The Hippocampus and the Sense of Smell. A Review, by Alf Brodal

Alastair Compston


Brain. 2010;133(9):2509-2513. 

Abstract and Introduction


Writing in 1587, Giulio Cesare Aranzi (1530–1589) describes a structure 'continuous with the vaulted body or tortoise (fornix) which has an uneven or bent form that resembles the appearance of a hippocampus, that is a sea-horse' (De humano foetu liber tertio editus, ac recognitus. Euisdem anatomicarum observationum liber, Chapter 3, pp. 45). Paul Broca (1824–1880) and Ludwig Edinger (1855–1918) traced direct connections of the olfactory tract into the hippocampus. But in Trabajos del Laboratorio de Investigaciones Biologicas del la Universidad de Madrid (Tomo 1: 1901–02; 1–227. Translated as Studies on the Cerebral Cortex by Lisbeth M Kraft, London 1955), Santiago Ramón y Cajal (1852–1934) writes: ' … the acceptance of the existence of direct communicating pathways between the primary and secondary olfactory centres … and Ammon's horn, the fascia dendata, septum lucidum, cingulated gyrus [and] suprasellar striae … finds its way into the field of anatomical investigation with the greatest of difficulties'. On the olfactory brain, Cajal and Camillo Golgi (1843–1926) were of one voice in declaring that there are no direct connections between the olfactory tract and the hippocampus.

Forty-five years later, during the tenure of his Rockefeller Fellowship in the Department of Human Anatomy in Oxford (UK), while on leave from the Anatomical Department of the University of Oslo (Norway), Dr Brodal aims to challenge one of the several 'conceptions [that] survive almost like proverbs and become proclaimed as long-established truths … show[ing] a remarkable tendency to outlast the tenability of the original observations on which they were based'. Specifically, why do neurologists support the 'credundum' that the hippocampus is an important olfactory centre? Comparative anatomists know that phylogenetically the hippocampus develops in association with the olfactory system and a strong sense of smell. (Sir David) Ferrier (1843–1928) has shown that electrical stimulation of the simian hippocampus results in sniffing movements of the lip and nostril. (John) Hughlings Jackson (1835–1911) and (Charles) Beevor (1854–1908) have reported olfactory sensations in cases of epilepsy associated with lesions of the uncinate gyrus (Brain 1890: 12; 346–357; and see Brain 2007; 130: 1712–1714). But 'no case with a lesion restricted to the hippocampus has yet been shown to be accompanied by uncinate fits … by some diffuseness of thought the alleged olfactory functions of the uncus have been attributed to the hippocampus as well'. Alf Brodal considers that the only secure means of establishing the olfactory role of the hippocampus is to trace fibre connections of the olfactory bulb, ideally in association with physiological studies.

Many fibres from the olfactory epithelium terminate in the anterior olfactory nucleus, which lies posterior within the olfactory bulb, and pass from there (with others that do not relay in the anterior olfactory nucleus) to the piriform lobe cortex (Fig. 1). Allegedly, connections exist between the two olfactory bulbs and both anterior olfactory nuclei through the anterior commissure. In making this claim, Cajal had almost certainly failed to avoid concomitant injury of each olfactory bulb. However, close analysis suggests that commissural fibres do connect the two anterior olfactory nuclei. Fibres reaching the nucleus of the lateral olfactory tract project to the amygdala, especially its medial and central nuclei. Others terminate in the olfactory tubercle (corresponding in man to the anterior perforated space and the diagonal band of Broca). From here, a few also reach the septal nuclei. Overall, the evidence from human anatomy is sparse and more is known from comparative anatomy of the bat, cat, rat, rabbit, mink, opossum and alligator. The most comprehensive anatomical analysis, using the silver impregnation method to trace myelinated and unmyelinated nerve fibres, has been carried out by Dr Brodal's host as head of department in Oxford, Dr Lee's Professor of Anatomy, (Sir) Wilfrid Le Gros Clark (1895–1971) who has confirmed connections between the olfactory bulb and the amygdala, piriform lobe, olfactory tubercle and stria terminalis.

Figure 1.

A diagram of the distribution of afferent olfactory fibres from the olfactory bulb and anterior olfactory nucleus. Connections that appear to be definitely established drawn with full lines; certain other connections that appear equivocal are indicated by stippled lines.

Do the connections of the hippocampus support an anatomical basis for its role in olfaction? Comparative anatomists 'express themselves very cautiously concerning this point' and go no further than the possibility of olfactory connections with the most anterior continuation of the hippocampus. Dr Brodal reads the existing literature as providing 'quantitatively negligible support for the existence of olfacto-hippocampal connections'. But that is not to say that the hippocampus receives no indirect olfactory fibre input, especially since, as Cajal has established, most parts of the hippocampus receive fibres from the lateral entorhinal area, arrangements that are enriched by additional intra-hippocampal connections. Since the entorhinal region and the piriform lobe are not identical structures [the entorhinal area being posterior and constituting (Korbinian) Brodmann (1868–1918) area 28; and sometimes including the perirhinal structure, Brodmann area 35], and the olfactory projection is to the latter, whereas the hippocampal input comes from the former, a question still remains relating to olfactory functions of the hippocampus based on anatomical considerations (Fig. 2). (ED) Adrian (1889–1977) has observed electrical potentials in the piriform cortex of the hedgehog after stimulation with odours in the nasal cavity. Others have made similar recordings from the olfactory bulb, olfactory tubercle and septal nuclei. Electrical responses are not recorded from the entorhinal area following olfactory stimulation—the size of the potential reducing as more posterior parts of the piriform lobe, approaching the entorhinal area, are studied. Thus far, the amydgala has also remained electrically silent. 'It may be briefly stated, that, excepting some small and indefinite fibre bundles described by some authors, conclusive evidence appears to be lacking of contributions to the hippocampus proper from the amygdaloid nuclei, the nucleus of the olfactory tract and the tuberculum olfactorium'. Any olfactory fibre input to the hippocampus is indirect (Fig. 3).

Figure 2.

A diagram of the arrangement of the fibres from the entorhinal area to the hippocampus and dentate gyri after Lorente de Nó. The entorhinal area is subdivided into three parts (A, B and C). The four regions of the hippocampus are labelled CA1–4, respectively. The commissural fibres entering in the fimbria have been included.

Figure 3.

A diagram of the afferent fibres to the hippocampus. Only connections that appear to be definitely established are shown. The afferent fibres to the anterior continuation of the hippocampus are stippled, since they appear to be sparse. The commissural fibres are omitted. The differential distribution of the hippocampal afferents is shown as stated by Lorente de Nó.

The main efferent connections of the hippocampus are to the fornix and from there to the medial nucleus of the mamillary body, and the anterior nucleus of the thalamus, septal nuclei, pre-optic region, medial habenula and anterior hypothalamus (Fig. 4). The presence of commissural fibres indicates that each hippocampus is able to influence the septal, pre-optic and hypothalamic structures bilaterally, whereas the mamillary body and habenula are connected only to the ipsilateral hippocampus. Fibres in the anterior thalamic nuclei project diffusely to the cortex, especially that of the cingular gyrus. The eventual distribution of the remaining efferent hippocampal fibres is much less clear but there are projections to the neuro-hypophysis. There are efferent connections between the hippocampus and the stria medullaris and, from there, to the habenula, the interpeduncular nucleus and the dorsal tegmental nucleus. The mamillary body also has efferent connections through the mamillo-tegmental tract, supplemented by direct outputs from the amygdala to these same brain stem structures via the medial forebrain bundle. 'The stria medullaris thus appears to be, predominantly at least, a link in a descending pathway, capable of transmitting olfactory impulses, or olfactory impulses integrated with others, in a caudal direction to lower centres of the brain-stem', and from there to the spinal cord.

Figure 4.

A diagram of the efferent fibres to the hippocampus and of the connections from the mamillary body via the anterior nucleus of the thalamus to the cingular gyrus, the areas of which are indicated by numbers referring to Brodmann's map. ML = lateral mamillary nucleus. MLL and MMM = lateral and medial part of the medial mamillary nucleus, respectively.

Fibre connections are far more decisive as evidence than cytoarchitecture. Nonetheless, the morphology of its pyramidal cells suggests that the function of the hippocampus is mainly efferent: 'from a morphological point of view there is no reason to assume that the hippocampus is to any considerable extent concerned in receptory or associative functions, be these olfactory or of other kinds … [and] direct olfactory impulses are probably not transmitted to the hippocampus … the primary olfactory cortex is to be found in the prepiriform and peri-amygdaloid areas' (in man the gyrus semilunaris and anterior gyrus ambiens). The entorhinal area is concerned with the association and integration of olfactory impulses 'and possibly with the finer analysis and interpretation of olfaction'. From the perspective of comparative anatomy, the olfactory dominance of cortical representation that supports foraging and reproduction (interoceptive olfaction) and awareness of danger (exteroceptive olfaction) in reptiles is displaced with development of the increasingly large mammalian neocortex that receives afferents from sensory modalities—especially vision and discriminative sensation—other than smell. Olfaction loses its cortical dominance and critical role in behaviour and now plays only an activating role for these increasingly sophisticated other special senses. Whereas the size of the hippocampus and olfactory bulb correlate in the whale and dolphin, neither of which have a sophisticated sense of smell, the discrepancy between the relatively large hippocampus, fornix, mamillo-thalamic tract, anterior thalamus and cingulate cortex of 'microsmatic' man and his somewhat paltry olfactory apparatus suggests that the hippocampus must receive many significant non-olfactory inputs. Lesion-based studies do not suggest that hippocampal efferent connections to the neocortex and brainstem are involved in reflex responses of the oro-pharynx to olfactory stimulation in the decorticate cat. Conditioned reflexes of the canine leg, in response to clove oil and asafoetida, but not crude olfactory stimuli, are abolished by lesioning the piriform–amygdaloid areas but not the hippocampus or fornix.

The clinical evidence is that the sense of smell is not impaired in patients with hippocampal cell loss in association with epilepsy. Individuals with arhinencephaly usually have a normal hippocampus. Direct stimulation of the hippocampus during surgery in the awake individual does not elicit an olfactory response. Patients with uncinate seizures do indeed have lesions involving the primary olfactory cortex and entorhinal area; but the occasional lip-smacking and oro-facial movements seen in such cases does not implicate the hippocampus. As for 'dreamy states … these are … mainly cortical phenomena … [that] may occur unaccompanied by olfactory sensations. There seems to be no reason to associate them particularly with the hippocampus'. Nor is there evidence that the sense of taste is any more intimately related to the hippocampus than smell. Pathological sleep seems more closely associated with lesions of the posterior hypothalamus not the hippocampus. The symptoms of Wernicke's syndrome reveal damage to the mamillary body rather than the hippocampus. There are no olfactory correlates of anterior thalamic nucleus injury. And the cinguate gyrus seems more important for emotional and autonomic responses than olfaction.

It seems therefore that only when a more detailed account of the anatomical connections of the hippocampus—afferent and efferent—involving the entorhinal area, the fornix and the cingulate cortex are known, will the time 'perhaps have come to comprehend to a certain extent the function of the hippocampus'. In a footnote, Alf Brodal qualifies that position: 'when … mention is made of the function of any particular part of the brain, such as the hippocampus, this does not, of course, mean that the structure in question is considered as a functional unit. This mode of speaking is employed only to facilitate the presentation of the material. Indeed, it is doubtful whether we are entitled to consider any part of the central nervous system as a functional unit'. As for olfaction, 'recent … experiments have yielded no support for the conception that the hippocampus has important relations to the sense of smell in mammals, nor does clinical evidence seem to favour this view'. Not much had changed when Alf Brodal wrote his magisterial work Nevro-anatomi i relasjon til klinisk nevrologi (1943. Translated as Neurological Anatomy in Relation to Clinical Medicine, 1948); but by 1969 and 1981 (2nd and 3rd editions, respectively) not only had knowledge on the efferent outputs from the hippocampus been refined and revised but also observations from the 1950s in patients with bilateral hippocampal damage had established its importance for learning and memory. Professor Brodal (1910–1988) concludes his last account of olfaction and the hippocampus by quoting Larry Weiskrantz (Deputy Editor of Brain, 1982–1991): 'the striking aspect of the hippocampus is the anatomical elegance of its structure, revealed in detail in the past few years. In contrast there is really appalling ignorance about what this elegance means'.