens, in the brain, links the medial prefrontal cortex with the midline thalamus, and regulates the amount of neural traffic with changes in attentiveness....

 of the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

 to field CA1. A very important projection comes from the medial septal area, which sends cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...

 and GABAergic
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...

 fibers to all parts of the hippocampus. The inputs from the septal area play a key role in controlling the physiological state of the hippocampus: destruction of the septal area abolishes the hippocampal theta rhythm
Theta rhythm
A theta rhythm is an oscillatory pattern in EEG signals recorded either from inside the brain or from electrodes glued to the scalp. Two types of theta rhythm have been described...

, and severely impairs certain types of memory.

The cortical region adjacent to the hippocampus is known collectively as the parahippocampal gyrus
Parahippocampal gyrus
The parahippocampal gyrus is a grey matter cortical region of the brain that surrounds the hippocampus. This region plays an important role in memory encoding and retrieval....

 (or parahippocampus). It includes the EC and also the perirhinal cortex
Perirhinal cortex
Perirhinal cortex is a cortical region in the medial temporal lobe that is made up of Brodmann areas 35 and 36. In rats, it is located along and dorsal to the rhinal sulcus. It receives highly-processed sensory information from all sensory regions, and is generally accepted to be an important...

, which derives its name from the fact that it lies next to the rhinal sulcus. The perirhinal cortex plays an important role in visual recognition of complex objects, but there is also substantial evidence that it makes a contribution to memory which can be distinguished from the contribution of the hippocampus, and that complete amnesia occurs only when both the hippocampus and the parahippocampus are damaged.

Physiology

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.

The theta mode appears during states of active, alert behavior (especially locomotion), and also during REM (dreaming) sleep. 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 cell
Pyramidal cell
Pyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...

s and granule cell
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...

s) 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
Slow-wave sleep
Slow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...

 (non-dreaming) sleep, and also during states of waking immobility, such as resting or eating. In the LIA mode, the EEG is dominated by sharp waves, which are randomly timed large deflections of the EEG signal lasting for 200–300 ms. These sharp waves also determine the population neural activity patterns. Between them, pyramidal cells and granule cells are very quiet (but not silent). During a sharp wave, as many as 5–10% of the neural population may emit action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s during a period of 50 ms; many of these cells emit bursts of several action potentials.

These two hippocampal activity modes can be seen in primates as well as rats, with the exception that it has been difficult to see robust theta rhythmicity in the primate hippocampus. There are, however, qualitatively similar sharp waves, and similar state-dependent changes in neural population activity.

Theta rhythm

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 potential
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...

s 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
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...

. 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
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...

 projections to the hippocampus. It has not been established that septal lesions exert their effects specifically by eliminating the theta rhythm.

Sharp waves

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.

One of the most interesting aspects of sharp waves is that they appear to be associated with memory. Wilson and McNaughton 1994, 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
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...

 during sleep: sharp waves are suggested to drive Hebbian synaptic changes
Hebbian theory
Hebbian theory describes a basic mechanism for synaptic plasticity wherein an increase in synaptic efficacy arises from the presynaptic cell's repeated and persistent stimulation of the postsynaptic cell...

 in the neocortical targets of hippocampal output pathways.

Long-term potentiation

Since at least the time of Ramon y Cajal
Santiago Ramón y Cajal
Santiago Ramón y Cajal ForMemRS was a Spanish pathologist, histologist, neuroscientist, and Nobel laureate. His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience...

, 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
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...

, 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 spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...

s 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
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...

, the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

, which has the special property of allowing calcium to enter the postsynaptic spine only when presynaptic activation and postsynaptic depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...

 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
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...

 in ways that disable the LTP mechanism, also generally show severe memory deficits.

Aging

Age-related conditions such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 (for which hippocampal disruption is one of the earliest signs) 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
Episodic memory
Episodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...

 and working memory
Working memory
Working memory has been defined as the system which actively holds information in the mind to do verbal and nonverbal tasks such as reasoning and comprehension, and to make it available for further information processing...

. 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
Old age
Old age consists of ages nearing or surpassing the average life span of human beings, and thus the end of the human life cycle...

, but later studies using more precise techniques found only minimal differences. Similarly, some MRI studies have reported shrinkage of the hippocampus in elderly people, but other studies have failed to reproduce this finding. There is, however, a reliable relationship between the size of the hippocampus and memory performance—meaning that not all elderly people show hippocampal shrinkage, but those who do tend to perform less well on some memory tasks. There are also reports that memory tasks tend to produce less hippocampal activation in elderly than in young subjects. Furthermore, a randomized-control study published in 2011 found that aerobic exercise could increase the size of the hippocampus in adults aged 55 to 80 and also improve spatial memory.

In rats, where detailed studies of cellular physiology are possible, aging does not cause substantial cell loss in the hippocampus, but it alters synaptic connectivity in several ways. Functional synapses are lost in the dentate gyrus and CA1 region, and NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

-mediated responses are reduced. These changes may account for deficits in induction and maintenance of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...

, 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.

Stress

The hippocampus contains high levels of glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....

s, 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, show atrophy of the hippocampus, more than of other parts of the brain. These effects show up in post-traumatic stress disorder
Post-traumatic stress disorder
Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...

, and they may contribute to the hippocampal atrophy reported in schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

 and severe depression. A recent study has also revealed atrophy as a result of depression, but this can be stopped with anti-depressants, even if they are not effective in relieving other symptoms. Hippocampal atrophy is also frequently seen in Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...

, a disorder caused by high levels of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

 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.

Epilepsy

The hippocampus is often the focus of epileptic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s: hippocampal sclerosis
Hippocampal sclerosis
Ammon's horn sclerosis is the most common type of neuropathological damage seen in individuals with temporal lobe epilepsy . This type of neuron cell loss, primarily in the hippocampus, can be observed in approximately 65% of people suffering from this form of epilepsy.Histopathological hallmarks...

 is the most commonly visible type of tissue damage in temporal lobe epilepsy
Temporal lobe epilepsy
Temporal lobe epilepsy a.k.a. Psychomotor epilepsy, is a form of focal epilepsy, a chronic neurological condition characterized by recurrent seizures. Over 40 types of epilepsies are known. They fall into two main categories: partial-onset epilepsies and generalized-onset epilepsies...

. 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
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

 continue to be created throughout life.

Schizophrenia

The causes of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

 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. It is unclear whether hippocampal alterations play any role in causing the psychotic symptoms that are the most important feature of schizophrenia. Anthony Grace and his co-workers have suggested, on the basis of experimental work using animals, that hippocampal dysfunction might produce an alteration of dopamine release in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

, thereby indirectly affecting the integration of information in the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...

. Others have suggested that hippocampal dysfunction might account for disturbances in long term memory frequently observed in people with schizophrenia.

Transient global amnesia

A current hypothesis as to one cause of transient global amnesia
Transient global amnesia
Transient global amnesia is a syndrome in clinical neurology whose key defining characteristic is temporary but almost total disruption of short-term memory with a range of problems accessing older memories...

 -- a dramatic sudden temporary near-total loss of short-term memory—is that it may be due to venous congestion of the brain, leading to ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...

 of structures, such as the hippocampus, that are involved with memory.

Evolution

The hippocampus has a generally similar appearance across the range of mammal species, from monotreme
Monotreme
Monotremes are mammals that lay eggs instead of giving birth to live young like marsupials and placental mammals...

s such as the echidna
Echidna
Echidnas , also known as spiny anteaters, belong to the family Tachyglossidae in the monotreme order of egg-laying mammals. There are four extant species, which, together with the platypus, are the only surviving members of that order and are the only extant mammals that lay eggs...

 to primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...

s such as humans. The hippocampal-size-to-body-size ratio broadly increases, being about twice as large for primates as for the echidna. It does not, however, increase at anywhere close to the rate of the neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...

-to-body-size ratio. Therefore, the hippocampus takes up a much larger fraction of the cortical mantle in rodents than in primates. In adult humans, the volume of the hippocampus on each side of the brain is about 3–3.5 cm3, as compared to 320–420 cm3 for the volume of the neocortex.

There is also a general relationship between the size of the hippocampus and spatial memory. When comparisons are made between
similar species, those that have a greater capacity for spatial memory tend to have larger hippocampal volumes. This relationship also extends to sex differences: in species where males and females show strong differences in spatial memory ability, they also tend to show corresponding differences in hippocampal volume.

Non-mammalian species do not have a brain structure that looks like the mammalian hippocampus, but they have one that is considered homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 to it. The hippocampus, as pointed out above, is essentially the medial edge of the cortex. Only mammals have a fully developed cortex, but the structure it evolved from, called the pallium
Pallium (neuroanatomy)
In a neuroanatomy context, the word pallium refers to the layers of gray and white matter that cover the upper surface of the telencephalon in vertebrates. The non-pallial part of the telencephalon builds the subpallium. In basal vertebrates the pallium is a relatively simple three-layered...

, is present in all vertebrates, even the most primitive ones such as the lamprey
Lamprey
Lampreys are a family of jawless fish, whose adults are characterized by a toothed, funnel-like sucking mouth. Translated from an admixture of Latin and Greek, lamprey means stone lickers...

 or hagfish
Hagfish
Hagfish, the clade Myxini , are eel-shaped slime-producing marine animals . They are the only living animals that have a skull but not a vertebral column. Along with lampreys, hagfish are jawless and are living fossils whose next nearest relatives include all vertebrates...

. The pallium is usually divided into three zones: medial, lateral, and dorsal. The medial pallium forms the precursor of the hippocampus. It does not resemble the hippocampus visually, because the layers are not warped into an S shape or enwrapped by the dentate gyrus, but the homology is indicated by strong chemical and functional affinities. There is now evidence that these hippocampal-like structures are involved in spatial cognition in birds, reptiles, and fish.

In birds, the correspondence is sufficiently well established that most anatomists refer to the medial pallial zone as the "avian hippocampus". Numerous species of birds have strong spatial skills, particularly those that cache food. There is evidence that food-caching birds have a larger hippocampus than other types of birds, and that damage to the hippocampus causes impairments in spatial memory.

The story for fish is more complex. In teleost fish (which make up the great majority of existing species), the forebrain is distorted in comparison to other types of vertebrates: most neuroanatomists believe that the teleost forebrain is essentially everted, like a sock turned inside-out, so that structures that lie in the interior, next to the ventricles, for most vertebrates, are found on the outside in teleost fish, and vice versa. One of the consequences of this is that the medial pallium ("hippocampal" zone) of a typical vertebrate is thought to correspond to the lateral pallium of a typical fish. Several types of fish (particularly goldfish) have been shown experimentally to have strong spatial memory abilities, even forming "cognitive maps" of the areas they inhabit. There is evidence that damage to the lateral pallium impairs spatial memory.

Thus, the role of the hippocampal region in navigation appears to begin far back in vertebrate evolution, predating splits that occurred hundreds of millions of years ago. It is not yet known whether the medial pallium plays a similar role in even more primitive vertebrates, such as sharks and rays, or even lampreys and hagfish. Some types of insects, and molluscs such as the octopus, also have strong spatial learning and navigation abilities, but these appear to work differently from the mammalian spatial system, so there is as yet no good reason to think that they have a common evolutionary origin; nor is there sufficient similarity in brain structure to enable anything resembling a "hippocampus" to be identified in these species. Some have proposed, though, that the insect's mushroom bodies
Mushroom bodies
The mushroom bodies or corpora pedunculata are a pair of structures in the brain of insects and other arthropods.-Structure:Mushroom bodies are usually described as neuropils, i.e. as dense networks of neuronal processes and glia...

 may have a function similar to that of the hippocampus.

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