Edited by: Yuri B. Saalmann, Princeton University, USA
Reviewed by: José M. Delgado-García, University Pablo de Olavide, Seville, Spain; Ysbrand Van Der Werf, Netherlands Institute for Neuroscience, Netherlands
*Correspondence: Anna S. Mitchell, Department of Experimental Psychology, Oxford University, South Parks Road, Oxford, OX1 3UD, UK e-mail:
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dense amnesia can result from damage to the medial diencephalon in humans and in animals. In humans this damage is diffuse and can include the mediodorsal nuclei of the thalamus. In animal models, lesion studies have confirmed the mediodorsal thalamus (MD) has a role in memory and other cognitive tasks, although the extent of deficits is mixed. Anatomical tracing studies confirm at least three different subgroupings of the MD: medial, central, and lateral, each differentially interconnected to the prefrontal cortex (PFC). Moreover, these subgroupings of the MD also receive differing inputs from other brain structures, including the basal ganglia thus the MD subgroupings form key nodes in interconnected frontal-striatal-thalamic neural circuits, integrating critical information within the PFC. We will provide a review of data collected from non-human primates and rodents after selective brain injury to the whole of the MD as well as these subgroupings to highlight the extent of deficits in various cognitive tasks. This research highlights the neural basis of memory and cognitive deficits associated with the subgroupings of the MD and their interconnected neural networks. The evidence shows that the MD plays a critical role in many varied cognitive processes. In addition, the MD is actively processing information and integrating it across these neural circuits for successful cognition. Having established that the MD is critical for memory and cognition, further research is required to understand how the MD specifically influences these cognitive processing carried out by the brain.
It is now more widely recognized that the episodic memory processes disrupted in anterograde amnesia involve interactions between the medial temporal lobes and the medial diencephalon (Aggleton and Brown,
Animal models of diencephalic amnesia are critical in helping to determine the structures that are important for memory and other cognitive processes as well as understanding the neural circuitry of this region. The emphasis of this review is on the experiments in animal models (monkeys and rodents mainly) that assess the role of the MD in memory and other cognitive processes. The review will show how this research can extend our understanding about the functions of the MD that when damaged cause some of the symptoms of the human amnesic syndrome. There is also a section on anatomy of the MD and its interconnections with other brain structures: detailing the communication within these regions is critical for understanding their overall functioning. It is important to remember that lesion studies do not show what the area of the brain that has been lesioned does, rather they show how the rest of the brain functions and compensates after brain injury to a particular region has occurred. Furthermore, we know that a single region of the brain does not act alone. Thus, the brain structures of the medial thalamus are interconnected with other brain structures, together forming integrated neural networks of cognition. The review concludes with an overview of some of the theories of MD involvement in cognition and memory, current perspectives and possible future directions to investigate.
It is an exciting time to be studying the medial thalamus and its role in cognitive processing as the work of many is challenging the long held beliefs that the thalamus is only passively relaying information from the basal ganglia, midbrain and brainstem onto the prefrontal cortex (PFC). For example, more recent neuroanatomical and neuromodulatory studies highlight how the thalamus is providing a critical role in integrating communication between the basal ganglia, thalamus, and cortex, which is challenging many long standing theoretical ideas related to the passive role of the thalamus (Haber and McFarland,
In addition, with advances in neuroimaging and its analyses, and different electrophysiology techniques that can help investigate functional and anatomical connectivity, the medial thalamus and specifically the MD has now been shown to influence many cognitive processes including memory, decision-making, and executive functions with comparative data across numerous species. The MD is also a critical structure linked to many neurological disorders (e.g., stroke, dementia, schizophrenia, major depressive disorder, Parkinson's disease, and Alzheimer's disease). Clearly, further research is needed on the MD to develop greater understanding of the neural mechanisms of its functioning and how it contributes to many neurological disorders.
Many of the structures in the brain can go by several names and this is the case with the MD, which is also referred to as medial dorsal thalamic nuclei, nucleus medialis dorsalis, and the dorsomedial thalamus. For the purposes of this review, the structure will be referred to as the mediodorsal thalamus (MD) and at some points will be distinguished by some of its subdivisions, that is, the magnocellular mediodorsal thalamus (MDmc) or medial MD, the parvocellular mediodorsal thalamus (MDpc) or central MD, and a lateral grouping that will include the densocellular (MDdc) and pars multiforms (MDmf) mediodorsal thalamic nuclei or lateral MD (MDl).
The MD is considered the largest of the nuclear structures in the medial thalamus, and it is most developed in primates, especially humans. The increase in the size of the MD in phylogenetic evolution parallels that of prefrontal, association and cingulate cortices (Bentivoglio et al.,
In rodents and non-human primates, there are substantial reciprocal interconnections between the PFC and the MD (Krettek and Price,
The major outputs of the MD are to the medial and lateral prefrontal and orbital frontal (OFC) cortices, and in some neuroanatomical tracing studies in rats, the medial PFC is said to be defined by the projections received from the MD nucleus (Groenewegen,
In non-human primates there are connections from the association cortex of the temporal lobes [i.e., the entorhinal (ERh) and perirhinal (PRh) cortices] to the MDmc (see Figure
There are also amygdala (Amyg) projections to the MD (see Figure
In contrast, the central MDpc and more lateral parts of the MD (see Figures
Some of the thalamic projections to the PFC represent in many instances the final link in fronto-striatal-thalamic circuits (Alexander et al.,
From the brainstem in the rat, the locus coeruleus projects to all segments of the MD (Groenewegen,
The MDpc and MDl receive non-dopaminergic projections from the ventral tegmental area (VTA) and SNr (Groenewegen et al.,
A significant amount of thalamic neuromodulatory input is also received from the basal forebrain. Amongst many studies it is reported that the largest amount of basal forebrain inputs reaching the medial thalamus terminate in the reticular nucleus, with moderate terminal fields in the MDmc and sparse terminals in other sites (Hallanger et al.,
Based on these differences in cortical-subcortical connectivity patterns among the MD, PFC, MTL, and basal ganglia, at least three separate MD thalamic neural circuits can be identified: a medial subdivision, including some of the midline nuclei and the MDmc, reciprocally connected to the OFC and vmPFC with further inputs from the VLPFC, rhinal cortex, amygdala, VS, and VP (Mitchell and Dalrymple-Alford,
Studying memory and cognition with animal models is extremely insightful, in addition to being a useful way to overcome some of the limitations that are inherent in the clinical evidence. There are many advantages to developing animal models of memory processing. Surgical lesions in animals can normally be somewhat more circumscribed and involve subtotal, complete or even contra-lateral neuronal damage to connected structures. These planned lesions, if produced with a high degree of selectivity to the target structures of interest, can encourage a greater certainty about identifying the critical locus and also the particular kinds of memory deficits than are evident in comparative human cases. In addition, direct comparisons are possible between control and lesion animals, within pre- vs. post-operative testing or between subtotal lesions to one structure vs. another nearby structure.
Despite the benefits of experimental thalamic lesions, animal studies have, like the clinical evidence, also encountered difficulties and produced conflicting findings. This has resulted from the use of different techniques to create lesions in the MD, differences in the size and location of these lesions, and the extent of atrophy to surrounding target structures due to the inherent complexity of the medial and “non-specific” regions of the thalamus. Fortunately, the extent of brain damage in the medial thalamus has been minimized more recently by using neurotoxins that produce selective lesions to the individual structures that make up the medial diencephalon in animals. Thus, recent studies in rodents and non-human primates with very selective lesions to the mediodorsal thalamus using neurotoxins have been most insightful (Chudasama et al.,
Standardization of memory tasks and testing procedures for animals has also met with difficulties. Interpreting findings across studies and species can be problematic. Nevertheless, it is widely accepted that some cognitive tests provide adequate measures of animal memory that are analogous to human episodic recall tasks (Aggleton and Pearce,
Earlier work in animals focused on determining the one critical structure within the medial thalamus that was causing the memory deficits associated with thalamic amnesia. As mentioned, there are many candidates within the medial thalamus to fulfill this critical role. Neuropathological evidence reported in clinical cases of Wernicke-Korsakoff's syndrome supported a role for the MD in memory (Victor et al.,
Moreau et al., |
Lateral MD + ILn rats: NMDA | Spatial water maze | Post-op | No | |
Visual water maze | No | ||||
Cross et al., |
MD rats: NMDA | Single item recognition | Post-op | 5 m, 3 h | No |
Spatial location | 5 m, 3 h | No | |||
Object-in-place | 5 m, 3 h | Yes | |||
Recency memory | 3 h | yes | |||
Izquierdo and Murray, |
MDmc +Amyg + OFC macaques: NMDA | Reward devaluation | Post-op | Yes, neural circuitry important for reward based decision making | |
Chauveau et al., |
MD mice: ibotenic | Contextual serial discrimin | Post-op | 24 h | With no stress MD only mildly impaired, with stress condition MD substantially impaired |
Retention with stress variable | |||||
Dolleman-van der Weel et al., |
MD rats: NMDA | Morris water maze | Post-op | Transient deficit only | |
Some impairments with strategy shifting | |||||
Lopez et al., |
Morris water maze | Post-op | No acquisition deficits, impaired in remote (25d) but not recent (5d) retrieval of correct quadrant | ||
Mitchell et al., |
MDmc + Fx macaques: NMDA/ibotenic + ablation | 300 OIP discriminations | Pre-op | Yes | |
100 OIP discriminations | Post-op | Yes, combined lesions produced substantial new learning impairments | |||
Mitchell and Gaffan, |
MDmc macaques: NMDA/Ibotenic | 300 OIP discriminations | Pre-op | No | |
100 OIP discriminations | Post-op | Yes, new learning impairments | |||
Ostlund and Balleine, |
MD rats: NMDA | Instrumental conditioning | Pre-op | Yes, disrupted influence of Pavlovian cues over action selection, no impact on selection of actions based on expected value | |
Pickens, |
MD rats: NMDA | Pavlovian devaluation | Post-op | Impaired when switching from Pavlovian to operant contingencies but not when switching from one reinforcer to multiple reinforcer conditions | |
Operant devaluation | Post-op | ||||
One vs. multiple reinforcers | |||||
Wolff et al., |
Lateral MD + ILn Rats: NMDA | Allocentric spatial water maze | Post-op | No | |
Egocentric spatial Y water maze | No | ||||
Block et al., |
MD rats: | Task set shifting T-maze | No, only impaired on new learning of strategies | ||
Mitchell et al., |
MDmc macaques: NMDA/ibotenic | Strategy implementation | Pre-op | No | |
OIP association | Pre-op | Yes, new objects-in-place post-op | |||
Mitchell et al., |
MDmc macaques: NMDA/ibotenic | Reward devaluation | Post-op | Yes | |
Gibb et al., |
Lateral MD + ILn | Odor-place associations Odor discriminations | Post-op | Yes | |
Rats: NMDA | No | ||||
Place discriminations | No | ||||
Mitchell and Dalrymple-Alford, |
Lateral MD + ILn | Egocentric responding X-maze 8 arm radial maze | Pre-op | Impaired at matching body turn after delay | |
rats: NMDA | Post-op | ||||
No | |||||
Chauveau et al., |
MD mice: ibotenic | Sequential alt | Post-op | 5–30 s | Only impaired when delays mixed (30-5) |
Go/ No-go temporal alt | 0–30 s | ||||
Impaired | |||||
Mitchell and Dalrymple-Alford, |
Medial MD; lateral MD + ILn | Radial maze | Post-op | 2 h | No |
Go/No-go devaluation | Post-op | Yes, MDmc | |||
rats: NMDA | Single item (SOR) | Post-op | No | ||
Recency memory (TOM) | Post-op | Yes, MDmc and MDpc+ILn | |||
Ridley et al., |
MD + IT marmosets: NMDA + ablation | Spatiovisual conditioning | Pre-op | Unilateral MD not impaired in retention. Combined crossed lesions caused mild impairments | |
Visuospatial conditioning retention and learning | Post-op | ||||
Corbit et al., |
MD rats: NMDA | Instrumental conditioning | Post-op | MD acquired conditioning then deficits in selective devaluation effect during extinction | |
Devaluation extinction tests | |||||
Ridley et al., |
MD+AT marmosets: NMDA | Visuospatial conditional task | Pre-op | Combined MD+AT impaired in retention but separate MD or AT lesions were not | |
Visuovisual conditional | Post-op | ||||
Concurrent discriminations | |||||
No | |||||
No | |||||
Alexinsky, |
MD rats: ibotenic, excision | 3/8 baited radial maze | Pre-op | MD = less correct visits only; | |
New Route—Pre-exp- Y/N | Pre-exposure –Y = MD deficits; | ||||
Contextual light change | |||||
MD adapted | |||||
Chudasama et al., |
MD rats: NMDA | Visual discriminations and reversals with touch-screen | Pre-op | MD = impaired at reversal of all three visual discriminations | |
Post-op | |||||
Gaffan and Parker, |
MDmc macaques: aspiration | Visual scene memory | Pre-op | Yes | |
Object-reward associations | Pre-op | Retention = No | |||
New Post-op Learning = Yes | |||||
Floresco et al., |
MD rats: bilateral lidocaine infusion | Delayed radial maze | Post-op | 30 min | Pre-test infusion severe deficits. |
Non delayed random foraging radial maze | Post-op | ||||
Not impaired. | |||||
Delayed radial maze and Pre-test infusion only | Post-op | 30 min | MD/N Acc. not impaired. A PL/N Acc. group were also impaired | ||
Kornecook et al., |
MD rats: electrode | Visual object discrimination | Pre-op | No deficits on retention of discriminations learnt pre-op up to 58 days prior to surgery | |
Post-op | |||||
No | |||||
Zhang et al., |
MD rats: NMDA | Go/no-go DNMTS odors | Pre-op | 4–20 s | MD mild and transient deficits; |
Olfactory discrimination | |||||
No | |||||
Burk and Mair, |
MD rats: NMDA | Place DMTS, operant boxes | Pre-op | 1–13 s | No |
Serial reversal learning | Post-op | No | |||
Hunt and Aggleton, |
MD rats: NMDA | Standard radial maze | Post-op | 60 s | No |
Radial maze (45° rotation) | Post-op | 60 s | Yes | ||
T-maze Alt | 10 s | No | |||
8-arm radial maze | 15, 60 min | Yes, exacerbated by AT damage | |||
SOR | |||||
No | |||||
Hunt and Aggleton, |
MD rats: NMDA | 8-arm radial maze CCP | Post-op | 10–40 s | No |
Exploratory Activity | No | ||||
T-Maze MTP | Yes, slower to acquired task but no delay deficits | ||||
T-Maze Reversal | No, MD more perseverative errors than controls | ||||
Parker et al., |
MD macaques: ablations | DMTS | Pre-op | 0–30 s | Yes for large stimulus set size but not small set size |
Concurrent discriminations | Post-op | ||||
Rule reversal learning | Post-op | No | |||
No | |||||
Peinado-Manzano and Pozo-Garcia, |
MD rats | Delayed alternation in operant boxes | Pre-op | 0–80 s | Moderate and transient impairment for 0–40 s and severe impairment for 80 s |
Young et al., |
MD rats: RF | DNMTS in operant boxes | Post-op | 1.8–8.8 s | MD produced deficits in acquisition of the radial maze task |
8-arm radial maze | |||||
Krazem et al., |
MD mice: ibotenic | T-Maze Spatial repetition | Post-op | 5 min, 24 h | No |
T-Maze Reversal | Yes, MD required more trials | ||||
Hunt et al., |
MD rats: NMDA | Object, concurrent and configural discrim | Post-op | MD mildly impaired on concurrent discriminations | |
Gaffan et al., |
MD + Amyg + VMPFC macaques: ablation | 2-choice visual discrim task with food reward for correct choices | Post-op | Crossed lesions caused severe deficits in post-op acquisition | |
Mumby et al., |
MD rats: electrolytic | Visual object recognition DNMS | Post-op | 4 s acq. | Yes, more trials to learn, then delay dependent deficits |
Pre-op | 4–300 | ||||
30–300 s | |||||
Yes, more trials to reacquire | |||||
Neave et al., |
MD rats: NMDA | DNMTP | Post-op | 0–32 s | No |
Spatial discrim and Reversal | No | ||||
Gaffan and Watkins, |
MD macaques: ablation | Learning of visual stimuli associated with different amounts of food | Pre-op | Yes, impaired on retention of pre-op reward stimuli associations and impaired in new learning of further reward stimuli associations | |
Post-op | |||||
Hunt and Aggleton, |
MD rats: RF, ibotenic | Y-Maze Object recognition | Post-op | 0–60 s | Yes |
T-Maze Delay alt | 10–60 s | Yes, spatial memory deficits only a consequence of anterior thalamic involvement | |||
M'Harzi et al., |
MD rats: electrolytic | Radial maze | Post-op | Yes | |
Place recognition | No | ||||
Object recognition | No | ||||
Peinado-Manzano and Pozo-Garcia, |
MD rats: electrolytic | Operant delay alt | Post-op | 0–80 s | Yes |
Gaffan and Murray, |
MD + Amyg + vmPFC macaques: ablation | 2-choice visual discrim with food reward for correct choices | Post-op | Bilateral lesions to MD impaired | |
Crossed unilateral lesions not as impaired as bilateral lesions to any of the single regions. | |||||
Stokes and Best, |
MD rats: electrolytic | 8-arm radial maze | Post-op | Yes, combined MD and AT damage | |
Stokes and Best, |
MD rats: ibotenic | 8-arm radial maze | Post-op | Yes, combined MD and AT damage | |
Winocur, |
MD rats: electrolytic | Memory for food preferences | Post-op | 0–8 d | No |
Pre-op | Yes, only if no delay btw acquisition and surgery Not impaired with 2 d between acquisition and surgery | ||||
Beracochea et al., |
MD rats: ibotenic | 8-arm radial maze | Post-op | 15, 45 s | No |
T-Maze temp alt | Yes = 15 s but not with 45 s delay | ||||
T-Maze spatial reversal | |||||
No | |||||
Stokes and Best, |
MD rats: electrolytic | 8-arm radial maze | Pre-op | 0 s | Yes, combined MD and AT damage |
Zola-Morgan and Squire, |
Posterior MD macaques: electrolytic | Visual DNMTS | Post-op | 8–60 s, 10 min | Yes, delay independent |
Pattern discrimination | No, analogous to preserved capacity for skill learning in human amnesic patients | ||||
Winocur, |
MD rats: electrolytic | Delayed alternation | Post-op | 0–21 d | Yes, impaired acquisition and impaired at all delays |
Passive avoidance | |||||
No | |||||
Aggleton and Mishkin, |
MD macaques: ablation | Object recognition | Post-op | 120 s | Yes |
Object-reward associations | Yes | ||||
Aggleton and Mishkin, |
MD +AT macaques: ablation | Object recognition | Post-op | 120 s | Yes |
Visual pattern discrim | No | ||||
Spatial delayed response | No | ||||
Isseroff et al., |
MD macaques: RF | Spatial delayed response | Post-op | 5 s | Yes |
Visual pattern discrim | No | ||||
Delayed alternation | Yes | ||||
Object discrim + reversals | No |
Monkey studies have demonstrated that aspiration lesions to the MD (i.e., typically including the magnocellular and the parvocellular subdivisions and other medial thalamic structures as well as potential fibers of passage passing through this region) cause impairments in recognition memory, deficits in new learning of object-in-place (OIP) discriminations and object-reward associations. These lesions also produce impaired performance in the spatial delayed alternation task and delayed response task but not in object reversal (associative memory task) and visual pattern discrimination (Isseroff et al.,
Parker and Gaffan (
More recently, selective neurotoxic lesions to the MDmc have confirmed the importance of this medial subdivision in new learning of OIP discriminations and in a reward satiety devaluation task, as neurotoxic lesions of the MDmc produce impaired performance on these tasks (Mitchell et al.,
In the same study, another task, the OIP discrimination learning task, was also learnt pre-operatively although in this task animals learn 20 new pairs of OIP discriminations (see Figure
In addition, the types of errors made in learning the OIP discriminations produced after bilateral MDmc lesions are not suggestive of problems with perseverative responding during learning (Mitchell et al.,
However, other studies (e.g., Parker et al.,
Further research from our laboratory has extended our understanding about some of the brain regions involved in retrograde amnesia and anterograde amnesia using this OIP retention and new learning task. The effects of lesions to different subcortical and cortical structures have been assessed (Mitchell et al.,
Clearly animals with bilateral MDmc lesions have provided greater understanding of the critical role that the MDmc plays in differing forms of memory processing. Animals with MDmc lesions have also been assessed on tasks investigating other cognitive processes e.g., reward (satiety) devaluation. For example, animals with selective bilateral neurotoxic lesions to the MDmc are also impaired on a computerized version of a classic food satiety devaluation task (Malkova et al.,
In contrast, MD lesions do produce deficits in new learning of larger sized samples of concurrent object-reward association problems over sessions, although the lesion does not impair the retention of pre-operatively acquired object-reward associations (Gaffan and Parker,
In rats, many studies assess the rats' ability to forage for food using T-mazes, water mazes and radial arm mazes, taking advantage of their natural curiosity to explore novel environments for food. Many strategies can be used by the animals to complete these tasks successfully (Dudchenko,
Other researchers have observed in rats with bilateral MD lesions certain behavioral deficits that could result in memory impairments, for example, an inability to adopt different strategies, or changes in activity and exploration levels or deficits in withholding spatial responses (Hunt and Aggleton,
Rodent studies have been instrumental in demonstrating the distinct, interdependent involvement of adjacent medial thalamic structures in memory and other cognitive deficits. Dissociable deficits between the MD and adjacent anterior thalamus (AT) have been reported (Chudasama and Muir,
The experiment demonstrating bilateral MD involvement in recency memory (Mitchell and Dalrymple-Alford,
Cross et al. (
After neurotoxic lesions to MD, rodents are not impaired at SOR tasks (Hunt and Aggleton,
As in monkey studies, researchers have investigated the devaluation effects after bilateral MD lesions in rodents. Pickens (
Thus, through experimental testing in both rats and non-human primates it has been shown that the different subdivisions of the MD provide critical contributions to successful cognitive processing in many different tasks. Principally, the MD in conjunction with its neuroanatomical connections is important for some forms of recognition memory, recency memory processing, and further prospective integration of the rewards associated with successful responses to govern additional responses, as well as new learning of OIP discriminations, but not their retention. The subdivisions of the MD provide key roles in helping integrate object/reward/response information for successful new learning and successful additional (future) responding. Furthermore, and most importantly, it has been demonstrated that the MD contributes to successful cognition, rather than causing memory and other cognitive deficits by simply causing a generalized dysfunction of the PFC.
A recent review of single unit recordings in macaques (Watanabe and Funahashi,
Further experiments have shown that the MD seems to contribute to prospective encoding more so than DLPFC during the delay period (Funahashi et al.,
Other electrophysiology studies have shown that the MDmc of primates contain neuronal populations that signal information concerning prior stimulus occurrence (Fahy et al.,
Finally, another study has used single unit recording to demonstrate how the PFC and MD interact in cognitive tasks. Recent work by Kellendonk and colleagues (Parnaudeau et al.,
Aggleton and Brown (
Other researchers have proposed that the MD has a deferential role in memory processing caused by disruptions in executive functioning which is processed by the PFC. It has been suggested that the memory impairments resulting from lesions to the MD are secondary to the primary disruptions in executive functioning, e.g., deficits in attention or withholding responses/inhibition and perseverative responding in both humans and animals (Zola-Morgan and Squire,
Van der Werf et al. (
In contrast to these proposals, Gaffan, Mitchell and colleagues have proposed that the MD, in particular MDmc has an important integrative role in conjunction with the PFC in episodic-like declarative memory, due to the prominent interconnections among these structures (Gaffan and Parker,
Aggleton et al. (
As indicated from the above survey of the contribution of the MD to specific forms of memory and decision-making, some conclusions have been drawn but much debate remains. Nevertheless, the evidence thus far provides some understanding and certainly helps with future directions. Thus, the animal evidence (and also the clinical evidence although not reviewed here) simply doesn't support the notion that there is a single structure within the medial diencephalon that is responsible for the extent of anterograde and retrograde memory deficits associated with diencephalic (or thalamic) amnesia. Furthermore, given the extent of variability in other cognitive deficits observed after damage to the MD it is not possible that one specific structure or subdivision of the MD is the critical locus of these deficits. Instead, the evidence suggests that the subdivisions of the MD, and subdivisions of other medial thalamic structures, are each functioning within independent but integrated neural circuits, all of which are important for specific aspects of cognitive processing, and together they form a group of critical networks in the brain that are important for learning and memory as well as many other forms of cognition.
The current evidence points to the role of higher order thalamic structures, in our case the MD, in mediating the complex functioning within the PFC, via the transthalamic route (Sherman and Guillery,
Thus, it may be proposed that the transthalamic connections linking the MD to the cognitive PFC are more important for supporting the learning of new information than for retention of previously acquired information (Mitchell et al.,
In contrast to deficits in new learning, the evidence suggests that cortical structures are more important for the retention of information learnt prior to brain injury (retrograde amnesia). Impairments in retention are reported after restricted damage to selective cortical structures highlighting how some of these cortical regions are more important for memory of previously acquired information (Dean and Weiskrantz,
Widespread global amnesia associated with anterograde and retrograde memory deficits may be caused by widespread damage to subcortical structures. For example, the combined bilateral lesion damage to MDmc and fornix results in both retrograde and anterograde amnesia of OIP discriminations (Mitchell et al.,
Further and combined behavioral, cognitive, and electrophysiology studies are required to gain greater understanding of the impact of disconnection lesions to the PFC, MD, and other interconnected structures. This research may also have clinical application in understanding the roles of the different subdivisions of the MD in many neuropsychological disorders (e.g., schizophrenia, obsessive compulsive disorder, and major depression). For example, recent studies across different species (Leal-Campanario et al.,
There needs to be more research on the understanding of the functional consequences of the communication links between the MD and PFC related to this higher order information transfer (Guillery and Sherman,
Finally, advances in neuroimaging are also illustrating the interconnections of the subcortical brain structures
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Anna S. Mitchell is a recipient of a UK MRC Career Development Award—G0800329.
1In the direct pathway, the neurotransmitter GABA is activated, which inhibits pallidal and nigral neurons and consequently disinhibits the thalamus and midbrain targets. In the traditional model, it is proposed that this pathway facilitates thalamocortical activity and behavioral and motor outputs. The cells express mainly dopamine D1 receptors in the direct pathway. In the indirect pathway, the neurotransmitters GABA and glutamate are activated. The GABA inhibits the pallidal neurons, which leads to less inhibition at the subthalamic level where glutamate has stronger activity levels as a result. The glutamate then influences GABA in the output neurons of the internal segment of globus pallidus and pars reticulata of the SN, which results in stronger inhibition of the thalamic and midbrain targets. It is proposed this indirect pathway then exerts an inhibitory influence on the thalamus and midbrain, equating to suppression of behavioral and motor outputs. The cells express mainly dopamine D2 receptors in the indirect pathway. These two hypotheses on the direct and indirect pathway modulation are particularly relevant to theories of motor output problems associated with Parkinson's and Huntingdon's diseases. Tekin and Cummings (