The role of the subiculum within the behavioural inhibition system

Behavioural Brain Research 174 (2006) 232–250

Review

The role of the subiculum within the behavioural inhibition system Neil McNaughton ∗ Department of Psychology, Neuroscience Research Centre, University of Otago, POB 56, Dunedin, New Zealand Received 14 April 2006; accepted 23 May 2006 Available online 2 August 2006

Abstract This paper summarises the picture of the subiculum presented by Gray and McNaughton [Gray JA, McNaughton N. The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system. Oxford: Oxford University Press; 2000]. It is a key node in their “Behavioural Inhibition System” and, as such, is embedded within a hierarchy of structures controlling anxiety that is in parallel with a separate hierarchy controlling fear. It can nonetheless be viewed as operating in a fairly simple manner. It receives information about available goals from areas that plan motor action. This is filtered by earlier elements of the essentially unidirectional hippocampal circuit that essentially block familiar and unimportant information while passing to the subiculum important information. The function of the subiculum is to compare and integrate this goal information and produce output when conflict between incompatible goals is detected. This output prevents execution of the responses that would address the conflicting goals, increases the valence of affectively negative stimuli and associations and releases external exploration and internal rumination intended to resolve the conflict. These subicular outputs are held to be computationally simple but to have complex consequences both because of the complexity of the target areas and because, in many cases, processing is recursive. It can involve multiple passages of essentially the same information round loops such as the circuit of Papez—each pass refining the solution to the original problem of conflicting goals. © 2006 Elsevier B.V. All rights reserved. Keywords: Subiculum; Hippocampal; Goal; Fear; Anxiety; Conflict

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A two-dimensional view of defense systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioural inhibition or anxiety? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Detection and resolution of goal conflict . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The place of the subiculum within the SHS—a “slice” perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The place of the subiculum within the SHS—stacking the slices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The place of the subiculum within the SHS—the two-dimensional sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The place of the subiculum within the SHS—a key recursive node . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The subiculum as one of the hippocampal comparators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subiculum versus posterior cingulate cortex as primary SHS output stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The outputs of the subiculum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gating of SHS input to the subiculum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gate interactions in the control of functional output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The place of direct cortical inputs to subiculum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction This paper was written in response to a request to summarise the picture of the subiculum presented in “The Neuropsychology of Anxiety” [36], in which it is a key node of the “Behavioural Inhibition System” (BIS, see Gray [30,32]). What follows is, therefore, subject to two caveats. The first caveat is that, the picture of the subiculum is that of the book and no fundamental changes have been made to accommodate new data. The neural structures of the BIS (and their allocated functions) are presented in a simpler, two-dimensional format [50] and some links made with newer data. But the picture of the subiculum is unchanged from the book. The second caveat is that, both in the book and here, the picture of the subiculum is incomplete. It, as well as a large number of other structures, is described as part of the BIS with a fundamental role in the control of anxiety. But there is no claim that it, or the other structures of the BIS, is solely involved in anxiety. Indeed, many are also included in the structures that the theory holds control fear. Particularly in the case of the amygdala, it is clear that there are many different modules within each structure and these can be involved in many emotions. However, there is one class of function, often attributed to the septo-hippocampal system (SHS), and so by implication to the subiculum, that the theory sees as inextricably linked with the control of behavioural inhibition: memory. We argue that the behavioural inhibition generated by the hippocampal formation is just the same for innate reactions and conditioned ones. On this view the SHS becomes involved in memory tasks for essentially non-memorial reasons. This allows us to account for the poor fit between proposed types of memory and hippocampal sensitivity. It also presents hippocampal operation as an essentially non-memorial means of solving the problem of catastrophic forgetting to which associative memories are subject [57]. On this view, the SHS does not actively form particular types of memory. It suppresses (preconsciously) the competing alternatives that would otherwise interfere with correct consolidation and recall (Fig. 1). In its absence, the preconscious pandemonium prevents the correct item from entering consciousness. Memory effects, then, are one special case of the more general function of conflict resolution that we see as fundamental to the operation of the BIS in general and the SHS in particular. It is important for the theory (and for its interpretation of, for example, “place fields” in the subiculum) that the conflicts resolved by the system are conflicts between competing goals (as in maze learning) not between competing responses that would fulfil a single goal (as in the learning of mirror drawing). Such conflicts may be approach–approach (more typical of memory experiments), avoidance–avoidance (as in two-way avoidance) or approach–avoidance (more typical of experiments on anxiety). “Approach–avoidance conflict is by far the most important and the most common form of conflict in animal behaviour” [47] and has been subjected to detailed analysis in the laboratory [33,44,48,61]. We will focus on it as the paradigm case below—but what is said applies equally to the other forms of conflict. Thus, while approach–avoidance may be the commonest conflict in the wild, approach–approach conflicts are

Fig. 1. List learning by amnesic patients. They and controls were first (A) asked to learn a list of words and tested for recall in response to presentation of the first three letters of each word. The words were chosen such that only one other word in common English shared the same initial three letters. They were then tested on four occasions (R1–R4) with a list made from these alternate words. The amnesics showed no difference from controls on learning of the initial list nor did they show greater interference with the first presentation of the second list. However, they showed an impairment in recovering from interference indicating that their primary problem was in suppressing incorrect alternatives rather than in remembering correct ones. Redrawn from Warrington and Weiskrantz [92].

likely to be a significant source of anxiety in urban human populations. 2. A two-dimensional view of defense systems Approach–avoidance in the laboratory is usually investigated within learning tasks. But it has also been subjected to ethoexperimental analysis [6,7], in which the use of naturalistic situations and innate stimuli not only eliminates learning as a confound but also allows assessment of the functional significance of the observed behaviour from its natural context. This analysis has demonstrated quite distinct types of behaviour when a rat is removing itself from threat (attributable to fear) and when it is approaching threat (attributable to anxiety). Fear, so defined, turns out to be generally sensitive to panicolytic but not anxiolytic drugs while anxiety, so defined, is generally sensitive to drugs that are effective in treating human clinical anxiety [8]. We have, then, quite distinct classes of innate behaviour and quite distinct pharmacological sensitivities depending on a dimension of “defensive direction” (move away from threat/move towards threat). We also have (as we do from studies of active avoidance learning) evidence that anxiolytic drugs do not affect innate avoidance itself. What they do is alter the balance between avoidance and approach when these are in conflict [31]. Perhaps more important for our conceptualisation of the functions of the subiculum is the demonstration, in these same experiments, of a dimension of “defensive distance”. With each defensive direction there is a hierarchy of distinct defensive behaviours that occur, for any specific individual and any spe-

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Fig. 2. The two-dimensional defense system. The subiculum is part of the septo-hippocampal system which, as shown, is a central node in a hierarchy of structures controlling defensive approach (which necessarily involves conflict). This hierarchy is in parallel with one that controls defensive avoidance. Ordinary behaviour (e.g. escape), symptoms and syndromes are all here tentatively mapped into areas of the brain primarily controlling them. From McNaughton and Corr [50], for which see a detailed analysis.

cific threat, at particular distances. (Defensive distance is best viewed as an internal construct. The actual distance for any particular behaviour will vary both with the sensitivity of the specific individual to threat and with the intensity of the threat.) This hierarchy of behaviours can be mapped to a hierarchy of neural structures [17,29] that, together with defensive direction, allows defensive behaviour, neural structures, and clinical symptoms and syndromes to be mapped [50] into a two-dimensional system (Fig. 2). The details of this two-dimensional system are explored elsewhere [36,50]. For our present purposes the important point is that the SHS is just one element (albeit a central one) in a much larger system that supports the BIS and this system is in parallel to an equally large system that supports Fight, Flight and Freezing. The SHS, then, discharges a limited set of functions within the BIS. In particular, in terms of simpler conflicts, it controls behavioural inhibition in which the amygdala has no involvement [36]. Conversely, the amygdala controls arousal in which the hippocampus has no involvement [58]. Anxiolytic drugs affect both behavioural inhibition and arousal because they act both on inputs to the SHS [52,53,69,70,95] and on the amygdala [16]. In terms of more complex conflicts (e.g. social anxiety), the operation of the SHS itself would be the same as

for the processing of simpler goals but it would be operating on inputs from the higher levels of the system. For the remainder of this paper, then, we will focus on the specific operations of the SHS (and particularly the subiculum) and ignore the complexities of the systems in which it is embedded. 3. Behavioural inhibition or anxiety? The BIS has been delineated, both behaviourally and neurally, by sensitivity to anxiolytic drugs as a class. Classical anxiolytics, acting via the GABA-A receptor [37,38] have a range of side effects that are quite distinct from those of novel anxiolytics that act via 5HT1A receptors [10,19,25,27]. Since the only known common action of novel and classical anxiolytic drugs is their clinical efficacy in treating anxiety disorders the argument is that when any behaviour or neural process is affected similarly by both types of anxiolytic then it must relate to the control of anxiety. The inclusion of the SHS within the BIS, then, is based not only on the extensive behavioural similarities between anxiolytic action and hippocampal lesions [36] but also on the fact that novel as well as classical anxiolytic drugs alter the control of hippocampal theta rhythm [13–15,49,51,56,97–104].

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Fig. 3. The hippocampal formation (and particularly subiculum) as a comparator. Detection of particular environmental situations (Sa, . . ., Sj) will result in the activation of goal representations (G1, . . ., Gn) in areas that elicit classes of motor action (R1, . . ., Ri). Goals can differ primarily in the class of response (R2Sb vs. R3Sb), the class of environmental situation (R3Sb vs. R3Sc) or can differ in both respects (R1Sa vs. R2Sb). As detailed in the text the hippocampal formation contains a set of such comparators with the resolution of more stimulus-based conflict held to occur in entorhinal cortex, more response-based conflict in the subiculum and stimulus-response conflict (essentially the result of orienting responses) in are CA3. Adapted from Gray and McNaughton [36].

However, the use of clinically effective anxiolytic drugs as diagnostic of the system is not to say that the system subserves anxiety, merely that it controls it. The theory holds that anxiety and amnesia are the consequences of extreme hyper- or hypoactivity of the behavioural inhibition system, respectively. They reflect (as consequences) opposite ends of a functional continuum. Consistent with this, anxiolytic drugs are effective in tests of hippocampal-sensitive memory [54,55,82] that have very little obvious relation to anxiety since they involve escape from not approach to threat (see above). The drugs also have a delayed rather than immediate action on clinical anxiety [93] reminiscent of the anterograde amnesia that results from hippocampal damage. Thus anxiolytic drugs and the SHS are important for functions such as behavioural inhibition that only then affect anxiety or memory as consequences. The nub of the theory, then, is that the SHS resolves conflict between mutually incompatible concurrent goals (as can happen in situations ranging from innate, predator–prey, approach–avoidance conflict to delayed matching to sample when there is interference). Critically the SHS resolves such conflict, even in nominally cognitive rather than emotional tasks, by increasing the valence of negatively affective associations. Before we consider the specific role of the subiculum we need to look at the mechanism of conflict detection and resolution in a bit more detail. 4. Detection and resolution of goal conflict The SHS appears on occasion, and has been supposed in many theories, to carry out a multitude of tasks and encode a massive amount of information. By contrast, our theory holds that the greater part of the critical information on which the SHS works is held in other structures and that the computational operation

of the SHS itself is relatively simple. On this view, for example, “place fields” of cells in the hippocampus do not store positions in space. Rather, they reflect input from other areas signalling the availability of certain goals (or general classes of goals) and, in a spatially consistent environment, these goals will be related to space and so their availability will be signalled at particular points in space. This accounts for the tendency of some fields to change location and others not when reward contingencies are changed [36, Appendix 6]. It also accounts for the fact that with temporally structured reinforcement in a spatially restricted environment hippocampal cells have temporally related not spatially related fields [96]. The place or time related to maximal cell firing is encoded outside the hippocampal formation—which encodes the available goals, not their location. Fig. 3 shows, diagrammatically, how the system operates. For simplicity, the hippocampal formation is represented here as a single module but, as we will see, the same basic machinery is replicated at different points, including the subiculum. The idea that it is goals that are in conflict is particularly important for the detailed operation of the model. A goal is neither a stimulus nor a response. It reflects a compound of some stimulus configuration (or a cognition arising from that configuration) and the availability of a class of responses. The theory is based on the idea that rats do not learn responses, they learn goals. Block their original response and they will immediately adopt a new means of achieving the same goal [40,83]. Food at the end of a runway constitutes a goal. Remove the food and the end of the runway is no longer the same goal (or perhaps any goal at all). Place the food in a different location and that location is not the same goal as the end of the runway. Goals are represented in the figure, then, as Ss (standing not only for stimuli but also inferences from them) compounded with Rs (standing for general classes of response not specific

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motor sequences). These are encoded in various parts of the nervous system outside the SHS. When a goal is activated it sends an efference copy to the SHS. Although this will activate hippocampal cells (producing, perhaps, a place field) this will not by itself generate output from the SHS. Conflict will occur when two incompatible goals are approximately equally activated. Both will send efference copies to the SHS (generating concurrent activity in separate clusters of cells) and circuits in the SHS will detect more conflict the higher the level of activation of the competing goals and the more similarly they are activated. It follows from this that different goals must activate different parts of the hippocampal formation so that each can be registered, their activity compared and, when necessary, feedback sent to the area that originally activated that part of the hippocampus. Both the distribution of place fields within the hippocampus and the functional segregation of, for example, the septal and temporal parts [2] are consistent with the idea that the hippocampus represents available goal fields topographically. This, in turn, is consistent with Risold and Swanson’s [75, p. 1484] conclusion “that different hippocampal regions map in an orderly way onto hypothalamic systems mediating the expression of different classes of goal-oriented behaviour”. Our hypothesis predicts, indeed, that similar topography will be apparent in the input and output connections of the hippocampal formation with areas other than the hypothalamus. Notably, many of the major targets of hippocampal efferents are areas concerned with planning (prefrontal cortex, cingulate cortex), response organisation (amygdala, accumbens, basal ganglia, hypothalamus) or internal adjustments related to the anticipation of action (amygdala, hypothalamus). An important feature of the theory is that local hippocampal activity (e.g. a place field) and its modulation by rhythmic “theta” activity occur independent of whether the hippocampal formation is functionally involved. Activity of a “place cell”, for example, registers a single goal. This by itself does not require hippocampal output. It is only the activation of two separate, incompatible, goals concurrently that represents conflict. Thus the hippocampus will usually be in “just checking mode” (only one major goal signalled with others at lower intensity) and only sometimes enter “control mode” (two or more concurrent, similarly activated goals). Detection of conflict produces several distinct effects. First, it sends a feedback signal to the areas coding the conflicting goals that prevents their execution (thus leaving the motor system free for other activities, which sometimes results in displacement activity controlled by a much weaker goal). Second, this feedback signal, or another in parallel with it, increases the valence of any negative affective associations of the goals. On occasion this will be sufficient to resolve the conflict. With 5 “units” of food to the left and 10 “units” of food and 5 “units” of shock to the right a simple (non-hippocampal) decision mechanism will not resolve the conflict—it will fail to make either choice. When the hippocampus detects such a conflict it increases negative valence and so the net value of turning right will be decreased but the net value of turning left (which has no negative associations) will not. The simple decision mechanism will then be

free to choose left. It makes evolutionary sense to be more risk averse in the face of uncertainty or unnecessary danger. Third, the SHS initiates both exploration of the external world and scanning of memory to attempt to obtain additional information (e.g. a downgrading or upgrading of aversive values) that will resolve the conflict if a simple increase in aversive valence (affecting the value of currently know aversive consequences) is ineffective. The diagram captures the fundamental comparator process we ascribe to the hippocampus. But this process is executed, in somewhat different ways, on different occasions in separate parts of the hippocampus. The precise details of this execution also vary depending on a range of modulatory inputs. We will deal in detail with the separate instantiations of the comparator function shortly. But the potential need for more than one can be seen by inspection of Fig. 3. Conflicting goals can reflect a choice between two stimuli to which a single class of response (e.g. approach) needs to be made; or, they can reflect a choice between two distinct classes of response (e.g. approach/avoid) that can be addressed to a single stimulus; or, they can differ in both the stimuli and responses. Conflicting stimulus components and conflicting response components will be coded in different parts of the brain and so map to different parts of the hippocampus. We suggest that as we go (via predominantly unidirectional circuitry) from the entorhinal cortex to the subiculum we go from more stimulus-oriented, to more response-oriented conflict resolution. Feedback from entorhinal cortex primarily to neocortex will tend to resolve stimulus–stimulus conflicts, feedback from subiculum primarily to subcortex will tend to resolve response–response conflicts. Feedback from area CA3 will tend to resolve stimulus–response conflicts. The modulation of the operations of the comparator (or comparators) can be thought of as producing variations in acuity. Thus neural (not external) spatial summation of inputs to the system is affected by monoaminergic inputs (when they are present they essentially increase the signal-noise ratio). Likewise, neural temporal summation and integration, is affected by the “theta” input (when it is present processing is more quantised in time). Theta is rhythmic input to the SHS that, essentially through inhibitory action, causes the system to be largely phase locked at frequencies that are controlled by that of the input. It is significant in our model because the circuits we describe are fundamentally recursive. Input alters hippocampal activity, which then sends feedback that alters the source of the original input and so subsequent input to the hippocampus. We see this as operating to separate one goal from competing goals recursively in a fashion analogous to the tightly recursive neural mechanisms that can support global stereopsis and so separate a figure from its ground 5 [36,20]. The frequency of theta is, therefore, linked to the round-trip time between the SHS and its targets [62,63] and it is through alterations in the control of theta that anxiolytics achieve their hippocampal-like behavioural effects [36,95]. While fundamental to the original development of the theory the details of these proposed processes are not critical to the picture of the subiculum presented below and so have been omitted for the sake of simplicity.

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5. The place of the subiculum within the SHS—a “slice” perspective In what we have said so far the SHS has been treated almost as a single homogenous box. It is now time to open the box and look at the contents. To some extent, we are following in Pandora’s footsteps. It may seem we are letting all the troubles (or at least complexities) of the world out. But we will open it wide and so let Hope out along with all the rest. Let us start with the rule that, where the SHS is referred to as a whole, it includes the medial septum/diagonal band complex and all the areas which receive monosynaptic phasic inhibitory “theta” input from it [36, Appendices 5 and 6]. On current evidence, therefore, it includes at least the entorhinal cortex, the dentate gyrus, fields CA1–4 of the hippocampus proper, the subiculum, and the posterior cingulate cortex. It may be necessary, shortly, to add the perirhinal cortex. If one picks the right plane of section in the right species one can almost see all of these areas as divisions of a single curvilinear line of cells (discontinuous at the dentate gyrus). In terms of organisation, let us look first, then, at what can be thought of as a dimension defined by the genuinely continuous cell layer (CA3–CA1–subiculum) in the hippocampal formation. Much of the literature treats CA3, CA1 and subiculum as three distinct fields, but the mapping may be more continuous or complex than this. Area CA2 could be a transition zone but has long been recognized as potentially distinct both on morphological and connectional grounds. Indeed, while it could have been treated as a transition zone, it appeared peculiar enough to receive its own number in the original CA1–4 divisions of cornu ammonis. Likewise, CA4 could be viewed as an extension of CA3 but is morphologically and connectionally distinct. CA3 itself has occasionally been divided into subregions a, b and c. Of particular interest to those interested in the subiculum, the CA1/subiculum border appears to have a specific reciprocal relation to the amygdala (the amygdala has additional, more widespread, unidirectioal connections to the temporal parts of the hippocampal formation); and other sub-regional strips like it may be discovered in the future. (For details of all of the above see [36], including the Appendices.) In terms of superficial appearance, area CA1 is continuous with an area where the cells are no longer neatly packed in rows. This is conventionally the location of subicular cortex and has been viewed as a transitional zone between the simple archicortex of the hippocampus and the six-layered neocortex of the entorhinal area. On the basis of cytoarchitectonics, Lorente de No [107] divided this region into the prosubiculum (nearest CA1), the subiculum proper, and then (as one proceeds from cornu ammonis towards and reaches the entorhinal cortex) the pre- and para-subiculum. As we have seen there are good reasons to distinguish the CA1–subiculum “transition” zone as a distinct area because of it special connections with the amygdala. However, the pre- and para-subiculum, on connectional grounds, should probably be seen as input areas for the hippocampus (with their information relayed by entorhinal cortex), rather than being grouped with the prosubiculum and subiculum, which are output stages of the hippocampus.

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If we exclude the pre- and para-subiculum, we can follow the hippocampal cell layer round to posterior cingulate cortex and then ultimately anterior cingulate cortex. Posterior cingulate is [36, Appendix 3] a somewhat ambiguous structure. It is placed in the cortex close to the subiculum. It receives largely unidirectional links from subiculum, as does subiculum from other hippocampal areas. It shows the theta activity and perhaps theta rhythm which are characteristic of the hippocampal formation and does so because of monosynaptic control by a distinct part of the septal area that passes through a distinct, supracallosal, pathway. Yet it is separated physically from the subiculum and it is not normally treated as simply another module of the SHS. But because of its control by the theta system, because it is a component of the dorsal trend of cortex and because, unlike the anterior cingulate, it affects the paradigm test of hippocampal dysfunction, water maze learning (e.g. Riekkinen [109]) we include it with the SHS. But for the purposes of the current paper it can equally well be treated as just another target of the SHS output since subiculum is one of the main sources of hippocampal efferents, including to posterior cingulate cortex. Anterior cingulate cortex is a different matter. True, it is tightly linked to posterior cingulate. But the connection is reciprocal (unlike those within the hippocampus proper and unlike that of the subiculum with posterior cingulate). Further, stimulation of anterior cingulate elicits affective responses unlike that of posterior cingulate. We [36] argue on these and other functional grounds, therefore, that anterior cingulate is part of the FFFS whereas posterior cingulate is a matching part of the BIS and this allows for a symmetrical structural and function picture of the neural control of defense (Fig. 2). There are several reasons, however, for us to still want to see subiculum as the key final stage of the SHS proper. Posterior cingulate can be viewed as being tightly related to both anterior cingulate and the SHS [36, Appendix 3]. Its reciprocal links with the anterior cingulate mirror the reciprocal links between the dorsal and ventral trends, respectively, of frontal cortex. These ventral “what” and dorsal “where” trends of information processing are generally kept separate but are mixed on arrival in the entorhinal cortex (which we will argue below is the initial stage of the SHS). They appear to remain essentially mixed during transfer through the hippocampus. The cingulate may, then, be a transitional zone in which processing of the same general form as the SHS proper is carried out in a structure divided into separate parallel trends. If the perirhinal and parahippocampal cortices are shown to receive direct theta controlling input from the septum, they could represent a similar transitional zone—but on the input rather than output end of the SHS. There are two additional reasons for seeing posterior cingulate as a transitional zone and subiculum as more the final stage of the SHS. First, the posterior cingulate represents a reversal of the architectonic trend which progresses from the perirhinal and parahippocampal cortex, via entorhinal cortex to subiculum. On architectonic grounds the lateral septal area and hypothalamus would be better candidates for a “next stage” of the SHS. Second, the posterior cingulate cortex has return projections to the pre-subiculum, some parts of the subiculum, entorhinal, perirhi-

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nal, and parahippocampal cortices. Transmission within the rest of the SHS is more strictly unidirectional. The final module we need to consider is entorhinal cortex. As noted previously we include this within the SHS because of its receipt of direct theta controlling input from the septum. It is also the starting point of the predominantly unidirectional flow for which subiculum (and to a lesser extent posterior cingulate) is the end point. It is the entry point for cortical information to the SHS. But it is also the primary point at which the unidirectional flow of information is recirculated from the SHS back to itself. However, there is one reason to see subiculum and entorhinal cortex as qualitatively different. All of the subfields of the SHS appear to receive equivalent information from both the medial septum and the entorhinal cortex. The theory we present views the SHS as involving a series of comparators and, essentially, we see the medial septum (and other modulatory subcortical inputs) and the entorhinal cortex as providing the primary inputs to the comparators (although we also see entorhinal cortex, which receives septal and neocortical input, as being the first of this series of comparators). Our picture then (Fig. 4) is of an essentially linear stream of information processing starting at entorhinal cortex and finishing in posterior cingulate. Entorhinal cortex is reciprocally

connected with subiculum and posterior cingulate cortex and also has direct connections with the (largely common) targets of these two structures. These targets, in turn, send feedback to subiculum, posterior cingulate and, to a lesser extent entorhinal cortex. While the connections of entorhinal and posterior cingulate cortex partially overlap, the subiculum is of particular significance in receiving input from and sending output to areas that it shares with both of these cortical structures. 6. The place of the subiculum within the SHS—stacking the slices In the rat, the hippocampus, once dissected out of the brain, looks like a banana. Like a banana, if you cut across it at any point at the correct angle you get an essentially identical slice—each containing all the circuitry we have been describing. Our discussion so far has been of such a slice, albeit with a complicated (and discontinuous) line of seeds embedded in it. It is time to look at the length of the banana, to determine the relationship between the different slices that, when stacked together reconstitute the fruit. These slices, despite having essentially identical circuitry, are not exactly the same. There are gradients from one end

Fig. 4. The subiculum as the main output stage of a unidirectional circuit through the hippocampal formation. The operation of this circuit is modulated by subcortical inputs via gating or threshold mechanisms (see also Fig. 7). The hippocampal outputs are held to operate in a computationally simple fashion on their target structures with the resultant behavioural inhibition, negative bias, latent inhibition, etc. resulting from changes in processing within the targets. Abbreviations for this and Fig. 6: AVT, anteroventral thalamus; ADT, anterodorsal thalamus; AMT, anteromedial thalamus; LDT, latero-dorsal thalamus; Motor, motor and premotor cortex; DStr, dorsal striatum; DPal, dorsal pallidum; SN, substantia nigra; PreF, prefrontal cortex; VStr, ventral striatum; VPal, ventral pallidum; VTA, ventral tegmental area; AC, anterior cingulate cortex; Amyg, amygdala; VMH, ventromedial hypothalamus; PAG, periaqueductal grey; LS, lateral septum; MB, mammillary bodies; Tegm, dorsal and ventral tegmental nuclei; PC, posterior cingulate; SUB, subiculum; CA1, CA3, CA4, subfields of Ammon’s Horn (cornu ammonis); DG, dentate gyrus; EC, entorhinal cortex; Peri, perirhinal cortex; Para, parahippocampal cortex; dors, vent, dorsal and ventral streams of sensory cortex; Ins, insula.

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Fig. 5. Topographic mapping of hippocampal formation into the septal area and hypothalamus. The hippocampal formation can be viewed as a two-dimensional sheet (right-hand panel) with unfolding of the cell layers and removal of the curvature of the hippocampus resulting in the top of the sheet being the septal pole of the hippocampus and the bottom being the temporal pole, the left-hand side of the sheet being CA3 and the right-hand side being SUB. The hippocampus is topographically mapped into the lateral septal area which can also be viewed as a two-dimensional sheet which with the proper bending and orientation (middle panel) provides a direct correspondence with the hippocampal sheet (e.g. the shaded temporal portion of CA1 and SUB projects to LSv). The floor of the brain in the region of the hypothalamus can be viewed similarly, with the sheet essentially standing on edge (lSUM is largely dorsal to MB) with septal portions of the hippocampus projecting via the septum to caudal hypothalamic areas and temporal portions to rostral (giving approximately similar path lengths in the two cases). The most septal quarter of SUB appears to project directly to MB without relaying in the septum. As discussed in the text the density of connections is not related to the size of the boxes shown. Abbreviations as for Fig. 4. For LS, c, l, r and v are caudal, lateral, rostral and ventral, respectively; AHN, anterior hypothalamic nucleus; MPN, medial preoptic nucleus; PV, periventricular nucleus. (Redrawn following [75].)

to the other (from the septal to the temporal pole1 ) of various biochemical markers and of inputs and outputs. The latter are known to reflect a topographic mapping of hippocampal areas into hypothalamic “goal processing” areas [75]. Also, temporal hippocampus (in addition to the CA1/subicular boundary) is strongly related to the amygdala. Electrophysiologically, this septo-temporal differentiation may be fairly coarse (with, it has been suggested, only about four true lamellae in a rat hippocampus). But, in terms of the comparison of specific goals (represented by place fields) differentiation is likely to be much better. The longitudinal and commissural connections of the hippocampus proper would, on this view, not support an expansion of lamellae so much as supply the capacity for comparison of the level of activity between quite tightly localised sources of activity that under normal ecological circumstances would be represented in quite disparate parts of the SHS. Although this was not emphasised by Gray and McNaughton [36], consistent with the differentiation of external connections along the hippocampus, there appears to be functional differentiation. Septal portions appear more dedicated to spatial process-

1

“Septal” and “Temporal” refer to the parts of the hippocampus most closely associated with its septal and temporal cortical attachment points, respectively. This is unambiguous. In rats “dorsal” hippocampus is septal and, as it happens, anterior. In primates “anterior” hippocampus is temporal and, as it happens, ventral.

ing (consistent with its relatively more discrete “place” fields) and temporal portions appear more dedicated to processing in tasks involving anxiety [2]. 7. The place of the subiculum within the SHS—the two-dimensional sheet The hippocampal formation, like other cortical structures, can be thought of as a folded sheet. It is, in essence, a swiss roll that we can mentally unfold to produce a single layer of sponge cake. Its different fields, and its septo-temporal differentiation, can then be represented as two dimensions on a sheet of paper. This sheet, and its topographic relationship with the septum and thence the hypothalamus [75], is shown in Fig. 5. There are two contrasting points to make about the position of the subiculum within this topographic organisation. The first is that, in many respects, it is just like the rest of the hippocampal formation in terms of its mapping into its own portion of what can be thought of [75] as goal space. The second, in contrast, is that the mapping of the septal quadrant of subiculum has two special features: it is connected directly to the hypothalamus without relay in the septum; and its target, the mammillary body, is not typical of other hypothalamic nuclei. These efferent mappings are important. The lateral septum and the subiculum are the two most obvious sources of output from the hippocampal formation. Indeed, ‘until the mid-1970s,

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the prevailing view of the extrinsic connectivity of the hippocampal formation was that [it] received sensory information from a variety of cortical regions [and] was thought to funnel this sensory information through the [fimbria/fornix] to the mammillary bodies. [This] was such an obvious efferent pathway [that] little thought was given to alternative hippocampal efferents’ (Amaral, [105] p. 226). Since that time the fornix–fimbria has grown no smaller and yet recent ‘memory’-oriented views of the hippocampus have essentially ignored the role of the subcortical outputs of the hippocampus. They may note, in passing, that cutting the fornix–fimbria (which disconnects both subcortical output and input) produces effects very similar to those of hippocampal lesions but their focus is cortical. Yet, if hippocampocortical relations were the main basis for hippocampal function, it is difficult to see why subcortical disconnection should have such major effects (or why the hippocampus should be so prominent in relatively unencephalized species). Indeed, it is worth noting that the septum as a whole ‘undergoes a progressive increase. in size in primate development. Among primates it attains its greatest degree of development in the human brain’ (Andy and Stephan, [106] p. 3). So, while not showing the immense expansion of the neocortex, the septum cannot be considered vestigial or unrelated to the more human functions of the brain. Thus, the information relayed in the septum (which accounts for all but one of the nominal 12 subdivisions of the hippocampal formation) is substantial. But the remaining one, arising in the most septal quadrant of the subiculum and consisting of direct output to the mammillary bodies appears, relatively, much more important. This connection is also significant in that it is the first step in the “Papez circuit” [72] that circulates information from the subiculum to the mammillary bodies and then to the anteroventral thalamus, the cingulate gyrus, and back to the subiculum. This circuit, essentially, recirculates information (with implied recursive transformation on each pass round the loop). It is the most obvious of a range of other such circuits [73]. These circuits, in our view, support a crucial recursion implicit in all hippocampal processing. We will consider the general issue of recursion before discussing the reasons for a quantitatively large subicular contribution and the mechanisms that differentiate the different instantiations of the comparator function within the hippocampal formation. Our picture will be of the subiculum as perhaps the most important of a set of computationally similar comparators that, because of their different places within the hippocampal formation and their different afferent inputs, discharge superficially different psychological functions. 8. The place of the subiculum within the SHS—a key recursive node The core of the SHS itself is a set of essentially unidirectional connections. This contrasts with the immediate reciprocal connections typical of neocortex and of the subcortical structures to which the hippocampal formation is connected. This unidirectionality is continued in the immediate cortical and subcortical targets of hippocampal output.

This unidirectionality of connections between modules also contrasts with the strong tendency for polysynaptic return loops from its targets to the hippocampal formation with a large number (of many different lengths) returning to the entorhinal cortex, many to the posterior cingulate and, as noted above, the Papez circuit to the subiculum. There is also one internal set of loops connecting the dentate, CA3, and CA4 (see Fig. 6). The subiculum appears to be a key node within these multiple loops. It is the major source of outflow from the hippocampus proper with at least as diverse a range of targets as the entorhinal cortex, from which it receives input and with which it shares many outputs. The subiculum apparently starts out in receipt of the same information that is recirculated to it in several different ways, some longer, some shorter. There are inputs to the subicular cortex from the same areas in the temporal lobe that project also to the entorhinal area [85], and the subicular cortex also receives input from the entorhinal area itself. Thus the subicular cortex receives information from the neocortex via the temporal lobe; information from the same source, but relayed directly by the entorhinal area; and information which passes through the entorhinal area and trisynaptic hippocampal circuit, to be finally relayed by CA1. It then sends this multiply digested information out, only to have it come back yet again after a trip through the anterior thalamus both directly and via the mammillary bodies. The information from the anterior thalamus can also be sent to the cingulate cortex, whence it returns via direct projections to the entorhinal cortex or relayed to the entorhinal cortex via the para-subiculum. Of course, it is not “the same” information. If it were, we should need to suppose that a large part of the brain does nothing but echo back the news that it receives. Rather, it is the basis for extensive, recursive, interactions that progressively allow the selection of one from several conflicting goals. Consistent with this focus on goals, the septo-hippocampal system has major connections with many motor programming areas and, as we have noted, is topographically mapped into the hypothalamus [75]. Indeed, this “motivational” mapping is the only clear source of topographic organisation within the hippocampal formation. Relatively speaking, then, hippocampal links with pure sensory processing, and potentially with such memory as can be dissociated from action, are modest, although not negligible. Similarly, the subicular output is to higher (more “sensory”) levels of the motor systems (or to polymodal association cortex) and return input (often to the entorhinal cortex) is predominantly from the more motor levels of many of those same systems. Within the context of our basic comparator model (Fig. 3) this anatomy would fit with hippocampal output altering motivational valence and other factors involved in goal representation and with input to the hippocampus allowing it to calculate the extent to which currently activated goals are generating motor conflict. It is important to note that theories of the hippocampal formation that emphasise memory or spatial processing do not provide any account of the unidirectionality of flow within the SHS; nor its embedding within such a nest of long return loops; nor the

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Fig. 6. Outflow from the subiculum and posterior cingulate is generally to the higher (more perceptual) levels of motor programming areas. Feedback (to entorhinal cortex) is generally from the lower areas. For further details see text, for abbreviations see Fig. 4.

action-oriented and subcortical nature of the areas with which it clearly interacts. 9. The subiculum as one of the hippocampal comparators Fig. 3 represents the hippocampal formation as a single comparator as proposed by Vinogradova (see below). But if there were only one, then the hippocampal formation would require only a single level. The anatomy suggests, however, that there are several. There is major output from entorhinal cortex, CA3, and the subiculum as well as lesser output from CA1. We argue that each of these is a separate comparator or logical gate. Each addresses different subcortical, particularly hypothalamic, structures. Similarly, they are also likely to address different cortical structures. However, while we make specific assignments below, we cannot as yet unambiguously identify the function of any of these potential comparators (except in our acceptance of Vinogradova’s picture of CA3), as there are virtually no relevant data. The specific details of this aspect of the theory remain, therefore, highly speculative. The best understood comparator, in CA3, detects novelty or importance. We see this as auxiliary to the CA1 and subicular comparators. It sends them only signals that have special importance. The function of the subicular comparator is, so to speak, trouble shooting. It is called into play when the animal’s normal routine is faced with other, conflicting, response tendencies. These latter can be elicited, notably, by novelty, the threat of non-

reward, the threat of punishment and relational processing (or other means of generating interference). The task of the subicular comparator is recursively to increase negative affective bias in all of the active and conflicting goal processing areas until only one alternative is clearly dominant. In this way existing plans can be applied again or new ones substituted as appropriate. Where there is insufficient information for resolution of the conflict to occur, all of the alternative goals will be suppressed. Under these conditions, output from the first, CA3, comparator will initiate general information gathering behaviour (and particularly risk assessment); or output from the subiculum to the posterior cingulate cortex will initiate more complex forms of risk assessment, checking and safety-seeking behaviour, including, for example, innate routines that do not depend for their termination on the achievement of a specific reinforcer. The conflict should then be resolved once the existing internal positive and negative affective associations have been updated with external information. Fig. 3 represents the computational function executed by each of these separate comparators. However, that they compute the same class of algorithm does not mean that their output should be labelled with similar psychological functions. They are at different stages of the SHS; they receive (most obviously in the case of the subiculum) inputs in addition to those filtered through entorhinal cortex and previous stages of the SHS; and they have (most obviously in the case of CA3) differing output targets. The idea of the hippocampus as a comparator was taken by us from Vinogradova [87–91]. She developed the idea of a single

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comparator into a highly detailed model with the function of each component, and the interaction between them, based on single cell and lesion data [36, Appendix 6]. We have used her model as a paradigm case and then elaborated on it mainly by postulating additional, computationally similar, comparators. Our only significant departure from her model of the CA3 comparator itself (justified in [36, Appendix 6]) is to see hippocampal processing as operating on orienting responses generated by stimuli rather than operating on the stimuli themselves.2 Her comparator, located in area CA3, is essentially a novelty detector. Consistent with this, the hippocampus (and other components of the limbic circuit) is activated by novelty of stimuli in human beings [84]. It should be noted that “memory” theories of hippocampal function cannot account for the details of Vinogradova’s data nor the related data on eye-blink conditioning [36, Appendix 6]. From cellular discharge patterns she concluded that CA3 was the focus of a hippocampal habituation process (that is hippocampal responses habituated even when behavioural responses did not). Habituation was not seen extensively in the three structures which project to CA3 (the medial septal nucleus, entorhinal cortex, and dentate gyrus). It was, however, seen in the two structures which receive output from CA3 (the lateral septal nucleus and, less regularly, CA1). Thus, hippocampal habituation took place in CA3 and was then passed on to the latter two structures, as well as, potentially, the hypothalamus and other target areas. An active transfer of habituation, as opposed to a loss of previous excitation, was suggested by the fact that, if the connection between CA3 and the lateral septum was severed, habituation no longer occurred in the lateral septal area; on the contrary, unit responses tended to increase with stimulus repetition [88,91]. This habituation in CA3 was, in her view and ours, a comparator function. It resulted when there was a match between medial septal and entorhinal inputs. If the septum was disconnected from the hippocampus or if the entorhinal cortex was disconnected from the hippocampus, the ultimate response of CA3 cells was a gradual increase rather than decrease in firing rate. Further, the initial stimulus-non-specific responses in CA3 must come largely from the septum, while the stimulus-specificity of the habituation must come from the entorhinal cortex. Note that a mismatch in either direction resulted in CA3 output, and that a stimulus-specific signal could cancel a multimodal signal. Thus, stimuli that can produce an orienting response initially access CA3 (and thence lateral septal and subicular output from the hippocampus) that can interrupt ongoing motor pro-

2

Wiener and co-workers obtained sensory correlates of hippocampal unit activity in freely moving rats of a similar type to Vinogradova’s, and noted that “these discharges had no location-selective or task-related correlates . . . These were not simply novelty responses since the rats had experienced these stimuli in many training sessions . . . [They appear] linked, perhaps in an indirect manner, with movements triggered by the sensory stimuli . . . [For example,] visual stimuli could trigger orienting responses like eye movements; the latter have been shown to be correlated with hippocampal activity in the monkey” [26,45,94].

grams. With time, habituation to a familiar non-significant stimulus occurs in CA3 (after about 8–15 stimulus presentations) attributable to a build-up in the responses first in the entorhinal cortex (2–12 presentations of the stimulus) and then in the dentate gyrus (15–20 presentations). This is consistent with the recent view that familiarity as such (as opposed to the content of declarative memory) is registered in the perirhinal area [1]. Thus, the progression would start in perirhinal and be passed from there to entorhinal cortex before ultimately spreading to CA3. This progressive augmentation of response is most simply explained as a spread of long-term potentiation (LTP), probably starting in cortical areas which build-up a model of the stimulus, and progressing through the entorhinal cortex to the dentate gyrus. This potentiation could correspond to a build-up of ‘familiarity’ [91].3 Thus, according to Vinogradova, the same simple stimulus can affect the hippocampus through two routes. On first and subsequent presentations, it activates the reticular system and affects the hippocampus via input from the medial septum. Initially this signals novelty, and so can interrupt ongoing motor programs. Successive presentations allow a ‘cortical model’ of the stimulus to be built (which could be done by Hebbian association, initially depending on LTP or related mechanisms). Once this cortical model is sufficiently complete, it affects the hippocampus through the second route, the entorhinal cortex. This second input cancels the effects of the first, resulting in the observed habituation in CA3. We thus have, in CA3, a comparator that deals with a relation that is fundamentally between a response (the orienting response) and a stimulus (the cortical model of the expected upcoming stimulus). This is, perhaps, intrinsically more difficult to comprehend than the stimulus–stimulus (entorhinal cortex) and response–response (subiculum) comparators we will consider next and so it is lucky that its precise operation has been demonstrated in detail. Let us look somewhat closer at the idea of “stimulus” and “response” in the context of the hippocampal comparators. To those brought up with a radical behaviourist perspective it is tempting to take these words at face value. But we emphasised earlier that animals learn (and their hippocampus processes) goals not responses [40,83]. If we look at the details of Fig. 3 we can see that “stimulus–stimulus” and “response–response” reflect flavours of interactions between goal representations rather than being discrete entities. As shown in the figure a goal can be viewed as a compound of the availability of a particular class of consummatory (or motivated) response (R) with the context of a particular set of stimuli or other concatenation of circumstances (S). Conflict occurs when two goals are equally attractive (depending on the nature and history of the stimuli and of the 3

Vinogradova’s view, as modified by us, can be linked to a number of other theories of hippocampal function [18,21–23,42] that we will not go into here but are discussed by Gray and McNaughton [36]. These can be linked to Vinogradova’s ideas especially since hippocampal processing of orienting is separate from orienting itself [9].

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contexts in which they have been presented). On detecting conflicting goals, each priming a response system, the hippocampus will selectively dampen the probability of response output (via increased negative bias in both goal representations) so as to leave only one item that can capture motor mechanisms. (It will also as a result tag incorrect retrievals, so that their probability of occurrence in a similar context is reduced in future.) But, it can be seen that while two goals may differ in terms of both their stimulus context and the class of response which would be addressed to that context (R1Sa:R2Sb), they may differ in only one of these respects. In the paradigm tests of behavioural inhibition that demonstrate hippocampal involvement (with both innate and conditioned stimuli) the same behavioural context elicits differing response tendencies (R2Sb:R3Sb), e.g. both approach and avoidance of the same goal box at the end of a runway in a classic approach–avoidance conflict. By contrast in a typical memory experiment the response to be made (a lever press, for food) may be essentially the same for two choices to be made where only the stimuli to which the responses must be addressed differ (R3Sb:R3Sc), e.g. large circle versus small circle. Gray and McNaughton [36] view the entorhinal cortex as dealing primarily with these latter, stimulus–stimulus based conflicts.4 It receives important input from the cortex and can return information there fairly directly via its outputs to perirhinal and parahippocampal cortex (Fig. 6). (As noted above, within Vinogradova’s model, even when entorhinal cortex does not detect and deal with conflict itself, it can still act as an important relay of such stimulus-oriented information to other areas of the SHS such as CA3.) In part, this matches a classic “memory” view of the hippocampus except that we view the action of entorhinal cortex as the suppression of inappropriate information (suppressing interference) rather than the strengthening of appropriate information. By contrast to entorhinal cortex, Gray and McNaughton [36] see the subiculum as dealing primarily with response–response based conflicts. The information relating to these can reach the subiculum directly from the same areas in the temporal lobe that project to the entorhinal area [85], from the septum, and from both entorhinal cortex and septum relayed through area CA3. As noted before, the hippocampus proper, including the subiculum, can be seen as a set of comparators placed between the septal and entorhinal inputs. To understand the operation of the subiculum we will need to look both at the kind of output of which it is capable and the different ways in which the preceding hippocampal modules can send it information. While the other comparators (particularly entorhinal cortex and area CA3) are capable of their own specialised output, the subiculum represents an important target through which they execute some of their functions. They can equally well be seen as primary filters that provide the subiculum with the information through which it executes its own particular functions. 4

This activity of the entorhinal cortex involves additional interactions with other parts of the SHS as detailed by Gray and McNaughton [36] but these do not alter greatly the picture of the subiculum presented here.

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10. Subiculum versus posterior cingulate cortex as primary SHS output stage The subiculum is clearly the major terminal point of the cascade of processes generated by the parallel inflow of septal and entorhinal information into the interlinked modules of the hippocampus proper. It is the final point in the SHS up to which unidirectionality is largely maintained (output from the posterior cingulate is generally reciprocated by the areas to which it projects). It is also a major source of efferents from the hippocampus—an important fact not represented in simple block diagrams of connections between areas. The subiculum would, therefore, appear to be the paradigmatic example of a goal conflict detector of the form portrayed in Fig. 3. It receives general information (“arousal”) via the septum and aminergic inputs; information that predicted stimuli (goals) have occurred via the entorhinal cortex; details of motor programs/working memory (goals) from the prefrontal cortex; and details of innate programs (goals) from the cingulate cortex, amygdala, cerebellum, etc. It is then positioned so as to be able to interact recursively with all these areas (e.g. subiculum–mammillary body–anteroventral thalamus–cingulate cortex–subiculum) and so modify their function. (The CA3 comparator is more a simple non-recursive mismatch detector with its behavioural inhibition function executed through its output to the subiculum.) Such recursive modification could operate not only on a short, immediate feedback, timescale but also on a longer one, involving memory or memory-like processes. Changes based on long-term potentiation and depression could proceed progressively round the loop from the subiculum to other structures over a number of trials in much the same way as Vinogradova describes them progressing within the hippocampal formation (see above). Cingulate–subicular relations are of particular interest here. The parahippocampal isocortex (areas TH and TF, which provide input to the first stages of the SHS) projects to the isocortical area 23 within the cingulate, while the relatively undifferentiated, allocortical, subiculum projects to the relatively undifferentiated periallocortical and transitional areas 29a–c. This matching of cytoarchitectonics between sending and receiving areas is like that of connections between sensory cortex and frontal cortex and like that of the interconnections of the dorsal and ventral trends of frontal cortex. The subicular input to cingulate is notable as one of the few major inputs to the cingulate cortex which is not reciprocated. This suggests that the SHS, including areas 29a–c, is a unidirectional (allocortical and archicortical) loop superimposed on the bidirectional isocortical connections between temporal and cingulate isocortex. The subicular projection to the dorsolateral prefrontal cortex is also unidirectional [28]. In terms of the phylogentic elaboration of cortex by the superimposition of layers of ever more isocortical structures on existing allocortical ones [66] this suggests that subiculum could be the remains of a primordial original comparator. On the input side the functions of this primordium would have been made ever more sophisticated by its elaboration into the additional modules

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of the hippocampus proper and, ultimately, entorhinal cortex. On this view, the functional similarity of pigeon “hippocampus” to mammalian [12] and its possession of theta rhythm [81], despite little similarity in the organisation of cell layers, could reflect relatively less differentiation of a primordial, subicularlike, structure. On the output side its functions would have become elaborated on by and shared with the posterior cingulate cortex which seems not to be just another target of outflow from the subiculum. Certainly, the subiculum receives essentially the same thalamic inputs as does area 29. If we see the posterior cingulate as analogous to the frontal cortex, then this would argue that, relative to it, the hippocampal formation is analogous to the unimodal association cortex. Thus, if the parahippocampal and perirhinal cortex can be viewed as the ‘dorsal’ and ‘ventral’ components, respectively, of the ‘primary’ polysensory cortex (and hence, like the primary unimodal cortex, as the most laminated part of the system), then the subicular allocortex could be viewed as tertiary polymodal association cortex. While, as we have noted, the subiculum projects directly (and unidirectionally) mainly to area 29c, it can also influence area 29c via the anteroventral thalamus (through both a direct reciprocal projection to the anteroventral thalamus and through a relay to the anteroventral thalamus in the medial mammillary bodies). It also projects directly to 29ab (which it can in addition influence via the anteromedial thalamus and a relay to the anteromedial thalamus from the mammillary bodies). It can also influence the remainder of the cingulate (and some areas of the prefrontal cortex) indirectly via the anteromedial thalamic nucleus. We have focussed on the predominance of unidirectional, efferent, connections of the subiculum. So given the extensive reciprocal connections of posterior cingulate, this could lead one to question whether posterior cingulate is a phylogenetic extension of subiculum rather than just one of its many other cortical targets. However, subicular unidirectionality is not complete. We have already mentioned the CA1–subiculum transition zone that is distinctive in having reciprocal connections with the amygdala. The later stages of the subicular complex also receive [63,85] some afferents from the cingulate cortex, temporal cortex, frontal cortex (in monkeys), and occipital cortex (in cats). There are also various subcortical inputs, particularly that from the medial septum controlling subicular theta activity, which includes input from the nucleus reuniens of the thalamus. The nucleus reuniens also projects to CA1 and the entorhinal area [5,39,77]. 11. The outputs of the subiculum The outputs of the subiculum can be divided into three classes. First are those it shares with the lateral septum (either directly, for example the ventromedial hypothalamus, or by virtue of the fact that it projects to lateral septum). These can be viewed as a confluence of CA3 and subicular information. They include the ventromedial hypothalamus, lateral hypothalamus, dorsomedial hypothalamus, and preoptic area. Second are those it shares with the entorhinal cortex (which we will discuss below). Third is the output to the mammillary bodies which

it shares with both the entorhinal cortex and lateral septum. The septo-hippocampal projection provides the main source of afferents to the mammillary bodies. The principal cortical targets of subicular and entorhinal efferents appear to be the frontal and cingulate cortex [36, Appendix 3], although there are some reported weak connections to other areas [63, p. 54]. Given the subcortical topography of hippocampal outputs, it is interesting to note that there are signs of similar organisation of prefrontal connections [3]. The bulk of these outputs can be viewed as targeting goal processing areas and so being primarily involved in behavioural inhibition. However, Fig. 3 requires not only the cessation of ongoing behaviour but alterations in the perceived value of the stimuli eliciting that behaviour. This function is likely to involve output from the subiculum and entorhinal cortex to the dorsal and ventral striatum, and to the dorsomedial thalamus (which receives input from the dorsal and ventral striatum). The nucleus accumbens (ventral striatum) has been described as the gateway to the motor programming circuits of the basal ganglia [64]. Certainly, the dorsal and ventral striatum can be viewed as the input stages to two parallel, motor programming systems which also receive inputs from the prefrontal cortex (to the dorsal and ventral striatum) and from the primary motor (to the dorsal striatum) and the limbic (to the ventral striatum) cortex. However, unlike the subicular or entorhinal input to hypothalamic, cortical, and defence systems, the subiculum/entorhinal input to the more purely motor programming systems enters only at the highest subcortical levels where perceptual aspects of the perception–action cycle could predominate. In contrast, the feedback to the septo-hippocampal system can be from the lower levels of these systems (e.g. from the ventral tegmental area, A10). The subicular/entorhinal–accumbens route can have a more obvious role in the modulation of sensory processing as it can influence successively (via a series of GABAergic pathways) the ventral pallidum then the nucleus reticularis thalami and from there the whole array of thalamocortical sensory processing loops. Analysis of the likely mode of operation of this circuit suggests that activation of the subiculo-accumbens projection can boost thalamocortical sensory processing in all modalities [46]; while analysis of the likely behavioural effects of such activation suggests that it is particularly novel stimuli and stimuli with strong associative significance that are picked out for enhanced sensory processing via disinhibition [34]. Thus, two of the key outputs of the behavioural inhibition system [36], interruption of ongoing motor programs and increased attention to the perceptual world, are perhaps achieved simultaneously by activating the subiculo-accumbens projection. 12. Gating of SHS input to the subiculum The CA3 comparator provides not only a model of the possible workings of the other comparators in the hippocampus but also, at least in its relations with the subiculum, of their operation as logical gates. It filters information allowing it to influence, or preventing it from influencing, the subiculum. The septo-hippocampal system contains (because of its largely uni-

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directional connections) a series of such logical gates, which interact to determine the conditions under which it will produce functional output. In the case of the CA3 comparator, the gating can be viewed as performing a more cognitive function: signalling importance, or lack of familiarity. There is good evidence for a (possibly noradrenergically modulated) gate between the dentate gyrus and CA3 which determines whether (depending on the modulatory input) the dentate effectively excites or inhibits CA3—in essence changing the signal-noise ratio. There is also evidence for a cholinergically controlled gate within the medial septum (so that cholinergic input allows information from areas such as the supramammillary nucleus to reach the hippocampus) and for independent cholinergic and serotonergic gates within the hippocampus (gating input from the medial septum and probably other areas). There also appears to be a gate between CA3 and CA1 and, for consistency, we also postulate a gate between CA1 and its outputs, including the subiculum, and between the subiculum and its outputs such as the mammillary bodies. One, at least, of the latter two exists, since the eye-blink-related firing of CA1 is not normally transferred to the mammillary bodies. A subicular-related gate (on input to or output from the subiculum) is particularly important, theoretically, as it could account for the many instances where single cell or theta correlates (recorded in CA1) do not map to the effects of hippocampal lesions [36, Appendix 8]. In these cases, the hippocampus is receiving information with which it could control behaviour, but which does not result in significant functional output unless some other condition is fulfilled, so opening the final subicular gate. A similar gate in the lateral septum is likely to determine the functional consequences of CA3 activity [24]. Finally, it should be noted that a number of the steps in the main pathway through the hippocampal formation may be gated, not only by the presence or absence of some tonic (e.g. cholinergic) signal, but also by the temporal ordering of natural events. For example, there is depression of response to the second of two closely spaced tones [60] and there is phase precession of cell firing, relative to ongoing theta rhythm as the animal passes through a place field [68]. Given this array of postulated gates, it is of interest that septal inactivation (which can produce deficits in spatial tasks) disrupts CA3 place fields extensively, subicular and entorhinal place fields to some extent, but CA1 cell firing not at all (see Mizumori [108]). This pattern of results shows that the logical gates in the system are not simply sequential. Certain information (represented by place fields in this case) is sent directly to all levels of the system and then the operation of the various gates determines which levels (CA3, subiculum, etc.) of the system can produce functional output. There appears, then, to be a fairly complex set of logical gates which takes a relatively non-specific septal signal and combines it with a specific entorhinal/dentate signal and with cholinergic and aminergic input to determine the extent to which each stage of the trisynaptic pathway will be activated, and the extent to which such activation has functional consequences. Place fields, on this scenario, are recorded with both the dentate–CA3 and CA3–CA1 gates open. The effects of lesions on place fields sug-

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gest that septal input relates to the local presence of important stimuli (and hence rather gross response tendencies, consistent with the multimodality found in septal firing repertoires in the simpler single-unit recording paradigms); while entorhinal input, once processed in the dentate, provides more specific positional information (and hence relates to the more detailed organisation of response programs, consistent with the modalityspecific firing repertoires of entorhinal cells found in the simpler paradigms). We presume that CA3 activity is the result of the integration of dentate with septal input. Consistent with this assumption, as we go from dentate to CA3 [41] to CA1 and then subiculum [4,80], spatial specificity decreases implying generalisation. If the system were constructing a spatial map [67] one would, instead, expect a sharpening of such fields. 13. Gate interactions in the control of functional output If simple detection of conflict between alternative courses of action, independent of type, were the sole basis for hippocampal function, then perhaps direct input of information about those courses of action to the subiculum would be all that is required. However, both behavioural data and the general theory [36] require us to treat presentation of a punisher differently from presentation of a reward. The theory needs, in particular, to suppose that the omission of an expected punisher can produce, in the hippocampal circuitry and particularly in the subiculum, an effect equivalent to that of the occurrence of an expected reward, i.e. leaving the system in the “just checking” mode where it receives and processes input but produces no functional output. We propose that differing treatments are accorded to conflicts of different types as a result of the interaction of the series of gates between the different hippocampal subfields. The anatomy suggests that essentially the same neural messages, representing the animal’s current goals, can be sent to the subicular area both via all the steps in the hippocampal circuit and directly from the entorhinal cortex [86]. These inputs interact with the gates in the circuit in a way akin to the execution of logical functions (Fig. 7). In some cases, then, the subiculum will receive only a direct input from the entorhinal cortex, while in others it will receive parallel input both from the entorhinal cortex and, as a result of specific gates being open, from the hippocampus proper. Vinogradova’s basic comparator function (see above), then resides in the four synapses of the hippocampus proper (Fig. 7; [88]). The interaction of the gates habituates, or preserves from habituation (depending on the importance of the message), signals emanating from the entorhinal cortex and destined for the subicular area. The main purpose of this circuitry (we propose) is to filter information destined for the subiculum, so that the latter receives only those items of information which need to be assessed for conflict value. It passes on information about stimuli which are novel (i.e. for which there is no coincidence between septal and entorhinal input), but not those which are both familiar and lacking in behavioural significance [88]. However, if there is monoamine input, familiar stimuli are also passed on as they have been associated (by classical conditioning) with events of primary biological importance, or if they are of conflicting significance [78,79].

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Fig. 7. The gating of the hippocampal comparators and their output. This is discussed in detail by Gray and McNaughton. The key point is that different subcortical inputs (from the medial septum, MS; locus coeruleus, LC; or raphe) can interact with entorhinal input to allow or prevent subicular output and allow or prevent ouput from EC or CA3 depending on the importance and motivational quality of stimuli. From Gray and McNaughton [36].

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Note, that “passes on information” does not imply detail of the sort that might be required for, say, memory formation. Vinogradova’s experiments make it very clear that the information which is processed in CA3 is of a very non-specific kind. As she puts it “the neuronal reactions in CA3 do not code (and consequently cannot transmit) information about the quality of their sensory input. Their activity appears to be a strong generalized regulatory signal, which may possibly exert modulatory effects on the output structures” [88, p. 10]. The dentate–CA3 gate must work, therefore, in parallel with the direct pathway from the entorhinal area to the subiculum. Thus, specific information is sent continuously to the subiculum, but it only affects processing in the loops connecting the subiculum with other areas if it receives an “enabling signal” from CA1. This enabling signal is sent only in connection with combinations of inputs that signify conflict, otherwise they are filtered out during their passage through the dentate–CA3 gate. Thus, direct input from the entorhinal area to the subiculum describes the state of the world (at least in terms of available goals), while the input relayed via the other subfields of the hippocampus, utilising the gating capacities illustrated in Fig. 7, determines the precise kind of comparison which is carried out, depending on the way in which the stimuli are important to the animal. If one views the hippocampal circuits in this way, then the known effect upon them of monoamine inputs [36, Chapter 9] could be phrased in English as a tag stating “the current entorhinal input is important, it needs checking.” 14. The place of direct cortical inputs to subiculum The entorhinal area is probably the major funnel for cortical information arriving in the subiculum, and appears to be the only funnel for cortical information to other areas of the hippocampus in non-primates. However, in primates there are inputs to subiculum, as well as to other parts of the hippocampus proper, directly from prefrontal cortex, parietal cortex, temporal cortex and cingulate cortex. Such direct inputs could fulfill the same general functions as the information from those areas which is normally relayed by the entorhinal cortex. While our above argument, therefore, has been phrased in terms specifically of entorhinal cortex (and in the absence of much further data should continue to be so), it can be applied with no functional distortion to any route by which cortical information reaches the subiculum. In this context, we should note the type of information which arrives via the septum. We have already alluded to the fact that cellular responses in area CA3 are too broad to code for the external stimulus features of the world which the subiculum will require for conflict resolution. This problem is not so severe if we assume that the information is coded in rather general “goal” terms; but, even so, the pathways reaching the hippocampus via the septum are far too modest to code highly specific information of the type needed for conflict resolution. In the same way that we viewed CA3 as providing a general signal which then determines whether or not the subiculum processes information, it seems reasonable to suppose that the information arriving from the septum codes for quite general properties (perhaps simply “importance”, as indexed by intensity of activation), and

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that other routes provide specific information as to the nature of the goal giving rise to this alerting signal. This is in keeping with both the reticular origin of the septal information and the indiscriminate integration of activity apparently carried out by the theta-frequency-coding supramammillary nucleus [71]. Thus the input from the septum can be seen as classifying information as important in the same general way as do the monoamine inputs (a view consistent with the similar effects of acetylcholine, noradrenaline and 5HT on neuronal signal-tonoise ratios), but on a dimension of potential response intensity rather than the dimensions of response quality (determined by the nature of reinforcement) signalled by the monoamine inputs. 15. Conclusions Gray and McNaughton [36] link hippocampal function (often via subicular output) to what can seem a bewildering range of processes: behavioural inhibition, increased negative affective bias, exploration, risk assessment and various aspects of learning and memory. However, these processes are executed by large parts of the rest of the brain in response to hippocampal output. They are not executed within the hippocampal formation itself. In relation to Fig. 3, then, the subiculum is located firmly within the shaded box labelled hippocampal formation. It executes both of the primary outputs to goal processing areas shown in the figure. One is an inhibitory signal that blocks output from the area registering the presence of a goal (e.g. G1) and so prevents execution of the related motor programme (R1Sa). Second is a signal that alters processing of the sensory components (e.g. Sa) of goals. This increases attention and arousal and, in particular, it increases negative affective bias (altering the influence of Sa− but not Sa+). These two outputs can clearly be computationally simple, indeed modulatory, with the observed complexity of consequences determined by the relative reactions of the different target areas. (For any output to occur at least two goals must be concurrently registered by the hippocampal formation.) The effects of these outputs on subsequent memory and performance are indirect. Current changes in valence (represented by changes in activity) will produce plasticity through long-term potentiation and long-term depression in the target areas. (Hence the sometimes dramatic changes in the location of “place fields” when reinforcement contingencies change.) Such output signals might have no target specificity. However, the topographic mapping of hippocampal output and the specificity of, for example, place fields suggest that outputs are quite target specific. This specificity accounts for both exploration and risk assessment (that could be viewed as being simply released once more prepotent behaviours were inhibited) and for displacement activities (that would be directed to weak goals that are unmasked once stronger goals are specifically inhibited). It is also possible that the subicular area provides direct excitation to systems that control exploratory behaviour (locomotion, eye movements, vibrissal movements, etc.). This could occur via its projection to the cingulate cortex [59], which appears to control of a variety of innate motor programs, possibly originating in the striatum. Excitation of systems controlling exploratory behaviour could also occur via the subicular projection to the

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nucleus accumbens and thence to superior colliculus, the mesencephalic motor area and thalamocortical sensory pathways [35]. Exploration and risk assessment in the face of conflict are externally directed. They, and behavioural inhibition, could often be controlled by a simple linear system. However, the subicular and entorhinal conflict detectors are embedded in notable recursive loops [72–74]. Subicular output initiates recursive processing of stimuli in the environment and their associations in memory, particularly those that constitute or are closely related to the source of conflict. This can be viewed as an analysis that ranges over as many dimensions as possible (e.g. brightness, hue, position, size, relation to other stimuli, repetition rate, etc.). The dependencies between the animal’s responses and the results of its behaviour are subjected to a similar multidimensional analysis (e.g. a turn in a maze can be classified as left-going, white-approaching, etc.). As with the behavioural output discussed above, the apparent complexity of what has just been described at the psychological level does not require fundamentally complex computation by the subiculum. Rather, in a process akin [36, Chapter 1] to that which can solve the global stereopsis problem and separate an essentially hidden figure from a ground [20] the superficial complexity results from multiple recursive passes round the subicular loops. This iterative processing would occur in cycles held in register by the phases of theta activity. The processes postulated here have results similar to those of the relational theory of hippocampal function [11]. They also make up the process described by Kimble [43] as hypothesis generation and testing. The internal component of this recursive processing is particularly important since the origin of this view of the subiculum is a neural account of anxiolytic drug action. One way to think of it is that, when conflict is detected, the motor program that has just resulted in conflict and the stimuli associated with it (both those that were predicted to occur and those which actually occurred) are “replayed” by the loops which connect the subiculum to the areas representing the information. This allows enhanced analysis to commence immediately, essentially re-evaluating any existing affectively negative associations. If extended for any great length of time its effect on cognitive processing would constitute the rumination typical of anxiety. Consistent with this the effects of subicular lesions on water maze learning [65,76] are very similar to those of anxiolytic drugs [54,55].

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