Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory

Odour Discrimination

The anterior thalamic nuclei (ATN), a central node in a complex memory system, process spatial and temporal memory. Here, we show that ATN lesions do not affect acquisition of a simple odour discrimination or a simple object discrimination in a runway apparatus. The same procedures were used to test learning of an arbitrary association between non-spatial object-odour pairings (A+X or B+Y were rewarded; but not A+Y or B+X). If ATN lesions recapitulate hippocampal function, specifically CA1 function, then they should disrupt acquisition only when an explicit delay (i.e., a 10-second trace) is inserted between the odour and object. Acquisition was completely abolished by ATN lesions, irrespective of the presence of the temporal trace, and despite extensive training (50x12-trial sessions). Faster acquisition with the 10-second trace was found in the sham-lesion rats. During recall, 5 days after criterion, sham rats but not ATN-lesion rats showed elevated Zif268 expression in hippocampal CA1 for the trace compared to no-trace condition; both sham and lesion rats tested in the trace condition showed increased IEG expression in the superficial layers of the prefrontal cortex and retrosplenial cortex. ATN lesions markedly reduced Zif268 expression in the prefrontal cortex and retrosplenial cortex. This is the first evidence that ATN lesions impair non-spatial paired-associate tasks. The findings suggest that the ATN influence memory beyond time and space, and constitute a critical neural structure for learning arbitrary associations even in the task version that is not disrupted by hippocampal lesions.

Hippocampal–diencephalic–cingulate networks for memory and emotion: An anatomical guide

Brain and Neuroscience Advances ◽

10.1177/2398212817723443 ◽

2017 ◽

Vol 1 ◽

pp. 239821281772344 ◽

Cited By ~ 64

Author(s):

Emma J. Bubb ◽

Lisa Kinnavane ◽

John P. Aggleton

Keyword(s):

Prefrontal Cortex ◽

Medial Temporal Lobe ◽

Current Knowledge ◽

Hippocampal Formation ◽

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

Mammillary Bodies ◽

Individual Site ◽

Multi Stage ◽

This review brings together current knowledge from tract tracing studies to update and reconsider those limbic connections initially highlighted by Papez for their presumed role in emotion. These connections link hippocampal and parahippocampal regions with the mammillary bodies, the anterior thalamic nuclei, and the cingulate gyrus, all structures now strongly implicated in memory functions. An additional goal of this review is to describe the routes taken by the various connections within this network. The original descriptions of these limbic connections saw their interconnecting pathways forming a serial circuit that began and finished in the hippocampal formation. It is now clear that with the exception of the mammillary bodies, these various sites are multiply interconnected with each other, including many reciprocal connections. In addition, these same connections are topographically organised, creating further subsystems. This complex pattern of connectivity helps explain the difficulty of interpreting the functional outcome of damage to any individual site within the network. For these same reasons, Papez’s initial concept of a loop beginning and ending in the hippocampal formation needs to be seen as a much more complex system of hippocampal–diencephalic–cingulate connections. The functions of these multiple interactions might be better viewed as principally providing efferent information from the posterior medial temporal lobe. Both a subcortical diencephalic route (via the fornix) and a cortical cingulate route (via retrosplenial cortex) can be distinguished. These routes provide indirect pathways for hippocampal interactions with prefrontal cortex, with the preponderance of both sets of connections arising from the more posterior hippocampal regions. These multi-stage connections complement the direct hippocampal projections to prefrontal cortex, which principally arise from the anterior hippocampus, thereby creating longitudinal functional differences along the anterior–posterior plane of the hippocampus.

Organization of projections of rat retrosplenial cortex to the anterior thalamic nuclei

European Journal of Neuroscience ◽

10.1046/j.1460-9568.1998.00328.x ◽

1998 ◽

Vol 10 (10) ◽

pp. 3210-3219 ◽

Cited By ~ 49

Author(s):

Hideshi Shibata

Keyword(s):

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons

10.1101/427179 ◽

2018 ◽

Cited By ~ 3

Author(s):

Naoki Yamawaki ◽

Xiaojian Li ◽

Laurie Lambot ◽

Lynn Y. Ren ◽

Jelena Radulovic ◽

...

Keyword(s):

Long Range ◽

Pyramidal Neurons ◽

Dorsal Hippocampus ◽

Retrosplenial Cortex ◽

Molecular Profile ◽

Thalamic Nuclei ◽

Cellular Mechanisms ◽

Ca1 Neurons ◽

Apical Tuft ◽

AbstractDorsal hippocampus, retrosplenial cortex (RSC), and anterior thalamic nuclei (ATN) interact to mediate diverse cognitive functions, but the cellular basis for these interactions is unclear. We hypothesized a long-range circuit converging in layer 1 (L1) of RSC, based on the pathway anatomy of GABAergic CA1 retrosplenial-projecting (CA1-RP) neurons and thalamo-restrosplenial projections from ATN. We find that CA1→RSC projections stem from GABAergic neurons with a distinct morphology, electrophysiology, and molecular profile, likely corresponding to recently described Ntng1-expressing hippocampal interneurons. CA1-RP neurons monosynaptically inhibit L5 pyramidal neurons, principal outputs of RSC, via potent GABAergic synapses onto apical tuft dendrites in L1. These inhibitory inputs align precisely with L1-targeting thalamocortical excitatory inputs from ATN, particularly the anteroventral nucleus, forming a convergent circuit whereby CA1 inhibition can intercept ATN excitation to co-regulate RSC activity. Excitatory axons from subiculum, in contrast, innervate proximal dendrites in deeper layers. Short-term synaptic plasticity differs at each connection. Chemogenetically abrogating inhibitory CA1→RSC or excitatory ATN→RSC connections oppositely affects the encoding of contextual fear memory. Collectively, our findings identify multiple cellular mechanisms underlying hippocampo-thalamo-retrosplenial interactions, establishing CA1 RSC-projecting neurons as a distinct class with long-range axons that target apical tuft dendrites, and delineating an unusual cortical circuit in the RSC specialized for integrating long-range inhibition and thalamocortical excitation.

EPS Mid-Career Award 2006: Understanding anterograde amnesia: Disconnections and hidden lesions

Quarterly Journal of Experimental Psychology ◽

10.1080/17470210802215335 ◽

2008 ◽

Vol 61 (10) ◽

pp. 1441-1471 ◽

Cited By ~ 71

Author(s):

John P. Aggleton

Keyword(s):

Anterograde Amnesia ◽

Functional System ◽

Brain Regions ◽

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

Neural Basis ◽

Lesion Effect ◽

Colloid Cysts ◽

The Many

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesia associated with damage to the diencephalon. First, new anatomical studies have refined our understanding of the links between diencephalic and temporal brain regions associated with amnesia. These studies direct attention to the limited numbers of routes linking the two regions. Second, neuropsychological studies of patients with colloid cysts confirm the importance of at least one of these routes, the fornix, for episodic memory. By combining these anatomical and neuropsychological data strong evidence emerges for the view that damage to hippocampal—mammillary body—anterior thalamic interactions is sufficient to induce amnesia. A third development is the possibility that the retrosplenial cortex provides an integrating link in this functional system. Furthermore, recent evidence indicates that the retrosplenial cortex may suffer “covert” pathology (i.e., it is functionally lesioned) following damage to the anterior thalamic nuclei or hippocampus. This shared indirect “lesion” effect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia but may also help to explain the many similarities between temporal lobe and diencephalic amnesia.

Thanks for the memories: Extending the hippocampal-diencephalic mnemonic system

Behavioral and Brain Sciences ◽

10.1017/s0140525x99482032 ◽

1999 ◽

Vol 22 (3) ◽

pp. 471-479 ◽

Cited By ~ 2

Author(s):

John P. Aggleton ◽

Malcolm W. Brown

Keyword(s):

Prefrontal Cortex ◽

Recognition Memory ◽

Episodic Memory ◽

Temporal Lobe ◽

Thalamic Nuclei ◽

Target Article ◽

Relationship Of ◽

The Relationship ◽

Key Questions

The goal of our target article was to review a number of emerging facts about the effects of limbic damage on memory in humans and animals, and about divisions within recognition memory in humans. We then argued that this information can be synthesized to produce a new view of the substrates of episodic memory. The key pathway in this system is from the hippocampus to the anterior thalamic nuclei. There seems to be a general agreement that the importance of this pathway has previously been underestimated and that it warrants further study. At the same time, a number of key questions remain. These concern the relationship of this system to another temporal-lobe/diencephalic system that contributes to recognition, and the relationship of these systems to prefrontal cortex activity.

Anterior thalamic nuclei, but not retrosplenial cortex, lesions abolish latent inhibition in rats.

Behavioral Neuroscience ◽

10.1037/bne0000265 ◽

2018 ◽

Vol 132 (5) ◽

pp. 378-387 ◽

Cited By ~ 3

Author(s):

Andrew J. D. Nelson ◽

Anna L. Powell ◽

Lisa Kinnavane ◽

John P. Aggleton

Keyword(s):

Latent Inhibition ◽

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

BIFURCATING NEURONS IN THE ANTERIOR THALAMIC NUCLEI

10.1101/2021.08.21.457238 ◽

2021 ◽

Author(s):

Y Pei ◽

S (Yee T) Tasananukorn ◽

M Wolff ◽

JC Dalrymple-Alford

Keyword(s):

Hippocampal Formation ◽

Nodal Point ◽

Primary Source ◽

Brain Structures ◽

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

Neural Ensembles ◽

Multiple Structures ◽

New Perspective

AbstractThe anterior thalamic nuclei (ATN) form a nodal point within a hippocampal-cingulate-diencephalic memory system. ATN projections to different brain structures are conventionally viewed as distinct, but ATN neurons may send collaterals to multiple structures. The anteromedial subregion (AM) is the primary source of efferents to the medial prefrontal cortex (mPFC). Using a dual-retrograde neurotracer strategy, we discovered bifurcating AM neurons for tracers placed in the mPFC when paired with other regions. A semi-quantitative analysis found a high proportion of AM neurons (~36%) showed collateral projections when the mPFC was paired with dorsal subiculum (dSub); 20% were evident for mPFC paired with caudal retrosplenial cortex (cRSC); and 6% was found for mPFC and ventral hippocampal formation (vHF). About 10% of bifurcating AM neurons was also identified when the mPFC was not included, that is, for cRSC with dSub, and cRSC with vHF. Similar percentages of bifurcating neurons were also found within the anterior region of the adjacent nucleus reuniens (Re). The high frequency of bifurcating neurons suggests a new perspective for ATN function. These neurons would facilitate direct coordination among distal neural ensembles to support episodic memory and may explain why the ATN is a critical region for diencephalic amnesia.

Afferent Projections to Area Prostriata of the Mouse

Frontiers in Neuroanatomy ◽

10.3389/fnana.2020.605021 ◽

2020 ◽

Vol 14 ◽

Author(s):

Jin-Meng Hu ◽

Chang-Hui Chen ◽

Sheng-Qiang Chen ◽

Song-Lin Ding

Keyword(s):

Visual Information ◽

Retrosplenial Cortex ◽

Anterior Cingulate ◽

Thalamic Nuclei ◽

Unique Region ◽

Fast Detection ◽

Afferent Projections ◽

Cells Of Origin ◽

Auditory Cortices

Area prostriata plays important roles in fast detection and analysis of peripheral visual information. It remains unclear whether the prostriata directly receives and integrates information from other modalities. To gain insight into this issue, we investigated brain-wide afferent projections to mouse prostriata. We find convergent projections to layer 1 of the prostriata from primary and association visual and auditory cortices; retrosplenial, lateral entorhinal, and anterior cingulate cortices; subiculum; presubiculum; and anterior thalamic nuclei. Innervation of layers 2–3 of the prostriata mainly originates from the presubiculum (including postsubiculum) and anterior midline thalamic region. Layer 5 of the prostriata mainly receives its inputs from medial entorhinal, granular retrosplenial, and medial orbitofrontal cortices and anteromedial thalamic nucleus while layer 6 gets its major inputs from ectorhinal, postrhinal, and agranular retrosplenial cortices. The claustrum, locus coeruleus, and basal forebrain provide relatively diffuse innervation to the prostriata. Moreover, Cre-dependent tracing in cortical areas reveals that the cells of origin of the prostriata inputs are located in layers 2–4 and 5 of the neocortical areas, layers 2 and 5 of the medial entorhinal cortex, and layer 5 of the retrosplenial cortex. These results indicate that the prostriata is a unique region where primary and association visual and auditory inputs directly integrate with many limbic inputs.

Multiplexed code of navigation variables in anterior limbic areas

10.1101/684464 ◽

2019 ◽

Author(s):

Jean Laurens ◽

Amada Abrego ◽

Henry Cham ◽

Briana Popeney ◽

Yan Yu ◽

...

Keyword(s):

Navigation System ◽

Neural Coding ◽

Hippocampal Neurons ◽

Large Fraction ◽

Retrosplenial Cortex ◽

Field Analysis ◽

Head Direction ◽

Thalamic Nuclei ◽

Anterior Thalamus ◽

AbstractThe brain’s navigation system integrates multimodal cues to create a sense of position and orientation. Here we used a multimodal model to systematically assess how neurons in the anterior thalamic nuclei, retrosplenial cortex and anterior hippocampus of mice, as well as in the cingulum fiber bundle and the white matter regions surrounding the hippocampus, encode an array of navigational variables when animals forage in a circular arena. In addition to coding head direction, we found that some thalamic cells encode the animal’s allocentric position, similar to place cells. We also found that a large fraction of retrosplenial neurons, as well as some hippocampal neurons, encode the egocentric position of the arena’s boundary. We compared the multimodal model to traditional methods of head direction tuning and place field analysis, and found that the latter were inapplicable to multimodal regions such as the anterior thalamus and retrosplenial cortex. Our results draw a new picture of the signals carried and outputted by the anterior thalamus and retrosplenial cortex, offer new insights on navigational variables represented in the hippocampus and its vicinity, and emphasize the importance of using multimodal models to investigate neural coding throughout the navigation system.

Lesions of retrosplenial cortex spare immediate-early gene activity in related limbic regions in the rat

Brain and Neuroscience Advances ◽

10.1177/2398212818811235 ◽

2018 ◽

Vol 2 ◽

pp. 239821281881123 ◽

Cited By ~ 1

Author(s):

Anna L Powell ◽

Emma Hindley ◽

Andrew JD Nelson ◽

Moira Davies ◽

Eman Amin ◽

...

Keyword(s):

Cell Loss ◽

Immediate Early Gene ◽

Retrosplenial Cortex ◽

Anterior Cingulate ◽

Early Gene ◽

Immediate Early ◽

Tissue Loss ◽

Thalamic Nuclei ◽

Subcortical Structures ◽

The retrosplenial cortex forms part of a network of cortical and subcortical structures that have particular importance for spatial learning and navigation in rodents. This study examined how retrosplenial lesions affect activity in this network by visualising the expression of the immediate-early genes c- fos and zif268 after exposure to a novel location. Groups of rats with extensive cytotoxic lesions (areas 29 and 30) and rats with lesions largely confined to area 30 (dysgranular cortex) were compared with their respective control animals for levels of c- fos expression measured by immunohistochemistry. These cortical lesions had very limited effects on distal c- fos activity. Evidence of a restricted reduction in c-fos activity was seen in the septal dentate gyrus (superior blade) but not in other hippocampal and parahippocampal subareas, nor in the anterior cingulate and prelimbic cortices. Related studies examined zif268 activity in those cases with combined area 29 and 30 lesions. The only clear evidence for reduced zif268 activity following retrosplenial cell loss came from the septal CA3 area. The confined impact of retrosplenial tissue loss is notable as, by the same immediate-early gene measures, retrosplenial cortex is itself highly sensitive to damage in related limbic areas, showing a marked c- fos and zif268 hypoactivity across all of its subareas. This asymmetry in covert pathology may help to explain the apparent disparity between the severity of learning deficits after retrosplenial cortex lesions and after lesions in either the hippocampus or the anterior thalamic nuclei.