The hippocampus is located in the medial temporal lobe, near the entorhinal cortex and olfactory cortex, on each side of the brain. Hippocampus translates to seahorse& early anatomists felt the curved shape of this structure resembled a seahorse. The hippocampus, together with the cingulate cortex, olfactory cortex, and amygdala, form the limbic system. Limbus is Latin for border, implying these structures form a border at the lower edge of the cortex. Damage to the hippocampus is often manifested as an inability to form, consolidate, and store memories.
The hippocampus is a key structure in episodic or autobiographical memory as well as declarative memory-especially the formation of these memories. This role of the hippocampus was discovered when the hippocampus was removed from a patient, known as H. M., to relieve epileptic seizures. As Scoville and Milner reported, H. M. was unable to remember episodes and events that had transpired in the last few years before the surgery. In addition, H. M. was not able to remember events that followed the surgery (see also O'Kane, Kensinger, & Corkin, 2004). Hence, the hippocampus might not be essential to memories that were consolidated many years ago, although this issue remains contentious.
Drugs have also shown to affect these episodic or autobiographical memories. For example, the putative "date-rape" drugs are assumed to obstruct memories by inhibiting the cholinergic projection that connects the medial septum to the hippocampus
Learning new skills, such as musical instruments, usually remains intact. Thus, the hippocampus might be more likely to impair declarative memory-in which memories need to be verbalized-than procedural memory. In addition, semantic learning seems to remain largely intact, as demonstrated by H. M. (O'Kane, Kensinger, & Corkin, 2004)
The hippocampus most likely underpins episodic memory because this structure facilitates the capacity of individuals to bind distinct features to form a single unit (e.g. Cohen & Eichenbaum, 1993;; Eichenbaum, 1999, 2001). Both human lesion studies (e.g. Kan, Giovanello, Schnyer, Makris, & Verfaellie, 2007) and functional neuroimaging studies (Jackson & Schacter, 2004) attest to the role of this structure in binding features, called associative memory.
In contrast, regions immediately outside the hippocampus, especially the perirhinal cortex, are more involved in tasks in which familiarity supports recognition, such as item recognition (see Aggleton & Brown, 2006).
The precise role of the hippocampus in associative memory depends on the precise features and objectives of the task. The perirhinal cortex, not the hippocampus, seems to be involved in unitization-binding together separate features, like the colour and shape of a car, to form a single unit (Mayes et al., 2007). Likewise, the perirhinal cortex seems to underpin the capacity to bind to items in the same domain, such as two words or two faces (Giovanello, Keane, & Verfaellie, 2006). In contrast, the hippocampus is involved in the binding of items that correspond to different domains, times, locations, or sensory modalities. Hence, the hippocampus assimilate separate entities into a unified experience or episode (Mayes et al., 2007).
In addition, the hippocampus and perirhinal cortex utilize different models to learn information (see McClelland, McNaughton, & O'Reilly, 1995;; Norman & O'Reilly, 2003). The hippocampus, when binding items, attempts to maximize the extent to which the distinct units differ from each other-which is optimal to support pattern completion or matching. Accordingly, the hippocampus forms a vast array of distinct episodes. In contrast, neocortical regions, including the perirhinal cortex, attempt to maximize similarities between units-to generalize patterns across different episodes.
Minor, rather than marked, degeneration of the hippocampus might manifest itself in associative memory tasks-but in recall rather than recognition (see Eichenbaum, 2004). The hippocampus, after some decline, might enable partial encoding of the associations-sufficient for subsequent recognition but not recall. For example, suppose individuals needed to learn a series of paired items, such as pairs of words. They might be able to recognize that a pair of words is familiar. However, when one of these words is presented, they might not be able to recall the other item in that pair.
Nevertheless, different areas in the hippocampus may be involved in encoding or retrieval. The rostral areas seem to be involved in encoding and the caudal areas seem to be involved in retrieval (Lepage, Habib, & Tulving, 1998).
When individuals can readily retrieve a memory, such as the name of someone, activation of the hippocampus increases. To illustrate, in a study conducted by Oztekin, Davachi, and McElree (2010), on each trial, a series of 12 unrelated words was presented. Then, another pair of words appeared, only one of which was derived from the previous series. Participants had to decide which of these words was presented earlier. Furthermore, during this fMRI was applied to identify the brain regions that were activated during this task.
In general, recognition time was fastest for the last item. This last item is often assumed to be the focus of attention and does not need to be retrieved from a memory story. Recognition time was moderate for the next three or so items before this last word. These three items are potentially words that are represented in a more active state, perhaps in long term memory or working memory. Recognition time was slowest for the first eight or so items. These items are words that are represented in a passive state in long term memory.
The hippocampus was negligibly activated when individuals needed to recognize the last item, presumably because no retrieval processes were needed. Furthermore, the hippocampus was slightly more activated when items were derived from the active set compared to the passive set. Hence, the probability of successful retrieval might correlate with activation of the hippocampus (Oztekin, Davachi, & McElree, 2010).
Second, the hippocampus is involved in spatial learning and memory, as proposed by O'Keefe and Nadel (1978). That is, the hippocampus might represent cognitive maps of the spatial environment. For example, when this structure is not intact, performance of rats on spatial memory tasks-such as navigating through an environment-is impaired (e.g., Morris, Garrud, Rawlins, & O'Keefe, 1982). Humans also are more inclined to become lost.
For example, if the hippocampus is intact, rats learn to traverse mazes to locate food efficiently. That is, with practice, they learn never to proceed down the same arm of a maze more than once. In contrast, rats with hippocampal damage do not seem to learn this efficient strategy (see Cohen & Eichenbaum, 1993). They often traverse the same arm many times.
Variations of this study revealed some key insights into the hippocampus. If, across all trials, some of the arms never comprise food, rats will learn to avoid these passages--regardless of whether or not their hippocampus is intact. Hence, despite hippocampal damage, rats can learn to avoid arms that are never rewarding.
In rats, neurons in the hippocampus were shown to be activated by stimuli in specific spatial fields, called place cells. Most, but not all, of these cells are also sensitive to the direction in which the animal is travelling, not merely the location of stimuli. Similar findings have been observed in humans, by Ekstrom, Kahana, Caplan, Fields, Isham, Newman, and Fried (2003).
More importantly, these place cells develop the capacity to respond to specific locations even in novel contexts. In other words, these place cells seem to underpin the learning of additional locations or spatial contexts. When the hippocampus is damaged, individuals thus cannot readily and flexibly learn additional spatial contexts--which could explain the limited flexibilty and efficiency of rats in mazes (O'Keefe & Nadel, 1978)
As imaging studies show, the hippocampus has been shown to be more activated when individuals need to negotiate through cities to locate specific places. For example, this posterior portion of this structure is larger in experienced taxi drivers (Maguire, Gadian, Johnsrude, Good, Ashburner, Frackowiak, & Frith, 2000), but the anterior portion is reduced.
Two-step theories of memory formation imply the transmission of information between the neocortex and hippocampus depends on whether individuals are sleeping. Specifically, according to these theories, when individuals are awake, they often encode or learn information. At this time, information that is represented in the neocortex, such as intentions or events, is transferred to the hippocampus. Then, when individuals are asleep, they consolidate this information. Activity within the hippocampus is transferred to the neocortex, enabling individuals, in essence, to replay these episodes, which facilitates consolidation (for a review, see Wagner, Axmacher, Lehnertz, Elger, & Fell, 2010).
Wagner, Axmacher, Lehnertz, Elger, and Fell (2010) undertook a study that challenges this proposition. They measured EEG recordings to examine the temporal relationship between activation of the neocortex and hippocampus. They computed a measure, called the directionality index, to examine whether activation in the neocortex tends to precede or follow activation of the hippocampus. Contrary to expectations, activation of the neocortex was more likely to precede, and thus elicit, activation of the hippocampus while participants were asleep. According to Wagner, Axmacher, Lehnertz, Elger, and Fell (2010), information represented in the neocortex, such as goals, might incite retrieval of information in the hippocampus, facilitating retention and consolidation.
The hippocampus is also involved in emotional regulation (see Campbell, Marriott, Nahmias, & MacQueen, 2004;; Sheline, Mittler, & Mintun, 2002). In particular, the hippocampus inhibits cells in the hypothalamus that generate corticotrophin-releasing factor. These cells thus reduce the concentration of glucocorticoids-a manifestation of the stress response corresponding to the hypothalamo-pituitary-adrenal axis (see Sapolsky, 2002).
In particular, stress provokes the adrenocortex to release cortisol, which stimulates the hippocampus. The hippocampus, in turn, inhibits this hypothalamo-pituitary-adrenal axis, thus representing a negative feedback loop.
In addition, the hippocampus is involved in learning emotional responses to complex stimuli. For example, suppose one stimulus, like a tiger, evokes an unconditional stress response, but only when separated from another stimulus, such as the cage (Gluck & Myers, 1993, 2001). When the hippocampus is not functioning correctly, the unconditional stress is still evoked, even after repeated exposure to the stimulus pair. Hence, a hippocampus that has developed properly enables individuals to inhibit the stress that simple stimuli might otherwise evoke.Historical beliefs about the hippocampus
Initially, the hippocampus was assumed to be integral to olfaction, primarily because this structure is located alongside the olfactory cortex. In addition, in the 1960s, the hippocampus was assumed to underpin inhibitory processes, as reviewed by O'Keefe and Nadel (1978). In particular, hippocampal damage in animals induced hyperactive behaviour and an incapacity to inhibit responses that had been learned previously.
Activity in the hippocampus may underpin the capacity of some people to imagine future rewards vividly and, therefore, value these rewards over more immediate gratification (Lebreton et al., 2013). In particular, data from structural MRI and functional MRI, when combined, show that density of gray matter is associated with elevated levels of activity in the hippocampus. This activity in the hippocampus also coincided with the tendency of people to rate future images of a reward more favorably than immediate rewards--a tendency that correlated with more detailed simulations of future possibilities.
Specifically, in this study, participants needed to decide between two options, such as between two foods or two sporting items. The first option was mildly pleasant but immediate. The second option was more pleasant but delayed by a month, year, or 10 years. In addition, one or both options were presented as pictures or described in words--and, therefore, needed to be imagined or mentally simulated. In everyday life, the delayed option would usually need to be imagined rather than observed.
The task of participants was to decide which of the two options they prefer. Next, participants indicated the extent to which they liked or desired each option, disregarding the delay. Finally, they indicated the degree to which each imagined option evoked many details in their mind.
Options that elicited many details were more likely to be perceived as likeable and desirable. As functional MRI showed, hippocampal activity was especially pronounced on trials in which participants chose a delayed, imagined option over an immediate, observed alternative. This hippocampal activity was associated with grey matter density. Furthermore, in patients with Alzheimers and thus atrophy in the hippocampus, observed options were more likely to be chosen than simulated options.
These findings are consistent with the notion that hippocampal activity enables individuals to imagine future possibilities in detail, and that such details increase the perceived desirability of these alternatives. In particular, the hippocampus enables people to retrieve details from past episodes and construct a novel vision of the future. These findings are consistent with the past observation that patients with medial temporal lobe damage exhibit deficits in both episodic memory and future simulation.
The hippocampus seems to underpin many of the problems that manifest in Alzheimer's disease. Neuronal atrophy disconnects pathways that connect the hippocampus to the cortex (Hyman, Van Hoesen, Damasio, & Barnes, 1984). Atrophy of the hippocampus and the entorhinal cortex is observed even in mild Alzheimer's disease (Scahill, Schott, Stevens, Rossor, & Fox, 2002) even before clinical symptoms are observed (see Twamley et al., 2006).
Furthermore, in Alzheimer's Disease, amyloid plaques are dispersed throughout the cortex (see Braak & Braak, 1991). A gradual and incessant imbalance between the production and eradication of amino acid peptide fragments, called beta-amyloid, consolidate to form these amyloid plaques. These plaques first appear in the neocortex, followed by the hippocampus, entorhinal cortex, and insular cortex (Thal, R?b, Orantes, & Braak, 2002).
In addition, Alzheimer's Disease si characterized by neurofibrillary tangles, which are dispersed throughout the cortex. Neurofibrillary tangles appear within neurons and comprise hyper-phosphorylated tau protein. This tau a protein is needed to stabilize the microtubule system, which supports transport within cells. Extra phosphate groups combine with the tau protein to forms pairs of helical filaments called neurofibrillary tangles-a process that beta-amyloid deposits seem to accelerate (e.g., Selkoe, 2000). These tangles first form in the trans-entorhinal region before extending to the hippocampus, entorhinal cortex, and neocortex (Braak & Braak, 1991).
Atrophy in the hippocampus is not only implicated in Alzheimer's Disease, but has also been demonstrated in mild cognitive impairment-which is often a precursor to Alzheimer's Disease. For example, MRI studies have uncovered atrophy in the hippocampus and entorhinal cortex in individuals with mild cognitive impairment (see deToledo-Morrell et al., 2004). PET and SPECT studies have uncovered a diminution in blood flow and glucose metabolism in the hippocampus and posterior cingulate (see Wolf et al., 2003).
Researchers recognized the possibility that dysfunction of the hippocampus might be involved in depression. That is, depression is associated with impairments in episodic, declarative, and spatial memory as well as emotional regulation-all of which are associated with the hippocampus.
Meta-analyses confirm that volume of the hippocampus is smaller in clinical depression, although diversity across studies is apparent (see Czeh & Lucassen, 2007;; Mervaala, Fohr, Kononen, Valkonen-Korhonen, Vainio, Partanen, et al., 2000;; Newmeister, Wood, Bonne, Nugent, Luckenbaugh, Young, et al., 2005;; Rosso, Cintron, Steingard, Renshaw, Young, & Yurgelun- Tood, 2005;; Sheline, Gado, & Kraemer, 2003;; for a meta-analysis, see Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G. (2004). This diversity partly arises because some research includes bipolar patients, the level or duration of depression varies considerably across samples, and scan thickness diverges across studies as well.
Sheline, Gado, and Kraemer (2003) argue that atrophy of the hippocampus seems to be dependent upon the number and duration of untreated depressive episodes. For example, many factors, such as antidepressants, might curb such atrophy. The hippocampus might be smaller for individuals in full remission if they have experienced depression recurrently in the past (e.g., Neumeister, Wood, Bonne, Nugent, Luckenbaugh, Young, et al., 2005) but larger in individuals with depression for the first time. Nevertheless, as Czeh and Lucassen (2007) highlighted, the hippocampus is smaller in other disorders, such as schizophrenia, Cushing's syndrome, and posttraumatic stress disorder (e.g., Bremner, Randall, Vermetten, & Staib, 1997)-and thus might not be characteristic of depression.
Most of the pathways that relate the hippocampus to the neocortex are mediated by the entorhinal cortex. In particular, information transmitted from the hippocampus tend to be directed towards the deeper layers of the entorhinal cortex. Information transmitted to the hippocampus usually emanates from the superficial layers of the entorhinal cortex.
The hippocampus demonstrates two distinct patterns of EEG waves, represent two separate modes: theta-large regular waves with a frequency range of 6-9 Hz-and large irregular activity (see Buzs?ki, 2006).
The theta mode is most prevalent when individuals are active and alert, particularly if moving, or experiencing REM sleep. During these times, only a fraction of the neurons are active, firing at almost 50 spikes a second. The pacemaker of this rhythm seems to emanate from the medial septal area. Which cells are active changes over time, and partly depends on the spatial location of the animals. The theta mode does not seem as prominent in humans, however.
The large irregular activity mode is prevalent during sleep, except during REM, as well as during resting, eating, or other states of immobility. This mode entails sharp, almost random, waves, which last .2 to .3 seconds.
The hippocmpus comprises two main sheets of neurons: the dentrate gyrus and Ammons's horn. The dentrate gyrus receives input from the entorhinal cortex. Ammon's horn comprises four divisions: CA1, CA2, CA3, and CA4. CA3 receives input from the dentrate gyrus. CA1 receives input from CA3.
Several events and factors can culminate in damage to the hippocampus, such as anoxia or limited oxygen as well as encephalitis or mesial temporal lobe epilepsy.
Several scholars, such as Campbell, Marriott, Nahmias, and MacQueen (2004) as ewll as Sheline, Mittler, and Mintun (2002), have discussed the mechanisms that underpin atrophy of the hippocampus in affective disorders, such as depression. The main mechanism probably relates to the hypothalamo-pituitary-adrenal axis. In particular, stress activates the hypothalamo-pituitary-adrenal axis, which in turn corresponds to an increase in the level of glucocorticoids-a class of steroid hormones, which includes cortisol, that bind with the glucocorticoid receptor. These glucocorticoids have been shown to damage neurons in the hippocampus, reducing dendritic branching.
That is, usually, the hippocampus inhibits the release of these glucocorticoids. However, if the level of these glucocorticoids, such as cortisol, exceeds some threshold, functioning of the hippocampus is impaired (Pavlides, Watanabe, Magarinos, & McEwen, 1995) and damage might ensue (Sapolsky, Uno, Rebert, & Finch, 1990). Consistent with the damaging role of stress to the hippocampus, research indicates that declarative memory (Sauro, Jorgensen, & Pedlow, 2003) and autobiographical memory (Wolf, Witt, & Hellhammer, 2004) are impaired when cortisol concentrations rise.
Many studies have examined the mechanisms by which cortisol damages the hippocampus. Specifically, cortisol seems to inhibit the uptake of glucose in neurons (Du et al., 2009). In addition, cortisol enhances calcium channel expression (Joels et al., 2004), ultimately impeding neurogenesis and increasing cell apoptosis.
Infants are especially sensitive to stress. Hence, if infants do not receive the requisite assistance from parents, development of the hippocampus might be impeded irreversibly (Heim, Ehlert, Hanker, & Hellhammer, 1998;; Heim & Nemeroff, 1999).
Often, this decline in dendritic branching is reversible. Indeed, antidepressant treatments, including electroconvulsive stimulation, can reverse the atrophy in the hippocampus (see Czeh & Lucassen, 2007). However, excessive glucocorticoids over months can induce permanent loss of neurons in the hippocampus (see Sheline, Gado, & Kraemer, 2003)
Aboitiz, F., Morales D., & Montiel, J. (2003). The evolutionary origin of the mammalian isocortex: Towards an integrated developmental and functional approach. Behavioral Brain Sciences, 26, 535-552.
Amaral, D. G. (1999). What is where in the medial temporal lobe? Hippocampus, 9, 1-6.
Avital, A., Ram, E., Maayan, R., Weizman, A., & Richter-Levin, G. (2006). Effects of early-life stress on behavior and neurosteroid levels in the rat hypothalamus and entorhinal cortex. Brain Research Bulletin, 68, 419-424.
Bartoo, G. T., Nochlin, D., Chang, D., Kim, Y., & Sumi, S. M. (1997). The mean A? load in the hippocampus correlates with duration and severity of dementia in subgroups of Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 56, 531-540.
Bell-McGinty, S., Butters, M. A., Meltzer, C. C., Greer, P. J., Reynolds III, C. F. & Becker, J. T. (2002). Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. American Journal of Psychiatry 159, 1424-1427.
Beyer, J. L., & Krishnan, K. R. R. (2002). Volumetric brain imaging findings in mood disorders. Bipolar Disorders, 4, 89- 104.
Bremner, J. D., & Narayan, M. (1998). The effects of stress on memory and the hippocampus throughout the life cycle: Implications for childhood development and aging. Development & Psychopathology, 10, 871-885.
Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., & Charney, D. S. (2000). Hippocampal volume reduction in major depression. American Journal of Psychiatry, 157, 115-117.
Bremner, J. D., Narayan, M., Staib, L. H., Southwick, S. M., McGlashan, T., & Charney, D. S. (1999). Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. American Journal of Psychiatry, 156, 1787-1795.
Bremner, J. D., Randall, P., Scott, T. M., & Bronen, R. A. (1995). MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. American Journal of Psychiatry, 152(7), 973-981.
Bremner, J. D., Randall, P., Vermetten, E., & Staib, L. (1997). Magnetic resonance imagingbased measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: A preliminary report. Biological Psychiatry, 41, 23-32.
Bobinski, M., de Leon, M. J., Wegiel, J., DeSanti, S., Convit, A., Saint Louis, L. A., et al. (2000). The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease. Neuroscience, 95, 721-725.
Braak, H., & Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica, 82, 239-259.
Buzsaki, G (2006). Rhythms of the Brain. Oxford University Press.
Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G. (2004). Lower hippocampal volume in patients suffering from depression: A meta-analysis. American Journal of Psychiatry, 161, 598-607.
Cantero, J. L., Atienza, M., Stickgold, R., Kahana, M. J., Madsen, J. R., & Kocsis, B. (2003). Sleep-dependent theta oscillations in the human hippocampus and neocortex. Journal of Neuroscience, 23, 10897-10903.
Cohen, N. J., & Eichenbaum, H. (1993). Memory, amnesia, and the hippocampal system. Cambridge: MIT press.
Czeh, B., & Lucassen, P. J. (2007). What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? European Archives of Psychiatry and Clinical Neuroscience, 257, 250- 260.
De Santi, S., de Leon, M. J., Rusinek, H., Convit, A., Tarshish, C. Y., Roche, A., et al. (2001). Hippocampal formation glucose metabolism and volume loss in MCI and AD. Neurobiology of Aging, 22, 529-539.
Devanand, D. P., Pradhaban, G., Liu, X., Khandji, A., De Santi, S., Segal, S. et al. (2007). Hippocampal and entorhinal atrophy in mild cognitive impairment: Prediction of Alzheimer disease. Neurology, 68, 828-836.
Dickerson, B. C., Goncharova, I., Sullivan, M. P., Forchetti, C., Wilson, R. S., Bennett, D. A., et al. (2001). MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease. Neurobiol Aging 2001;; 22: 747-54.
Drevets, W. C. (2000). Neuroimaging studies of mood disorders. Society of Biological Psychiatry, 48, 813- 829.
Du, A. T., Schuff, N., Amend, D., Laakso, M. P., Hsu, Y. Y., & Jagust, W. J. et al. (2001). Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer's disease. Journal of Neurology, Neurosurgery, and Psychiatry, 71, 441-447.
Du, A. T., Schuff, N., Kramer, J. H., Ganzer, S., Zhu, X. P., & Jagust, W. J. et al. (2004). Higher atrophy rate of entorhinal cortex than hippocampus in AD. Neurology, 62, 422-427.
Du, J. et al., (2009). Dynamic regulation of mitochondrial function by glucocorticoids. Proceedings of the National Academy of Sciences, 106, 3543-3548.
Eichenbaum, H. (1999). The hippocampus and mechanisms of declarative memory. Behavioural Brain Research, 103, 123-133.
Eichenbaum, H. (2001). The hippocampus and declarative memory: Cognitive mechanisms and neural codes. Behavioural Brain Research, 127, 199-207.
Eichenbaum, H. (2004). Hippocampus: Cognitive processes and neural representations that underlie declarative memory. Neuron, 44, 109-120.
Eichenbaum, H., Schoenbaum, G., Young, B., & Bunsey, M. (1996). Functional organization of the hippocampal memory system. Proceedings of the National Academy of Science, USA, 93, 13500-13507.
Ekstrom, A. D., Kahana, M. J., Caplan, J. B., Fields, T. A., Isham, E. A., Newman, E. L., & Fried, I. (2003). Cellular networks underlying human spatial navigation. Nature, 425, 184-188.
Gluck, M., & Myers, C. (1993). Hippocampal mediation of stimulus representation: A computational theory. Hippocampus, 3, 491-516.
Gluck, M. A., & Myers, C. E. (2001). An introduction to neural network modeling of the hippocampus and learning. Cambridge: MIT Press.
Green, J. D., & Arduini A. A. (1954). Hippocampal electrical activity in arousal. Journal of Neurophysiology, 17, 533-557.
Hargreaves E., Rao G., Lee I., Knierim J. (2005). Major dissociation between medial and lateral entorhinal input to dorsal hippocampus. Science, 308, 1792-1794.
Heim, C., Ehlert, U., Hanker, J. P., & Hellhammer, D. H. (1998). Abuse-related posttraumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain. Psychosom Medicine, 60, 309-318.
Heim, C., Ehlert, U., & Hellhammer, D. H. (2000). The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 25, 1-35.
Heim, C., & Nemeroff, C. B. (1999). The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biological Psychiatry, 46, 1509-1522.
Hyman, B. T., Van Hoesen, G. W., Damasio, A. R., & Barnes, C. L. (1984). Alzheimer's disease: Cell-specific pathology isolates the hippocampal formation. Science, 225, 1168-1170.
Jack Jr. C. R., Shiung M. M., Weigand S. D., et al. (2005). Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology, 65, 1227-1231.
Joels, M. et al. (2004). Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress, 7, 221-231.
Kanner, A. M. (2004). Is major depression a neurologic disorder with psychiatric symptoms? Epilepsy and Behaviour, 5, 636- 644.
Konarski, J. Z., McIntyre, R. S., Kennedy, S. H., Rafi- Tari, s., Soczynska, J. K., & Ketter, T. A. (2008). Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disorders, 10, 1- 37.
Killiany, R. J., Hyman, B. T., Gomez-Isla, T., Moss, M. B., Kikinis, R., Jolesz, F., et al. (2002). MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;; 58: 1188-96.
Laakso, M. P., Frisoni, G. B., Kononen, M., Mikkonen, M., Beltramello, A., & Geroldi, C. (2000). Hippocampus and entorhinal cortex in frontotemporal dementia and Alzheimer's disease: A morphometric MRI study. Biological Psychiatry, 47, 1056-1063.
Lebreton, M., Bertoux, M., Boutet, C., Lehericy, S., Dubois, B., et al. (2013) A critical role for the hippocampus in the valuation of imagined outcomes. PLoS Biol, 11, (10): e1001684. doi:10.1371/journal.pbio.1001684
Lepage, M., Habib, R., & Tulving, (1998). Hippocampal PET activations of memory encoding and retrieval: The HIPER model. Hippocampus, 8, 313-322
Maguire, E. A., Burgess, N., Donnett, J. G., Frackowiak, R. S. J., Firth, C. D., O'Keefe, J. (1998). Knowing where and getting there: A human navigation network. Science, 280, 921-924.
Maguire, E. A., Gadian, D. G., Johnsrude, I. S., Good, C. D., Ashburner, J., Frackowiak, R. S., & Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Science, 97, 4398-4403.
Mayes, A. R., Holdstock, J. S., Isaac, C. L., Montaldi, D., Grigor, J., Gummer, A., et al. (2004). Associative recognition in a patient with selective hippocampal lesions and relatively normal item recognition. Hippocampus, 14, 763-784.
McClelland, J. L., McNaughton, B. L., & O'Reilly, R. C. (1995). Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457
Mervaala, E., Fohr, J., Kononen, M., Valkonen- Korhonen, M., Vainio, P., Partanen, K., et al. (2000). Quanitative MRI of the hippocampus and amygdala in severe depression. Psychological Medicine, 30, 117-125
Mesulam, M. M. (1999). Neuroplasticity failure in Alzheimer's disease: Bridging the gap between plaques and tangles. Neuron, 24, 521-529.
Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681-683.
Nagy, Z., Jobst, K. A., Esiri, M. M., Morris, J. H., King, E. M.-F., MacDonald, B., et al. (1996). Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: Clinicopathologic correlations using three sets of pathologic diagnostic criteria. Dementia, 7, 76-81.
Neumeister, A., Wood, S., Bonne, O., Nugent, A. C., Luckenbaugh, D. A., Young, T., et al. (2005). Reduced hippocampal volume in unmedicated remitted patients with major depression versus control subjects. Biological Psychiatry, 57, 935- 937.
Norman, K. A., & O'Reilly, R. C. (2003). Modeling hippocampal and neocortical contributions to recognition memory: A complementary-learning-systems approach. Psychological Review, 110(4), 611-646.
O'Brien, J., P. Desmond, D. Ames et al. (1997). Magnetic resonance imaging correlates of memory impairment in the healthy elderly: Association with medial temporal lobe atrophy but not white matter lesions. International Journal of Geriatric Psychiatry, 12, 369-374.
O'Kane, G., Kensinger, E. A., & Corkin, S. (2004). Evidence for semantic learning in profound amnesia: An investigation with patient H.M. Hippocampus, 14, 417-425.
O'Keefe, J., & Nadel, L. (1978). The Hippocampus as a cognitive Map. Oxford University Press.
Oztekin, I., Davachi, L., & McElree, B. (2010). Are representations in working memory distinct from representations in long-term memory? Neural evidence in support of a single source. Psychological Science, 21, 1123-1133.
Pavlides, C., Watanabe, Y., Magarinos, A., & McEwen, B. (1995). Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation. Neuroscience, 68, 387-394.
Pennanen, C., Kivipelto, M., Tuomainen, S., Hartikainen, P., H?nninen, T., Laakso, M. P., et al. (2004). Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiology of Aging, 25, 303-310.
Quamme, J. R., Yonelinas, A. P., & Norman, K. A. (2007). Effect of unitization on associative recognition in amnesia. Hippocampus, 17, 192-200.
Resende, R., Pereira, C., Agostinho, P., Vieira, A. P., Malva, J. O., & Oliveira, C. R. (2007). Susceptibility of hippocampal neurons to A? peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Research, 1143, 11-21.
Roder, S., Danober, L., Pozza, M. F., Lingenhoehl, K., Wiederhold, K.-H., & Olpe, H.-R. (2003). Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience, 120, 705-720.
Rosso, I. M., Cintron, C. M., Steingard, R. J., Renshaw, P. F., Young, A. D., & Yurgelun- Tood, D. A. (2005). Amygdala and hippocampus volumes in pediatric major depression. Biological Psychiatry, 57, 21- 26.
Sapolsky, R. M. (2002). Stress, the aging brain, and the mechanism of neuron death. Cambridge, MA: MIT press.
Sapolsky, R. M., Uno, H., Rebert, C., & Finch, C. (1990). Hippocampal damage associated with prolonged glucocorticoid exposure in primates. Journal of Neuroscience, 10, 2897-2902.
Sauro, M. D., Jorgensen, R. S., & Pedlow, C. T. (2003). Stress, glucocorticoids, and memory: A meta-analytic Review. Stress: The International Journal on the Biology of Stress, 6, 235-245.
Scoville, W. B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery, and Psychiatry, 20, 11-21.
Sheline, Y. (2000). 3D MRI studies of neuroanatomic changes in unipolar major depression: The role of stress and medical comorbidity. Society of Biological Psychiatry, 48, 791- 800.
Sheline, Y. (2003). Neuroimaging studies of mood disorder effects on the brain. Society of Biological Psychiatry, 54, 338- 352.
Sheline, Y., Gado, M. H., & Kraemer, H. C. (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry, 160, 1516- 1518.
Sheline, Y., Mittler, B. L., & Mintun, M. A. (2002). The hippocampus and depression. European Psychiatry, 17(Suppl 3), 300- 305.
Sheline, Y., Sanghavi, M., Mintun, M. A., & Gado, M. H. (1999). Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. The Journal of Neuroscience, 19(12), 5034- 5043.
Sheline, Y., Wang, P. W., Gado, M. H., Csernansky, J. G., & Vannier, M. W. (1996). Hippocampal atrophy in recurrent major depression. Proceedings of the National Academy of Sciences, 93, 3908- 3913.
Soares, J. C., & Mann, J. J. (1997). The anatomy of mood disorders- Review of strucutural neuroimaging studies. Biological Psychiatry, 41, 86- 106.
Squire, L. R. (1992). Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychological. Review, 99, 195-231.
Strakowski, S. M., Alder, C. M., & DelBello, M. P. (2002). Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disorders, 4, 80- 88.
Teipel, S. J., Pruessner, J. C., Faltraco, F., Born, C., Rocha-Unold, M., Evans, A., et al. (2006). Comprehensive dissection of the medial temporal lobe in AD: Measurement of hippocampus, amygdala, entorhinal, perirhinal and parahippocampal cortices using MRI. Journal of Neurology, 253, 794-800.
Wagner, T., Axmacher, N., Lehnertz, K., Elger, C. E., & Fell, J. (2010). Sleep-dependent directional coupling between human neocortex and hippocampus. Cortex, 46, 256-263.
Wolf, O. T., Witt, J., & Hellhammer, D. H. (2004). Autobiographic memory impairment following acute cortisol administration. Psychoneuroendocrinology, 29, 1093-1096.
Xu, Y., Jack, C. R., Jr., O'Brien, P. C., Kokmen, E., Smith, G. E., Ivnik, R. J., et al. (2000). Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD. Neurology, 54, 1760-1767.
Last Update: 6/16/2016