John Aggleton | Cardiff University (original) (raw)

Papers by John Aggleton

Nature Reviews Neuroscience

Standard models of episodic memory focus on hippocampal-parahippocampal interactions, with the ne... more Standard models of episodic memory focus on hippocampal-parahippocampal interactions, with the neocortex supplying sensory information and providing a final repository of mnemonic representations. However, recent advances have shown that other regions make distinct and equally critical contributions to memory. In particular, there is growing evidence that the anterior thalamic nuclei have a number of key cognitive functions that contribute to episodic memory. In this article, we describe these findings and argue for a core, tripartite memory system, comprising a 'temporal lobe' stream (hippocampal centred) and a 'medial diencephalic' stream (anterior thalamic centred) that together act on shared cortical areas. We demonstrate how these distributed brain regions form complementary and necessary partnerships in episodic memory formation.

It has been proposed that the retrosplenial cortex forms part of a "where/when" informa... more It has been proposed that the retrosplenial cortex forms part of a "where/when" information network. The present study focussed on the related issue of whether retrosplenial cortex also contributes to "what/when" information, by examining object recency memory. In Experiment 1, rats with retrosplenial lesions were found to be impaired at distinguishing the temporal order of objects presented in a continuous series ('Within-Block' condition). The same lesioned rats could, however, distinguish between objects that had been previously presented in one of two discrete blocks ('Between-Block' condition). Experiment 2 used intact rats to map the expression of the immediate-early gene c-fos in retrosplenial cortex following performance of a between-block, recency discrimination. Recency performance correlated positively with levels of c-fos expression in both granular and dysgranular retrosplenial cortex (areas 29 and 30). Expression of c-fos in the granular retrosplenial cortex also correlated with prelimbic cortex and ventral subiculum c-fos activity, the latter also correlating with recency memory performance. The combined findings from both experiments reveal an involvement of the retrosplenial cortex in temporal order memory, which includes both between-block and within-block problems. The current findings also suggest that the rat retrosplenial cortex comprises one of a group of closely interlinked regions that enable recency memory, including the hippocampal formation, medial diencephalon, and medial frontal cortex. In view of the well-established importance of the retrosplenial cortex for spatial learning, the findings support the notion that, with its frontal and hippocampal connections, retrosplenial cortex has a key role for both what/when and where/when information.

Large-scale simultaneous in vivo recordings of neurons in multiple brain regions raises the quest... more Large-scale simultaneous in vivo recordings of neurons in multiple brain regions raises the question of the probability of recording direct interactions of neurons within, and between, multiple brain regions. In turn, identifying inter-regional communication rules between neurons during behavioural tasks might be possible, assuming conjoint activity between neurons in connected brain regions can be detected. Using the hypergeometric distribution, and employing anatomically-tractable connection mapping between regions, we derive a method to calculate the probability distribution of ‘recordable’ connections between groups of neurons. This mathematically-derived distribution is validated by Monte Carlo simulations of directed graphs representing the underlying anatomical connectivity structure. We apply this method to simulated graphs with multiple neurons, based on counts in rat brain regions, and to connection matrices from the Blue Brain model of the mouse neocortex connectome. Over...

Behavioral and Brain Sciences, 1994

The Journal of Neuroscience, 2000

Activity of the immediate early gene c-foswas compared across hemispheres in rats with unilateral... more Activity of the immediate early gene c-foswas compared across hemispheres in rats with unilateral fornix lesions. To engage Fos production, rats first performed a radial arm maze task that is severely disrupted by bilateral fornix lesions. Using immunohistochemical techniques, Fos-positive cells were visualized and counted in 39 sites in both hemispheres. Fornix lesions led to a significant reduction in Fos in all ipsilateral hippocampal subfields, as well as the entorhinal cortex and most of the subicular complex. Other sites that showed reduced activity included the ipsilateral retrosplenial, anterior cingulate, and postrhinal cortices. Subcortical regions showing significant Fos decreases included the anterior thalamic nuclei, supramammillary nucleus, diagonal band of Broca, and lateral septum. Thus, the effects of fornix lesions extended beyond the hippocampal formation and included sites not directly innervated by the tract. These changes were nevertheless selective, as shown b...

The European journal of neuroscience, Jan 8, 2016

The origins of the hippocampal (subicular) projections to the anterior thalamic nuclei and mammil... more The origins of the hippocampal (subicular) projections to the anterior thalamic nuclei and mammillary bodies were compared in rats and macaque monkeys using retrograde tracers. These projections form core components of Papez circuit, which is vital for normal memory. The study revealed a complex pattern of subicular efferents, consistent with the presence of different, parallel information streams, whose segregation appears more marked in the rat brain. In both species, the cells projecting to the mammillary bodies and anterior thalamic nuclei showed laminar separation, but also differed along other hippocampal axes. In the rat, these diencephalic inputs showed complementary topographies in the proximal-distal (columnar) plane, consistent with differential involvement in object-based (proximal subiculum) and context-based (distal subiculum) information. The medial mammillary inputs, which arose along the anterior-posterior extent of the rat subiculum, favoured the central subiculum ...

Frontiers in Behavioral Neuroscience, 2015

The retrosplenial cortex supports navigation, but there are good reasons to suppose that the retr... more The retrosplenial cortex supports navigation, but there are good reasons to suppose that the retrosplenial cortex has a very different role in spatial memory from that of the hippocampus and anterior thalamic nuclei. For example, retrosplenial lesions appear to have little or no effect on standard tests of spatial alternation. To examine these differences, the current study sought to determine whether the retrosplenial cortex is important for just one spatial cue type (e.g., allocentric, directional or intra-maze cues) or whether the retrosplenial cortex helps the animal switch between competing spatial strategies or competing cue types. Using T-maze alternation, retrosplenial lesion rats were challenged with situations in which the available spatial information between the sample and test phases was changed, so taxing the interaction between different cue types. Clear lesion deficits emerged when intra-and extra-maze cues were placed in conflict (by rotating the maze between the sample and choice phases), or when the animals were tested in the dark in a double-maze. Finally, temporary inactivation of the retrosplenial cortex by muscimol infusions resulted in a striking deficit on standard T-maze alternation, indicating that, over time, other sites may be able to compensate for the loss of the retrosplenial cortex. This pattern of results is consistent with the impoverished use of both allocentric and directional information, exacerbated by an impaired ability to switch between different cue types.

Hippocampus, 2012

The projections to the retrosplenial cortex (areas 29 and 30) from the hippocampal formation, the... more The projections to the retrosplenial cortex (areas 29 and 30) from the hippocampal formation, the entorhinal cortex, perirhinal cortex, and amygdala were examined in two species of macaque monkey by tracking the anterograde transport of amino acids. Hippocampal projections arose from the subiculum and presubiculum to terminate principally in area 29. Label was found in layer I and layer III(IV), the former seemingly reflecting both fibers of passage and termination. While the rostral subiculum mainly projects to the ventral retrosplenial cortex, mid and caudal levels of the subiculum have denser projections to both the caudal and dorsal retrosplenial cortex. Appreciable projections to dorsal area 30 [layer III(IV)] were only seen following an extensive injection involving both the caudal subiculum and presubiculum. This same case provided the only example of a light projection from the hippocampal formation to posterior cingulate area 23 (layer III). Anterograde label from the entor...

Hippocampus, 2000

A consideration of the cortical projections to the hippocampus provides a number of candidate reg... more A consideration of the cortical projections to the hippocampus provides a number of candidate regions that might provide distal sensory information needed for allocentric processing. Prominent among the input regions are the entorhinal cortex, the perirhinal cortex, the postrhinal cortex, and the retrosplenial cortex. A review of these sites reveals the surprising fact that in spite of their anatomical connections, removal of the perirhinal and postrhinal cortices has little or no effect on spatial tasks and hence does not functionally disconnect the hippocampus. Extensive retrosplenial lesions have only mild effects, and even lesions of the entorhinal cortex only partially mimic the effects of hippocampal lesions upon tests of spatial memory. In contrast, studies using c-fos imaging support the involvement of the entorhinal, postrhinal, and retrosplenial cortices, but not the perirhinal cortex. It is argued that there exist multiple aspects of spatial memory, and this is reflected in the multiple routes by which cortical information can reach the hippocampus. One consequence is that lesions in a single site often have surprisingly mild effects on standard spatial tests. Hippocampus 2000;10: 466-474.

Hippocampus, 2007

The distribution of neurons contributing to the fornix was mapped by placing the retrograde trace... more The distribution of neurons contributing to the fornix was mapped by placing the retrograde tracer horseradish peroxidase (HRP) in polyacrylamide gels in different medial to lateral locations within the fornix of three rhesus monkeys (Macaca mulatta). The HRP was placed from 3 to 5 mm caudal to the descending columns of the fornix. Additional information came from a series of rhesus and cynomolgus monkeys (Macaca fasciculata) with anterograde tracer injections in the medial temporal lobe. The hippocampal formation, including the subiculum and presubiculum, together with the entorhinal cortex (EC) and perirhinal cortex (area 35) contribute numerous axons to the fornix in a topographical manner. In contrast, the lateral perirhinal cortex (area 36) and parahippocampal cortical areas TF and TH only contained a handful of cells labeled via the fornix. The medial fornix originates from cells in the caudal half of the subiculum, the lamina principalis interna of the caudal half of the presubiculum, and from the perirhinal cortex (area 35). The intermediate portion of the fornix (i.e., that part midway between the midline and most lateral parts of the fornix) originates from cells in the rostral half of the subiculum and prosubiculum, the anterior presubiculum (only from the lamina principalis externa), the caudal presubiculum (primarily from lamina principalis interna), the rostral half of CA3, the EC (primarily 28I and 28M), and the perirhinal cortex (area 35). The lateral parts of the fornix arise from the rostral EC (28L only) and the most rostral portion of CA3. Subcortically, the medial septum, nucleus of the diagonal band, supramammillary nucleus, lateral hypothalamus, dorsal raphe nucleus, and the thalamic nucleus reuniens all send projections through the fornix, which presumably terminate in the hippocampus and adjacent parahippocampal region. These results not only help to define those regions that project via the fornix, but also reveal those subcortical projections to the hippocampal formation most likely to rely entirely on nonfornical pathways.

Neuroscience, 2011

Hippocampally-driven oscillatory activity at theta frequency is found in the diencephalon, but an... more Hippocampally-driven oscillatory activity at theta frequency is found in the diencephalon, but an understanding of the fundamental role of theta in the hippocampo-diencephalic circuit remains elusive. An important strategy in determining how activity modifies oscillatory properties of hippocampo-diencephalic circuitry comprises investigations of anterior thalamic responses to their main inputs: the descending dorsal fornix and the ascending mammillothalamic tract. Here, we show that the amplitude of thalamic theta spectral power selectively increases after plasticityinducing stimulation of the dorsal fornix, but not of the mammillothalamic tract in urethaneanaesthetized young male rats. Furthermore, we show that low-frequency stimulation (LFS) significantly augments the fornix-driven theta ratio (theta over delta power, T-ratio), in parallel with depressing thalamic synaptic responses. However, the mammillothalamic synaptic response after LFS did not correlate with the slow band of theta oscillation (low T-ratio), but did correlate positively with the fast band of theta oscillation (high T-ratio). Our data demonstrate that the descending direct fornix projection is a pathway that modulates theta rhythm in the hippocampodiencephalic circuit, resulting in dynamic augmentation of thalamic neuronal responsiveness. These findings suggest that hippocampal theta differentially affects synaptic integration in the different structures with which the hippocampus is reciprocally connected.

The Journal of Comparative Neurology, 2002

A combination of anterograde and retrograde tracing techniques was used to study the projections ... more A combination of anterograde and retrograde tracing techniques was used to study the projections to the nucleus accumbens from the amygdala, the hippocampal formation (including the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help identify possible subregions within the nucleus accumbens, the distribution of calbindin was examined in two additional monkeys. Although this revealed evidence of "core"-and "shell"-like regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the medial and the lateral portions of nucleus accumbens, whereas projections arising from the middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude topography as parts of the basal and accessory basal nuclei terminated in different parts of nucleus accumbens. The subiculum was the major source of hippocampal projections to the nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle. The entorhinal projections were more evenly distributed between the medial nucleus accumbens and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.

European Journal of Neuroscience, 2005

A combination of anterograde and retrograde tracers mapped the direct hippocampal and parahippoca... more A combination of anterograde and retrograde tracers mapped the direct hippocampal and parahippocampal inputs to the mammillary bodies in two species of macaque monkey. Dense projections arose from pyramidal cells in layer III of the subiculum and prosubiculum, and terminated in the medial mammillary nucleus. While there was no evidence of an input from the dentate gyrus or fields CA1–3, a small contribution arose from the presubiculum and entorhinal cortices. All of the hippocampal and parahippocampal projections to the mammillary bodies appeared to use the fornix as a route. The caudal portions of the subiculum and prosubiculum contained the greatest numbers of cells projecting to the mammillary bodies. A light contralateral projection to the medial mammillary nucleus was also observed, although this appeared to arise primarily from the more rostral portions of the subiculum and prosubiculum. There was a crude topography within the medial mammillary nucleus, with the caudal subicul...

European Journal of Neuroscience, 2007

Mammillary body neurons projecting to the thalamus were identified by injecting retrograde tracer... more Mammillary body neurons projecting to the thalamus were identified by injecting retrograde tracers into the medial thalamus of macaque monkeys. The source of the thalamic projections from the medial mammillary nucleus showed strikingly different patterns of organization depending on the site of the injection within the two anterior thalamic nuclei, anterior medialis and anterior ventralis. These data reveal at least two distinct modes by which the primate medial mammillary bodies can regulate anterior thalamic function. Projections to the thalamic nucleus anterior medialis arise mainly from the pars lateralis of the medial mammillary nucleus. A particularly dense source is the dorsal cap in the posterior half of the pars lateralis, a subregion that has not previously been distinguished. In contrast, neurons spread evenly across the medial mammillary nucleus gave rise to projections more laterally in the anterior thalamic nuclei. A third pattern of medial mammillary neurons appeared ...

Behavioral Neuroscience, 2002

Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory,... more Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory, the lesion data to date have been equivocal. Whether subjects are impaired after retrosplenial lesions seems to depend on whether the lesions were aspirative or excitotoxic, with the latter failing to produce an impairment. A shortcoming of previous excitotoxic lesion studies is that they spared the most caudal part of the retrosplenial cortex. The present study thus used rats with extensive neurotoxic lesions of the retrosplenial cortex that encompassed the entire rostrocaudal extent of this region. These rats were consistently impaired on several tests that tax allocentric memory. In contrast, they were unimpaired on an egocentric discrimination task. Although the lesions did not appear to affect object recognition, clear deficits were found for an object-in-place discrimination. The present study not only demonstrates a role for the retrosplenial cortex in allocentric spatial memory, but also explains why previous excitotoxic lesions have failed to detect any deficits.

European Journal of Neuroscience, 2010

This review charts recent advances from a variety of disciplines that create a new perspective on... more This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal–anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal–diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal–anterior thalamic systems for recollective rather than familiarity‐based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimu...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 8, 2015

The prefrontal cortex mediates adaption to changing environmental contingencies. The anterior tha... more The prefrontal cortex mediates adaption to changing environmental contingencies. The anterior thalamic nuclei, which are closely interconnected with the prefrontal cortex, are important for rodent spatial memory, but their potential role in executive function has received scant attention. The current study examined whether the anterior thalamic nuclei are involved in attentional processes akin to those of prefrontal regions. Remarkably, the results repeatedly revealed attentional properties opposite to those of the prefrontal cortex. Two separate cohorts of rats with anterior thalamic lesions were tested on an attentional set-shifting paradigm that measures not only the ability of stimuli dimensions that reliably predict reinforcement to gain attention ("intradimensional shift"), but also their ability to shift attention to another stimulus dimension when contingencies change ("extradimensional shift"). In stark contrast to the effects of prefrontal damage, anter...

In this chapter, we review data from appetitive conditioning studies using measures of pavlovian ... more In this chapter, we review data from appetitive conditioning studies using measures of pavlovian approach behaviour and of the effects of pavlovian conditioned stimuli on instrumental behaviour, including the pavlovian-to-instrumental transfer effect and conditioned reinforcement. These studies consistently demonstrate double dissociations of function between the basolateral area and the central nucleus of the amygdala. Moreover, these data show marked parallels with data derived from studies of aversive (fear) conditioning, and are consistent with the idea that these subsystems of the amygdala use different associative representations formed during conditioning, as part of a larger limbic cortico-striatal circuit. We suggest that the basolateral amygdala is required for a conditioned stimulus to gain access to the current value of its specific unconditioned stimulus, while the central nucleus is responsible for conditioned motivational responses using a simpler stimulus-response representation. Though these systems normally operate together, they modulate ongoing behaviour in distinct ways. We illustrate this by considering the contributions of both systems to the process of drug addiction, using second-order schedules of intravenous drug self-administration. Neural network underlying conditioned reinforcement and its potentiation by psychomotor stimulants CeN Appetitive CS VTA

Frontiers in Systems Neuroscience, 2013

The anterior thalamic nuclei (ATN), a central component of Papez' circuit, are generally assumed ... more The anterior thalamic nuclei (ATN), a central component of Papez' circuit, are generally assumed to be key constituents of the neural circuits responsible for certain categories of learning and memory. Supporting evidence for this contention is that damage to either of two brain regions, the medial temporal lobe and the medial diencephalon, is most consistently associated with anterograde amnesia. Within these respective regions, the hippocampal formation and the ATN (anteromedial, anteroventral, and anterodorsal) are the particular structures of interest. The extensive direct and indirect hippocampal-anterior thalamic interconnections and the presence of theta-modulated cells in both sites further support the hypothesis that these structures constitute a neuronal network crucial for memory and cognition. The major tool in understanding how the brain processes information is the analysis of neuronal output at each hierarchical level along the pathway of signal propagation coupled with neuroanatomical studies. Here, we discuss the electrophysiological properties of cells in the ATN with an emphasis on their role in spatial navigation. In addition, we describe neuroanatomical and functional relationships between the ATN and hippocampal formation.