Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures?

One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus). One literature treats the hippocampus as a purely cognitive structure involved in memory; another treats it as a regulator of emotion whose dysfunction leads to psychopathology. We review behavioral, anatomical, and gene expression studies that together support a functional segmentation into three hippocampal compartments: dorsal, intermediate, and ventral. The dorsal hippocampus, which corresponds to the posterior hippocampus in primates, performs primarily cognitive functions. The ventral (anterior in primates) relates to stress, emotion, and affect. Strikingly, gene expression in the dorsal hippocampus correlates with cortical regions involved in information processing, while genes expressed in the ventral hippocampus correlate with regions involved in emotion and stress (amygdala and hypothalamus). Despite over 50 years of research, attention, and debate, there is still controversy over the basic general function of the hippocampus. There is the cold cognitive hippocampus that stands as the gate to declarative memories, regardless of their emotional content or lack thereof. According to this view, hippocampal dysfunction leads to a "pure" amnesia. But the literature also shows another side to the hippocampus, a hot hippocampus that is intimately tied to emotion, regulates stress responses and whose dysfunction leads to affective disorders such as depression. The thesis of this brief review is that there is sufficient behavioral evidence indicating the existence of both functions within the hippocampus. However, gene expression and anatomical projections patterns that vary along the rostral/caudal-dorsal/ventral extent of the hippocampus suggest that it can be divided into separate structures or zones. We argue that the hippocampus can be thought of as a set of separate structures with a rostral/dorsal zone that serves the cold cognitive function and a caudal/ventral zone that corresponds to the hot/affective hippocampus. An intermediate region that has only partly overlapping characteristics with its neighbors separates the two. We review recently published data on CA1 (Dong et al., 2009Dong H.W. Swanson L.W. Chen L. Fanselow M.S. Toga A.W. Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1.Proc. Natl. Acad. Sci. USA. 2009; 106: 11794-11799Crossref PubMed Scopus (56) Google Scholar) and CA3 (Thompson et al., 2008Thompson C.L. Pathak S.D. Jeromin A. Ng L.L. MacPherson C.R. Mortrud M.T. Cusick A. Riley Z.L. Sunkin S.M. Bernard A. et al.Genomic anatomy of the hippocampus.Neuron. 2008; 26: 1010-1021Abstract Full Text Full Text PDF Scopus (84) Google Scholar) and add a similar analysis of dentate gyrus. This approach allows us to provide a precise definition of these zones as an alternative to the more arbitrary reference to dorsal and ventral hippocampus that is common in the literature. Furthermore, this definition corresponds well with the available behavioral evidence. The coherence among gene expression, behavioral function, and anatomical projections indicates that segmentation of the hippocampus along its rostral/caudal axis can guide future research toward a resolution of controversies surrounding the general function of the hippocampus. Since the groundbreaking case of H.M., who lost much of his memory when his medial temporal lobe was extirpated for the treatment of his intractable epilepsy, a vast amount of data has linked the hippocampus to memory in humans, other primates, rats, and mice (Scoville and Milner, 1957Scoville W.B. Milner B. Loss of recent memory after bilateral hippocampal lesions.J. Neurol. Neurosurg. Psychiatry. 1957; 20: 11-21Crossref PubMed Google Scholar, Squire, 1992Squire L.R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans.Psychol. Rev. 1992; 99: 195-231Crossref PubMed Google Scholar). While the volumes of data on this subject are beyond the scope of any single review, it is important to point out that many of the specifics of amnesia following hippocampal loss in humans, such as temporally graded retrograde amnesia, are recapitulated in rodents, making these experimentally and genetically tractable species appropriate models (Kim and Fanselow, 1992Kim J.J. Fanselow M.S. Modality-specific retrograde amnesia of fear.Science. 1992; 256: 675-677Crossref PubMed Google Scholar, Squire et al., 2001Squire L.R. Clark R.E. Knowlton B.J. Retrograde amnesia.Hippocampus. 2001; 11: 50-55Crossref PubMed Scopus (96) Google Scholar). Additionally, the hippocampus is involved in some but not all types of memory. Certainly there is debate over how best to conceptualize the distinction over what makes memory hippocampus dependent versus independent. However, there can be no argument that following removal of the hippocampus several forms of memory suffer (e.g., episodic memory, spatial learning, or contextual fear). Most behavioral tests using rodents require some level of positive or negative emotion to motivate the animal to respond (e.g., hunger/food). For example, a common test to assess hippocampal function in rodents, contextual fear conditioning uses aversive electric shock. In the standard version of this task, rats or mice are placed in a chamber where they receive a mild electric shock signaled by a brief tone (Kim and Fanselow, 1992Kim J.J. Fanselow M.S. Modality-specific retrograde amnesia of fear.Science. 1992; 256: 675-677Crossref PubMed Google Scholar). When returned to the same chamber where it was shocked the rat freezes, but there is no freezing when the animal is placed in a sufficiently different chamber. This shows that the animal has associated the shock with the training context. The rat will also freeze if the tone is presented, and this tone test is typically done in an untrained chamber, so a measure of the tone-shock association, in the absence of context fear, can be gained. Genetic, pharmacological, and lesion manipulations of the hippocampus all produce a deficit in context but not tone fear. This selectivity to context suggests that the context fear deficit is caused by a failure in context processing and not by a general emotional deficit. Contextual fear learning requires a period of exploration during which it is hypothesized that the many features of the context are integrated into a coherent representation of the context (Fanselow, 2000Fanselow M.S. Contextual fear, gestalt memories, and the hippocampus.Behav. Brain Res. 2000; 110: 73-81Crossref PubMed Scopus (365) Google Scholar). If rats and mice are given insufficient time to explore the context prior to shock, they show little or no context conditioning (Fanselow, 1986Fanselow M.S. Associative vs. topographical accounts of the immediate shock freezing deficit in rats: Implications for the response selection rules governing species specific defensive reactions.Learn. Motiv. 1986; 17: 16-39Crossref Google Scholar). Formation of the contextual representation can be temporally segregated from learning the context-shock association by giving context pre-exposure (without shock) on one day and giving shock shortly after placement in the chamber on another day (Fanselow, 1990Fanselow M.S. Factors governing one trial contextual conditioning.An. Learn. Behav. 1990; 18: 264-270Crossref Google Scholar). Without the pre-exposure, rats will not learn context fear despite having the context-shock pairing. Using this context pre-exposure effect it has been found that NMDA antagonists and protein synthesis inhibitors directed at the hippocampus block contextual fear memories if given prior to the context pre-exposure but not when given prior to the context-shock pairing (Barrientos et al., 2002Barrientos R.M. O'Reilly R.C. Rudy J.W. Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration.Behav. Brain Res. 2002; 134: 299-306Crossref PubMed Scopus (64) Google Scholar, Stote and Fanselow, 2004Stote D.L. Fanselow M.S. NMDA receptor modulation of incidental learning in Pavlovian context conditioning.Behav. Neurosci. 2004; 118: 253-257Crossref PubMed Scopus (27) Google Scholar). Thus NMDA-mediated plasticity in the hippocampus is important for the more cognitive contextual integration and not the emotion-based context-shock association. This corresponds well with the finding that place fields form in the hippocampus during exploration of an environment even in the absence of any explicit motivation (O'Keefe and Dostrovsky, 1971O'Keefe J. Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat.Brain Res. 1971; 34: 171-175Crossref PubMed Google Scholar). Thus, there is good evidence to believe that the hippocampus supports memory and cognitive functions that do not have an emotional/motivational component. Historically, the longstanding link between the hippocampus and emotion owes itself to this region's prominent position in Papez's limbic circuit and its hypothesized role in controlling emotion. Early, support for this view was taken from Klüver and Bucy's classic finding that removal of the medial temporal lobe caused profound emotional disturbances in monkeys (Klüver and Bucy, 1937Klüver H. Bucy P.C. "Psychic blindness" and other symptoms following bilateral temporal lobectomy in Rhesus monkeys.Am. J. Physiol. 1937; 119: 352-353Google Scholar). Building upon such observations as well as Sokolov and Vinograda's findings of hippocampal orienting responses to novelty and change, Gray suggested that the hippocampus is involved in "states of emotion, especially disappointment and frustration" (Gray and Jeffrey, 1971Gray J. Jeffrey A. The Psychology of Fear and Stress. World University Library. McGraw-Hill, New York1971Google Scholar, p. 201; Gray and McNaughton, 2000Gray J. McNaughton N. The Neuropsychology of Anxiety: an Enquiry into the Functions of the Septo-hippocampal System.Second Edition. Oxford University Press, Oxford2000Google Scholar, Sokolov and Vinograda, 1975Sokolov E.N. Vinograda O.S. Neuronal Mechanisms of the Orienting Reflex. Erlbaum, Mahwah, NJ1975Google Scholar). The hippocampus exerts strong regulatory control of the hypothalamic-pituitary-adrenal axis. Hippocampal lesions impair control of the hormonal stress response (Dedovic et al., 2009Dedovic K. Duchesne A. Andrews J. Engert V. Pruessner J.C. The brain and the stress axis: the neural correlates of cortisol regulation in response to stress.Neuroimage. 2009; 47: 864-871Crossref PubMed Scopus (89) Google Scholar, Jacobson and Sapolsky, 1991Jacobson L. Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis.Endocr. Rev. 1991; 12: 118-134Crossref PubMed Google Scholar). In turn, it is clear that elevations of stress hormones lead to hippocampal dysfunction in both humans and rodents (McEwen et al., 1997McEwen B.S. Conrad C.D. Kuroda Y. Frankfurt M. Magarinos A.M. McKittrick C. Prevention of stress-induced morphological and cognitive consequences.Eur. Neuropsychopharmacol. 1997; 7: S323-S328Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, Herman et al., 2005Herman J.P. Ostrander M.M. Mueller N.K. Figueiredo H. Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005; 29: 1201-1213Crossref PubMed Scopus (454) Google Scholar). In humans, decreased hippocampal volumes and hippocampal dysfunction are associated with psychological disorders with strong affective components such as posttraumatic stress disorder, bipolar disorder, and depression (Bonne et al., 2008Bonne O. Vythilingam M. Inagaki M. Wood S. Neumeister A. Nugent A.C. Snow J. Luckenbaugh D.A. Bain E.E. Drevets W.C. Charney D.S. Reduced posterior hippocampal volume in posttraumatic stress disorder.J. Clin. Psychiatry. 2008; 69: 1087-1091Crossref PubMed Google Scholar, Frey et al., 2007Frey B.N. Andreazza A.C. Nery F.G. Martins M.R. Quevedo J. Soares J.C. Kapczinski F. The role of hippocampus in the pathophysiology of bipolar disorder.Behav. Pharmacol. 2007; 18: 419-430Crossref PubMed Scopus (61) Google Scholar). Indeed, effective pharmacological treatments of these disorders target hippocampal function and physiology. Thus, the linkage of the hippocampus with emotion and affect is as striking as its relationship with memory. In an influential review, Moser and Moser, 1998Moser M.B. Moser E.I. Functional differentiation in the hippocampus.Hippocampus. 1998; 8: 608-619Crossref PubMed Scopus (507) Google Scholar suggested that the hippocampus may not act as a unitary structure with the dorsal (septal pole) and ventral (temporal pole) portions taking on different roles. Their argument was based on three data sets. First, prior anatomical studies indicated that the input and output connections of the dorsal hippocampus (DH) and ventral hippocampus (VH) are distinct (Swanson and Cowan, 1977Swanson L.W. Cowan W.M. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat.J. Comp. Neurol. 1977; 172: 49-84Crossref PubMed Google Scholar). Second, spatial memory appears to depend on DH not VH (Moser et al., 1995Moser M.B. Moser E.I. Forrest E. Andersen P. Morris R.G. Spatial learning with a minislab in the dorsal hippocampus.Proc. Natl. Acad. Sci. USA. 1995; 92: 9697-9701Crossref PubMed Scopus (376) Google Scholar). Third, VH, but not DH, lesions alter stress responses and emotional behavior (Henke, 1990Henke P.G. Hippocampal pathway to the amygdala and stress ulcer development.Brain Res. Bull. 1990; 25: 691-695Crossref PubMed Scopus (27) Google Scholar). Behavioral tests of spatial navigation and memory have been particularly illuminating with regard to hippocampal function. An informative task for assessing spatial cognition in rodents is the Morris water maze, where animals must swim to a hidden location using landmarks placed outside the pool (Morris, 1981Morris R.G.M. Spatial localization does not require the presence of local cues.Learn. Motiv. 1981; 12: 239-260Crossref Google Scholar). This task clearly implicates the DH in spatial memory. Lesions restricted to as little as 25% of the DH impair acquisition on the water maze and additional damage to the ventral region does not exacerbate the deficit (Moser et al., 1995Moser M.B. Moser E.I. Forrest E. Andersen P. Morris R.G. Spatial learning with a minislab in the dorsal hippocampus.Proc. Natl. Acad. Sci. USA. 1995; 92: 9697-9701Crossref PubMed Scopus (376) Google Scholar). Lesions restricted to the VH have no effect on this behavior. Consistent with the lesion data, there is a greater density of place fields in the DH as opposed to VH (Jung et al., 1994Jung M.W. Wiener S.I. McNaughton B.L. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat.J. Neurosci. 1994; 14: 7347-7356PubMed Google Scholar). Rats that learn the water maze show significant changes in expression of a large number of genes in the DH that is disproportionately greater (≈8-to1) in the right than left DH (Klur et al., 2009Klur S. Muller C. Pereira de Vasconcelos A. Ballard T. Lopez J. Galani R. Certa U. Cassel J.C. Hippocampal-dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation.Hippocampus. 2009; 19: 800-816Crossref PubMed Scopus (32) Google Scholar). Again consistent is the finding that inactivation of the right but not left DH abolishes retrieval of this spatial memory (Klur et al., 2009Klur S. Muller C. Pereira de Vasconcelos A. Ballard T. Lopez J. Galani R. Certa U. Cassel J.C. Hippocampal-dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation.Hippocampus. 2009; 19: 800-816Crossref PubMed Scopus (32) Google Scholar). Similarly, when taxi drivers recall complex routes through a city the right but not left posterior hippocampus is differentially activated compared to the anterior hippocampus (Maguire et al., 1997Maguire E.A. Frackowiak R.S.J. Frith C.D. Recalling routes around London: activation of the right hippocampus in taxi drivers.J. Neurosci. 1997; 17: 7193-7210Google Scholar). In primates, the posterior portions of the hippocampus correspond to the rodent DH, while the anterior portions are analogous to the VH. Recall of verbal material also preferentially activates the human posterior over anterior hippocampus but now the left shows greater activation than the right (Greicius et al., 2003Greicius M.D. Krasnow B. Boyett-Anderson J.M. Eliez S. Schatzberg A.F. Reiss A.L. Menon V. Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study.Hippocampus. 2003; 13: 164-174Crossref PubMed Scopus (119) Google Scholar). Another fMRI study by Kumaran et al., 2009Kumaran D. Summerfield J.J. Hassabis D. Maguire E.A. Tracking the emergence of conceptual knowledge during human decision making.Neuron. 2009; 63: 889-901Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar is particularly informative in this regard. They found that activity of the left posterior hippocampus tracks the emergence of new conceptual information. Conceptual information is typically thought of as the acquisition of rules that can guide behavior in novel situations. But it is also easy to see how such relational rules could guide the navigational behavior needed to find a safe platform when starting in a novel location. Like the water maze, the radial arm maze tests spatial memory by requiring rodents to return to locations not previously visited to find food (Olton and Samuelson, 1976Olton D.S. Samuelson R.J. Remembrance of places passed: Spatial memory in rats.J. Exp. Psychol. Anim. Behav. Process. 1976; 2: 97-116Crossref Scopus (644) Google Scholar). Using the radial arm maze, Pothuizen et al., 2004Pothuizen H.H. Zhang W.N. Jongen-Rêlo A.L. Feldon J. Yee B.K. Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory.Eur. J. Neurosci. 2004; 19: 705-712Crossref PubMed Scopus (97) Google Scholar, found that while DH lesions caused a deficit in spatial memory, VH lesions did not. Returning to an arm previously associated with food is reduced by DH lesions and enhanced by VH lesions (Ferbinteanu and McDonald, 2001Ferbinteanu J. McDonald R.J. Dorsal/ventral hippocampus, fornix, and conditioned place preference.Hippocampus. 2001; 11: 187-200Crossref PubMed Scopus (99) Google Scholar). That the same procedure shows opposite effects for DH and VH lesions provides strong support for the idea that dorsal and ventral zones support different functions. One can interpret these data as being consistent with the dorsal/spatial memory and ventral/emotion distinction. If DH lesions cause a loss of spatial information then the rats would be unable to return to the place associated with food. Rats with VH lesions necessarily had spatial information as they returned to the food-associated location. Rather, the enhancement in preference suggests an altered memory for the affective aspects of food. In a study that clearly manipulated stress over cognition, Henke, 1990Henke P.G. Hippocampal pathway to the amygdala and stress ulcer development.Brain Res. Bull. 1990; 25: 691-695Crossref PubMed Scopus (27) Google Scholar reported that VH but not DH lesions enhanced cold/restraint stress ulcers. Furthermore, Kjelstrup et al., 2002Kjelstrup K.G. Tuvnes F.A. Steffenach H.A. Murison R. Moser E.I. Moser M.B. Reduced fear expression after lesions of the ventral hippocampus.Proc. Natl. Acad. Sci. USA. 2002; 99: 10825-10830Crossref PubMed Scopus (279) Google Scholar reported that lesions of the most ventral quarter of the hippocampus increased entry into the open (unprotected) arms of an elevated plus maze and decreased defecation in a brightly lit chamber, both of which are consistent with a reduction in anxiety. The VH lesioned animals also showed less of an increase in corticosterone in response to confinement in the brightly lit chamber. Fear conditioning tasks offer a test of spatial (context fear) and nonspatial (cued fear) memory where performance is motivated by emotion. For the DH, the data are clear that dorsal lesions cause an impairment in retention of contextual as opposed to cued fear (Kim and Fanselow, 1992Kim J.J. Fanselow M.S. Modality-specific retrograde amnesia of fear.Science. 1992; 256: 675-677Crossref PubMed Google Scholar), and this contextual deficit may be more related to dorsal CA1 than CA3 (Hunsaker and Kesner, 2008Hunsaker M.R. Kesner R.P. Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear.Neurobiol. Learn. Mem. 2008; 89: 61-69Crossref PubMed Scopus (48) Google Scholar, Hunsaker et al., 2008Hunsaker M.R. Fieldsted P.M. Rosenberg J.S. Kesner R.P. Dissociating the roles of dorsal and ventral CA1 for the temporal processing of spatial locations, visual objects, and odors.Behav. Neurosci. 2008; 122: 643-650Crossref PubMed Scopus (41) Google Scholar). As pointed out earlier, the contextual pre-exposure effect described above offers a way of separating the contextual and emotional learning components of contextual fear conditioning, and pharmacological manipulations aimed at DH are highly effective during the pre-exposure period. While the effects of VH manipulations on fear conditioning tasks are a bit less straightforward, they suggest if anything the deficits are more pronounced and more general. As in DH (Quinn et al., 2005Quinn J.J. Loya F. Ma Q.D. Fanselow M.S. Dorsal hippocampus NMDA receptors differentially mediate trace and contextual fear conditioning.Hippocampus. 2005; 15: 665-674Crossref PubMed Scopus (68) Google Scholar) NMDA antagonists infused into the VH block the acquisition of context fear but not fear to a tone that accurately signals shock (Zhang et al., 2001Zhang W.N. Bast T. Feldon J. The ventral hippocampus and fear conditioning in rats: different anterograde amnesias of fear after infusion of N-methyl-D-aspartate or its noncompetitive antagonist MK-801 into the ventral hippocampus.Behav. Brain Res. 2001; 126: 159-174Crossref PubMed Scopus (66) Google Scholar). However, VH lesions or infusions of muscimol (which temporarily inactivates neurons) block tone fear and produce less consistent effects on context fear (Hunsaker and Kesner, 2008Hunsaker M.R. Kesner R.P. Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear.Neurobiol. Learn. Mem. 2008; 89: 61-69Crossref PubMed Scopus (48) Google Scholar, Maren and Holt, 2004Maren S. Holt W.G. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.Behav. Neurosci. 2004; 118: 97-110Crossref PubMed Scopus (93) Google Scholar, Rogers and Kesner, 2006Rogers J.L. Kesner R.P. Lesions of the dorsal hippocampus or parietal cortex differentially affect spatial information processing.Behav. Neurosci. 2006; 120: 852-860Crossref PubMed Scopus (30) Google Scholar). The greater, or at least more consistent, effects of VH lesions on tone than context fear cannot be attributed to sensory modality. Contexts usually contain an olfactory component and Hunsaker et al., 2008Hunsaker M.R. Fieldsted P.M. Rosenberg J.S. Kesner R.P. Dissociating the roles of dorsal and ventral CA1 for the temporal processing of spatial locations, visual objects, and odors.Behav. Neurosci. 2008; 122: 643-650Crossref PubMed Scopus (41) Google Scholar using a temporal-order discrimination task found that VH lesions had more pronounced effects when olfactory cues as opposed to visual or spatial cues were used. The opposite was true for DH lesions. This role of the VH in Pavlovian fear is consistent with the suggestions of the Moser group, that the hippocampus regulates emotion, and Anagnostaras et al., 2002Anagnostaras S.G. Gale G.D. Fanselow M.S. The hippocampus and Pavlovian fear conditioning: reply to Bast et al.Hippocampus. 2002; 12: 561-565Crossref PubMed Scopus (15) Google Scholar, that VH manipulations alter fear conditioning by depriving the amygdala of both dorsal and ventral hippocampal information. The amygdala has a very general role in mediating fear memory and only receives direct hippocampal input via the VH (Maren and Fanselow, 1995Maren S. Fanselow M.S. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo.J. Neurosci. 1995; 15: 7548-7564PubMed Google Scholar). However, the idea that the VH plays no role in spatial memory is not ubiquitous. Ferbinteanu et al., 2003Ferbinteanu J. Ray C. McDonald R.J. Both dorsal and ventral hippocampus contribute to spatial learning in Long-Evans rats.Neurosci. Lett. 2003; 345: 131-135Crossref PubMed Scopus (56) Google Scholar using a "match-to-position" version of the water maze found a perfect parallel in the deficits in spatial memory produced by just DH or just VH lesions, both slowed acquisition and the deficit was overcome by repeated training. Additionally, Rudy and Matus-Amat, 2005Rudy J.W. Matus-Amat P. The ventral hippocampus supports a memory representation of context and contextual fear conditioning: implications for a unitary function of the hippocampus.Behav. Neurosci. 2005; 119: 154-163Crossref PubMed Scopus (59) Google Scholar challenged the idea that the VH has no role in context processing using the context pre-exposure design to isolate context learning from emotional learning. They found that inactivating the VH before and blocking protein synthesis immediately after context pre-exposure attenuated the benefits of pre-exposure. Since no shock is given during the pre-exposure, these VH effects seem unlikely to be through affective processing. To further support this argument, infusion of the protein synthesis inhibitor immediately after context-shock pairing had no effect on subsequent fear memory even though this is the period during which an affective memory should be consolidated. There are substantial data supporting the Moser theory that the dorsal or septal pole of the hippocampus, which corresponds to the human posterior hippocampus, is specifically involved in memory function and the ventral or temporal pole of the hippocampus, which corresponds to the anterior hippocampus in humans, modulates emotional and affective processes. Consistent with Gray and Jeffrey's original idea that the hippocampus is involved in negative affect such as frustration and anxiety (Gray and Jeffrey, 1971Gray J. Jeffrey A. The Psychology of Fear and Stress. World University Library. McGraw-Hill, New York1971Google Scholar), VH manipulations tend to decrease fear and anxiety (Kjelstrup et al., 2002Kjelstrup K.G. Tuvnes F.A. Steffenach H.A. Murison R. Moser E.I. Moser M.B. Reduced fear expression after lesions of the ventral hippocampus.Proc. Natl. Acad. Sci. USA. 2002; 99: 10825-10830Crossref PubMed Scopus (279) Google Scholar, Maren and Holt, 2004Maren S. Holt W.G. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus.Behav. Neurosci. 2004; 118: 97-110Crossref PubMed Scopus (93) Google Scholar) and increase motivation for food (Ferbinteanu and McDonald, 2001Ferbinteanu J. McDonald R.J. Dorsal/ventral hippocampus, fornix, and conditioned place preference.Hippocampus. 2001; 11: 187-200Crossref PubMed Scopus (99) Google Scholar). However, there are several pieces of data that do not fit easily into this distinction. One potential explanation of the discrepancies is that the field has not adopted a single definition of what exactly is the DH versus VH that is based on a set of independent and objective criteria. Bannerman et al., 1999Bannerman D.M. Yee B.K. Good M.A. Heupel M.J. Iversen S.D. Rawlins J.N. Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions.Behav. Neurosci. 1999; 113: 1170-1188Crossref PubMed Google Scholar suggested that DH be defined as 50% of the total hippocampus starting at the septal pole, with VH as the remaining half. This is an arbitrary definition as it relies on no independent objective attributes. Studies from the Moser group are clearest in separating function when lesions are restricted to 25% of hippocampal volume starting at either the septal pole (spatial tasks, Moser et al., 1995Moser M.B. Moser E.I. Forrest E. Andersen P. Morris R.G. Spatial learning with a minislab in the dorsal hippocampus.Proc. Natl. Acad. Sci. USA. 1995; 92: 9697-9701Crossref PubMed Scopus (376) Google Scholar) or temporal pole (emotion, Kjelstrup et al., 2002Kjelstrup K.G. Tuvnes F.A. Steffenach H.A. Murison R. Moser E.I. Moser M.B. Reduced fear expression after lesions of the ventral hippocampus.Proc. Natl. Acad. Sci. USA. 2002; 99: 10825-10830Crossref PubMed Scopus (279) Google Scholar). Studies that implicated the VH in spatial learning have had drug infusion sites or lesioned regions that extended dorsally to at least the intermediate hippocampus. Therefore, the next section of this paper uses newly available gene expression data to try to help define DH and VH.