Hippocampus: Anatomy and functions
The hippocampal formation is an important component of the limbic system, along with the amygdala and septal area (although some also include the cingulate gyrus and prefrontal cortex as part of this system). The world “hippocampus” is derived from the Greek words “hippos” meaning horse and “kampos” meaning sea monster, and refers to the structure’s shape resembling a seahorse. The elongated hippocampal structures lie along the longitudinal axis of the brain, one in each of the medial parts of the temporal lobes, and form the medial walls of the inferior horns of the lateral ventricles. It is made up of three components:
- the hippocampus
- dentate gyrus
- subicular cortex
- Hippocampus: Structure and organisation
- Dentate gyrus
- Subicular cortex
- Hippocampal connections: Ins and outs!
- Clinical correlations
Hippocampus: Structure and organisation
The hippocampus is comprised primarily of pyramidal cells. Like all cells, pyramidal cells have afferent processes (dendrites) and efferent processes (axons). It should be noted that the dendrites of a pyramidal cell extend from both the apex and base. The basal dendrites extend toward the surface of the lateral ventricles; while the apical dendrites extend away from the lateral ventricles and toward the dentate gyrus.
The axons of pyramidal cells take information received by the hippocampus and send it to other structures in the brain: these efferent processes extend from the pyramidal cell body, travel through a structure called the alveus‒a fiber layer next to the inferior horn of the lateral ventricle‒and then enter into either the entorhinal cortex or the fimbria-fornix.
The tissue comprising the hippocampus has many layers. From the ventricular surface to the dentate gyrus, the hippocampus is made up of:
- an external plexiform layer,
- a stratum oriens layer,
- a pyramidal cell layer,
- a stratum radiatum layer,
- a stratum lacunosum-moleculare layer.
The external plexiform layer is situated near the inferior horn of the lateral ventricle. It contains the alvear pathway, which is made up of pyramidal cell axons and hippocampal afferent fibers coming from the entorhinal cortex.
The stratum oriens layer contains two types of cells: basal dendrites and basket cells.
The pyramidal cell layer, consistent with its name, contains pyramidal cells of the hippocampus.
The stratum radiatum layer and stratum lacunosum-moleculare layer both contain the perforant pathway, which is composed of the apical dendrites of pyramidal cells and hippocampal afferent fibers coming from the entorhinal cortex.
The pyramidal cells in the hippocampus are arranged in a C-shaped pattern, and some of these cells also fit snugly into the C-shaped dentate gyrus.
To make matters even more complicated, the hippocampus is divided into different regions called fields. One classification divides the hippocampus into four fields (although thankfully with names much easier to remember than the names of the layers):
The CA1 field, also known as Sommer’s sector, contains the pyramidal cells located closest to the subiculum; whereas the CA4 field contains cells within the hilus of the dentate gyrus. Fittingly named with numbers in between 1 and 4, the CA2 and CA3 fields are located in between. One special feature of the CA3 field to note is that the collaterals of the axonal processes extending from the CA3 pyramidal cells are known as recurrent or Schaffer collaterals, and these fibers actually project back to the CA1 field.
Like the hippocampus, the dentate gyrus is also multilayered; but, unlike the hippocampus whose primary cell is the pyramidal cell, the primary cell of the dentate gyrus is the granule cell. Granule cell axons are called mossy fibers, and they synapse with the pyramidal cells in the CA3 field of the hippocampus.
The dentate gyrus, however, does also have pyramidal cells, although they are located deep to the granule cell layer. The pyramidal cell layer of the dentate gyrus is called the polymorphic cell layer. External to the granule cell layer is yet another layer of cells called the molecular layer, named as such because of its position next to the molecular layer of the hippocampus. Consistent with its name and location, the dentate gyrus’ molecular layer is made up of hippocampal axonal afferent fibers.
The subicular cortex represents a transitional area between the hippocampus and the entorhinal cortex. The main differentiating feature between the hippocampus and the subicular cortex is that the pyramidal cell layer in the subicular cortex is significantly thicker than it is in the hippocampus.
Feeling a bit confused? Why not try testing your understanding with some quiz questions? You can use them to learn the anatomy of the hippocampus from scratch, or to identify holes in your knowledge.
Hippocampal connections: Ins and outs!
Input to the hippocampus
The entorhinal cortex is an important source of two different groups of afferent fibers delivering information to the hippocampal formation. The lateral perforant pathway arises from the lateral entorhinal cortex and extends into the molecular layer of the hippocampus. The medial perforant pathway arises from the medial entorhinal cortex, extends through the white matter from the subicular cortex, and enters the alveus of the hippocampus. Many of these fibers carry olfactory, visual, and auditory information to the hippocampus.
The diagonal band of Broca originates from the septal area, and acts as part of a feedback circuit to the hippocampus from the septal area. The other part of this feedback circuit is the precommissural fornix, which allows the septal area to receive feedback from the hippocampus.
|Layers||External plexiform layer, stratum oriens layer, pyramidal cell layer, stratum radiatum layer, stratum lacunosum-moleculare layer|
|Fields||CA1, CA2, CA3, CA4|
|Afferent Pathways||Entorhinal cortex, septal area, prefrontal cortex, anterior cingulate gyrus, premammillary region, reticular formation|
|Efferent Pathways||Septal area (precommissural fornix), anterior thalamic nucleus, hypothalamic mammillary bodies (postcommissural fornix), entorhinal cortex, cingulate cortex, prefrontal cortex, contralateral hippocampus|
|Functions||Learning, memory, aggression, rage, hormone regulation|
|Clinical||Temporal lobe epilepsy, rabies encephalitis, global cerebral ischemia, Alzheimer’s dementia, Korsakoff syndrome,|
The hippocampus also receives afferent input from the prefrontal cortex, anterior cingulate gyrus, and premammillary region of the brain, as well as from monoamine neuronal projections from the reticular formation in the brainstem (specifically from the locus coeruleus, raphe nucleus, and ventral tegmental area). The monoamine pathway in particular plays an essential role in regulating mood.
Because of these connections, the hippocampal formation is able to respond to changes in activity in the cortex and brainstem and relay this information to the hypothalamus, ultimately adding an emotional or visceral quality to these changes in brain activity.
Output from the hippocampus
The efferent fibers of the hippocampal formation, sending signals from the hippocampus to other parts of the brain, come from the pyramidal cells of the hippocampus and subicular cortex. Fibers from the amygdala, situated anteriorly to the hippocampus, also travel largely in tandem with the hippocampal fibers. These fiber bundles arising from the hippocampus and amygdala pass postero-dorsally along the body of the lateral ventricle, around the posterior part of the thalamus, and then anteriorly along the inferior horn of the lateral ventricle.
The fiber bundle that arises from the hippocampus is called the fornix; it runs just inferiorly to the corpus callosum. The fiber bundle that arises from the amygdala is called the stria terminalis, and it runs parallel and ventromedial to the tail of the caudate nucleus. The fornix and stria terminalis fiber networks eventually terminate in different parts of the hypothalamus and septal area.
Fibers from the fornix that travel rostrally to the anterior commissure are called the precommissural fornix. These originate from both the hippocampus and subicular cortex and terminate in the septal area. The fibers of the precommissural fornix are topographically organized: this means that fibers near the anterior pole of the hippocampal formation project to the lateral region of the lateral septal nucleus, whereas fibers near the posterior part of the hippocampal formation project to more medial parts of the lateral septal nucleus.
Fibers from the fornix that travel ventrally behind the anterior commissure are called the postcommissural fornix. These fibers originate in the subicular cortex and terminate either in the anterior thalamic nucleus or in the mamillary bodies of the hypothalamus. The postcommissural fornix innervates parts of the diencephalon, including the anterior thalamic nucleus, mammillary bodies, and parts of the medial hypothalamus.
Neurons from the subiculum also send axons to the entorhinal cortex, cingulate cortex, and regions of the prefrontal cortex. The entorhinal cortex subsequently sends axons to the amygdala and parts of the temporal cortex. These networks of connections allow the hippocampal formation to send signals throughout the cerebral cortex, including to regions which receive and process different types of sensory information.
There is also a commissural component of the fornix: the purpose of this part of the fornix is to connect the hippocampi on either side of the brain to each other. The axons that do this arise predominantly from the CA3-CA4 parts of the hippocampus and synapse in the contralateral hippocampus. It is theorized that these connective fibers may provide the pathway by which seizures spread from their primary epileptogenic focus in one hippocampus to the contralateral hippocampus, ultimately allowing for a secondary epileptogenic focus to form in the contralateral hippocampus.
Although it’s quite a small structure in the brain, size can be deceptive! The hippocampus plays a number of crucial roles, including regulating emotions, motivation, hormonal activity, autonomic activity, and memory formation. It is particularly important for the process of learning, and seeing relationships between what has been learned.
Probably the most well recognized function of the hippocampus is its role in learning and memory: although the exact mechanisms remain somewhat mysterious, it is believed that the hippocampus receives and consolidates information, allowing for establishment of long-term memories in a process known as long-term potentiation (LTP). It also plays a role in spatial memory, allowing us to keep track of where things are, as well as where they are in relation to each other; as such, it is instrumental in the formation of cognitive maps.
There have been numerous reports linking tumors, lesions, and epileptogenic activity in humans within the hippocampus to aggressive reactions, ranging from minor hostility to explosive acts of violence. The hippocampus’ role in mediating aggression and rage appears to be dependant on the region of the structure that is stimulated: activation of the temporal pole, i.e. the region closest to the amygdala, stimulates predatory or fight behavior; while activation of the region closest to the septal pole instead suppresses those impulses.
Given the numerous synaptic connections between the hypothalamus and hippocampus, it is not surprising that the hippocampus is also involved in hormone regulation and contributes to various endocrine functions. Ventral aspects of the hippocampus have been found to house dense regions of estradiol-concentrating neurons, as well as high concentrations of corticosterone which inhibits those estradiol-concentrating neurons. Furthermore, animal studies have demonstrated that stimulation of the hippocampus inhibits ovulation, and lesions in the hippocampus or division of the fornix disrupt the diurnal rhythmic release of adrenocorticotropic hormone (ACTH).
It has been postulated that the hippocampus may be selectively sensitive to varying hormone levels, playing a role in providing feedback to the pituitary gland via its hypothalamic connections. This is believed to occur indirectly via synaptic relay within the septal area, as well as directly via a pathway called the medial cortico-hypothalamic tract. The medial cortico-hypothalamic tract arises near the temporal pole of the hippocampus and projects to the ventromedial hypothalamus; it terminates between the suprachiasmatic and arcuate nuclei in a region containing hypophysiotrophic hormones that mediate functions of the anterior pituitary gland.
Temporal lobe epilepsy
Temporal lobe epilepsy is characterized by recurrent, unprovoked seizures which originate from the temporal lobe, arguably the most epileptogenic region of the brain. These seizures can be either focal aware seizures (simple partial seizures which occur without loss of awareness), and focal impaired awareness seizures (complex partial seizures with loss of awareness), although generalized seizures can also occur. The CA1 field of the hippocampus, known as Sommer’s sector, is particularly susceptible to the anoxia that can occur during temporal lobe epilepsy; this can be associated with agitation or aggression, anger, anxiety paranoia, and other emotional phenomena.
Rabies is a bullet-shaped, negative-sense, single-stranded RNA virus that is transmitted to humans via the bite of an infected animal (typically a dog, bat, or other mammal) and causes a lethal encephalitis (inflammation of the brain). Once the victim is inoculated with the virus via the bite, the virus ascends to the brain via the peripheral nerves. This can take weeks or even months depending on the bite site - the closer the bite is to the brain, the shorter the incubation period. Initial symptoms are nonspecific, including headache, fever, and malaise; but co-occurrence with paresthesias at or around the wound site is diagnostic. As the virus progresses, the victim experiences extreme central nervous system excitability manifesting as hypersensitivity to pain, violent motor responses, and convulsions. Violent contractions of the pharyngeal muscles make swallowing difficult and painful; this is the reason why those with symptomatic rabies will avoid drinking, even water, and are thus described as “hydrophobic”. These pharyngeal spasms are also the cause of the characteristic foaming at the mouth. Eventually, meningismus occurs, followed by flaccid paralysis; alternations between mania and stupor progress to coma, and eventual death due to failure of the brain’s respiratory center.
The pathognomonic histopathologic findings in rabies are round- or oval-shaped eosinophilic cytoplasmic inclusions called Negri bodies, which can be observed in the pyramidal neurons of the hippocampus and the Purkinje cells of the cerebellum.
Global cerebral ischemia
Global cerebral ischemia (otherwise known as diffuse hypoxic/ischemic encephalopathy) is the result of a severe hypotensive episode. Among the cells of the central nervous system, neurons are the most vulnerable to ischemia, although glial cells are sensitive as well. Different regions of the brain are also more susceptible than others: the pyramidal cells in the CA1 region of the hippocampus, Purkinje cells in the cerebellum, and pyramidal cells in the cortex are the most susceptible to global ischemia, and can be damaged even if the ischemic episode is short in duration.
If damaged, these cells will begin to show microvacuolation and eosinophilia of the cytoplasm, followed by nuclear pyknosis (condensation of the chromatin and shrinking of the nucleus) and karyorrhexis (fragmentation of the nucleus) within 12-24 hours after an insult.
The hippocampus, along with the entorhinal cortex and amygdala, are involved early on in the course of Alzheimer’s dementia, and are typically found to be severely atrophied in the late stages of the disease. The hippocampus in particular is a site of significant formation of both neuritic plaques (collections of dystrophic neurites around a central Aβ amyloid core) and neurofibrillary tangles (intracytoplasmic bundles of filaments containing hyperphosphorylated tau protein that surround or even displace the nucleus of the neuron). Granulovacuolar degeneration (formation of small, clear cytoplasmic vacuoles each containing an argyrophilic granule) are also observed in abundance in the hippocampi of patients with Alzheimer’s; and Hirano bodies (eosinophilic inclusion bodies composed primarily of actin filaments) may be observed particularly in hippocampal pyramidal cells.
Research also suggests that a reduction in the rate of insulin and insulin growth factors (IGF) in neurons contributes to the neuronal degeneration seen in Alzheimer’s disease (AD). In line with this observation, postmortem examinations revealed significantly decreased levels of insulin and IGFs particularly in the hippocampus, frontal lobes, and thalamus, whereas the cerebellum (typically unaffected in Alzheimer’s) had normal levels.
Korsakoff syndrome is a disorder in which hippocampal damage results in the inability to both form new memories (loss of anterograde memory) and recall memories made prior to the damage (loss of retrograde memory). It is typically associated with thiamine (vitamin B1) deficiency, which is frequently associated with chronic alcohol abuse and its toxic effects on neurons, particularly those of the hippocampal formation and the Papez circuit (the mammillary bodies, cingulate gyrus, and anterior thalamic nucleus).
H.M. was 27 years old when he received a bilateral temporal lobectomy for treatment of his epilepsy, which included removal of a great deal of both hippocampi. The operation treated his seizures quite well, but it left his memory forever changed. After the operation, he was able to remember aspects of his distant past, but was unable to form new memories of people he’d met, places he’d gone, or what he’d heard afterward. Other abilities, such as intellect and abstract reasoning, remained intact.
Bilateral loss of the hippocampi, either through trauma or surgical lesioning, affects the ability to form new memories. Memories formed prior to the damage remain intact, but patients are unable to make new memories from the time of the damage onward. As such, new people, places, and events are never encoded and thus are interpreted as “new” each and every time they are encountered. This is particularly interesting when patients with bilateral hippocampal damage or removal are taught a new task with motor components - because procedural memory remains intact, the patient will improve at the motor task with each encounter just as anyone else would, but with absolutely no memory of ever performing the task before. Heightened ability tends to be interpreted by the patient as “beginner’s luck.”