Leucotomized schizophrenics lose neurons in the mediodorsal thalamic nucleus

It has previously been shown that chronic schizophrenic patients have a 40–50% reduction in the total number of nerve and glia cells in the mediodorsal thalamic nucleus and the nucleus accumbens compared with controls, while the total neuron and glia number is the same in the two groups in the ventral pallidum. Using new stereological cell counting methods, neuron and glia cell numbers were estimated in the mediodorsal thalamic nucleus, the ventro-medial part of nucleus accumbens and the ventral pallidum in nine brains from leucotomized schizophrenics. This number was compared with counts from control cases and chronic schizophrenics without leucotomy. The results showed that the total number of nerve cells in the mediodorsal thalamic nucleus was statistically significantly reduced from 1.08 × 10⁶ in chronic schizophrenics to 0.88 × 10⁶ in leucotomized schizophrenics. Total neuron number was statistically significantly reduced in the ventro-medial part of the nucleus accumbens in schizophrenics without further reduction in leucotomized schizophrenics. The total neuron number in ventral pallidum was normal. With frontal leucotomy it is possible to investigate the consequences of disconnection of the prefrontal cortex to central regions in the human brain. The mediodorsal nucleus of thalamus represents a major efferent projection to the prefrontal cortex. The dorsal prefrontal cortex projects to nucleus caudatus and the orbital prefrontal cortex to the nucleus accumbens, a prominent region in the limbic system. It was expected that a lesion to the prefrontal region by anterograde, retrograde degeneration may affect the mediodorsal nucleus of thalamus.     

Volume and neuron number of the mediodorsal thalamic nucleus in schizophrenia: A replication study

Previous neuropathological studies on the mediodorsal thalamic nucleus (MD) in schizophrenia have yielded conflicting results. While some studies suggested that patients with schizophrenia have a pronounced reduction of the volume and neuron number in the MD, more recent data have not found anatomical alterations in this thalamic nucleus. However, most studies have considerable methodological shortcomings. In the present study, we investigated the volume, neuron density and neuron number in the left and right MD in patients with schizophrenia (n = 20) and normal control subjects without neuropsychiatric disorders (n = 18). Patients with schizophrenia showed no significant difference in neuron density and total neuron number in the MD. Compared with the control group, patients with schizophrenia had a smaller MD volume in both hemispheres, a difference that approached significance in the left MD (− 7.3%) when the whole brain volume was included as a covariate. No significant main group effect of diagnosis was found for the right MD volume. There were no significant correlations between MD volume, neuron density, total neuron number and the duration of illness or the age of the patients. Taken together, the present results suggest that schizophrenia is associated with a moderate volume reduction in the left mediodorsal thalamic nucleus, while the neuron density and the total neuron number are unchanged.     

Volume and neuron number of the mediodorsal thalamic nucleus in schizophrenia: a replication study

Previous neuropathological studies on the mediodorsal thalamic nucleus (MD) in schizophrenia have yielded conflicting results. While some studies suggested that patients with schizophrenia have a pronounced reduction of the volume and neuron number in the MD, more recent data have not found anatomical alterations in this thalamic nucleus. However, most studies have considerable methodological shortcomings. In the present study, we investigated the volume, neuron density and neuron number in the left and right MD in patients with schizophrenia (n=20) and normal control subjects without neuropsychiatric disorders (n=18). Patients with schizophrenia showed no significant difference in neuron density and total neuron number in the MD. Compared with the control group, patients with schizophrenia had a smaller MD volume in both hemispheres, a difference that approached significance in the left MD (-7.3%) when the whole brain volume was included as a covariate. No significant main group effect of diagnosis was found for the right MD volume. There were no significant correlations between MD volume, neuron density, total neuron number and the duration of illness or the age of the patients. Taken together, the present results suggest that schizophrenia is associated with a moderate volume reduction in the left mediodorsal thalamic nucleus, while the neuron density and the total neuron number are unchanged.     

The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics.

Reductions of 40% in total cell number and 25% in volume of the mediodorsal thalamic nucleus were recently reported in an unbiased neurostereological study of neuroleptic-treated schizophrenic patients. In order to investigate whether these results might be secondary to many years of treatment with neuroleptic drugs, eight brains from schizophrenics never treated with neuroleptics and eight controls were studied using the unbiased Cavalieri volume estimator. To compare left-right differences in this region, twelve neuroleptic-treated schizophrenics and eleven control cases were compared. The brains used for the left-right comparison study and five of 20 used for comparison of treated and untreated brain volumes have been used in an earlier study. The mediodorsal thalamus volume was reduced by 31% in untreated schizophrenics and by 22% in neuroleptic-treated schizophrenics. No differences were found in mean total volume of the left and right mediodorsal thalamus in brains from controls nor from schizophrenics. A major difference exists with respect to time of fixation in controls (12 years) and untreated schizophrenics (39 years) that makes shrinkage differences a possible confounding variable. The results suggest that the consistent reduction in number of neurons in the mediodorsal thalamic nucleus are not secondary to prolonged treatment with neuroleptic drugs and that asymmetry in this specific brain region is not a feature of the schizophrenia-afflicted brain.     

Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types

The mediodorsal thalamic nucleus (MD) is the principal relay nucleus for the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. Several, but not all, postmortem studies of the MD in schizophrenia have reported decreased volume and total neuronal number. However, it is not clear whether the findings are specific for schizophrenia nor is it known which subtypes of thalamic neurons are affected. We studied the left MD in 11 subjects with schizophrenia, 9 control subjects, and 12 subjects with mood disorders. Based on morphological criteria, we divided the neurons into two subclasses, presumably corresponding to projection neurons and local circuit neurons. We estimated MD volume and the neuron number of each subclass using methods based on modern unbiased stereological principles. We also estimated the somal volumes of each subclass using a robust, but biased, approach. In addition, we investigated the left MD in four cynomolgus monkeys chronically exposed to haloperidol and in four control monkeys in order to assess the possible effects of antipsychotic medications. The three human subject groups did not differ in any of the measures. In addition, no differences were observed between the two groups of monkeys. Thus, these findings do not support the hypothesis that the MD is a locus of pathology in schizophrenia, although they cannot rule out important functional or structural changes in parameters not measured. Like other studies, this investigation is subject to the limitations involved in sampling from a heterogeneous population emphasizing the need to continue to improve the application of robust, unbiased techniques to quantitative studies of this complex brain disorder.     

The mediodorsal thalamic nucleus and schizophrenia

The mediodorsal nucleus of the human thalamus is in a crucial position that allows it to establish connections with diverse cerebral structures, particularly the prefrontal cortex. The present review examines existing neurobiologic studies of the brains of people with and without schizophrenia that indicate a possible involvement of the mediodorsal nucleus in this psychiatric disorder. Studies at synaptic and cellular levels of the neurobiology of the mediodorsal nucleus, together with a better anatomic understanding of this diencephalic structure owing to neuroimaging studies, should help to establish a more deep and solid pathophysiologic model of schizophrenia.     

Prosencephalic afferents to the mediodorsal thalamic nucleus

The afferent projections from the prosencephalon to the mediodorsal thalamic nucleus (MD) were studied in the cat by use of the method of retrograde transport of horseradish peroxidase (HRP). Cortical and subcortical prosencephalic structures project bilaterally to the MD. The cortical afferents originate mainly in the ipsilateral prefrontal cortex. The premotor, prelimbic, anterior limbic, and insular agranular cortical areas are also origins of consistent projections to the MD. The motor cortex, insular granular area, and some other cortical association areas may be the source of cortical connections to the MD. The subcortical projections originate principally in the ipsilateral rostral part of the reticular thalamic nucleus and the rostral lateral hypothalamic area. Other parts of the hypothalamus, the most caudal parts of the thalamic reticular nucleus, the basal prosencephalic structures, the zona incerta, the claustrum, and the entopeduncular and subthalamic nuclei are also sources of projections to the MD. Distinct, but somewhat overlapping areas of the prosencephalon project to the three vertical subdivisions of MD (medial, intermediate, and lateral). The medial band of the MD receives a small number of prosencephalic projections; these arise mainly in the caudal and ventral parts of the prefrontal cortex. Cortical projections also arise in the infralimbic area, while subcortical projections originate in the medial part of the rostral reticular thalamic nucleus and lateral hypothalamic area. The intermediate band of the MD receives the largest number of fibers from the prosencephalon. These arise principally in the intermediate and dorsal part of the lateral and medial surface of the prefrontal cortex, the premotor cortex, and the prelimbic and agranular insular areas. Projections also originate in basal prosencephalic formations (preoptic area, Broca's diagonal band, substantia innominata, and olfactory tubercle), rostral reticular thalamic nucleus, and lateral hypothalamic area. A large number of prosencephalic structures also project to the lateral band of the MD. These are mainly the most dorsal and caudal parts of the lateral and medial surface of the prefrontal cortex, the premotor and motor cortices, and the prelimbic, anterior limbic, and insular areas. Projections arise also in the lateral rostral and caudal parts of the reticular thalamic nucleus, the zona incerta, the lateral and dorsal hypothalamic areas, the claustrum, and the entopeduncular nucleus. These and previous results demonstrate a gradation in the afferent connections to the three subdivisions of the MD. Brain structures related to the olfactory sensory modality and with allocortical formations of the limbic system project principally to the medial band of the MD. The intermediate band of the MD receives subcortical and cortical projections from structures mainly related to the limbic system and cortical regions related to sensory association cortices. The lateral band of the MD receives projections mainly originating in structures related to complex sensory associative processes and to the motor system (especially from brainstem and cortical structures implicated in the regulation of eye movements).     

Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages

Neurons in the macaque brain arise from progenitors located near the cerebral ventricles in a temporally segregated manner such that lethal doses of ionizing irradiation, if administered over a discrete time interval, can deplete individual nuclei selectively. A previous study showed that neuron number in the dorsal lateral geniculate nucleus is reduced following early gestational exposure to x‐irradiation (Algan and Rakic [ 1997 ] J. Comp. Neurol. 12:335–352). Here we examine whether similarly timed irradiation decreases neuron number in three associational thalamic nuclei: mediodorsal (MD), anterior, and pulvinar. Ten macaques were exposed to multiple doses of x‐rays (total exposure (175–350 cGy) in early gestation (E33–E42) or midgestation (E70–E90); eight nonirradiated macaques were controls. Only the early‐irradiated monkeys, not the midgestationally irradiated animals, exhibited deficits in whole‐thalamic neuron (–15%) and glia numbers (–21%) compared with controls. Reduction of neuron number (–26%) and volume (–29%) was particularly pronounced in MD. In contrast, cell number and volume were not significantly decreased in the anterior or pulvinar nuclei following early gestational irradiation. Thus, reduced thalamic neuron number was associated specifically with irradiation in early gestation. Persistence of the thalamic neuronal deficit in adult animals indicates that prenatally deleted neurons had not been replenished during maturation or in adulthood. The selective reduction of MD neuron number also supports the protomap hypothesis that neurons of each thalamic nucleus originate sequentially from separate lines of neuronal stem cells (Rakic [ 1977a ] J. Comp. Neurol. 176:23–52). The early gestationally irradiated macaque is discussed as a potentially useful model for studying the neurodevelopmental pathogenesis of schizophrenia. J. Comp. Neurol. 515:454–464, 2009. © 2009 Wiley‐Liss, Inc.     

Cortical projections of the thalamic mediodorsal nucleus in the rabbit

The cortical projection of the thalamic mediodorsal nuclear complex (MD) in the rabbit was mapped retrograde horseradish peroxidase and anterograde tritiated proline techniques. The projection field occupied the entire medial wall rostral to a mid corpus callosal level, wrapped around the frontal pole onto the lateral convexity and tailed off caudally on the dorsal bank of the rhinal sulcus. The projection of the lateral approximately one-half of MD, the half which does not receive olfactory input, was confined to medial cortex supply all but the most rostral region. This projection field of lateral MD was precisely organized in two dimensions with the most lateral part projecting most caudally and the most dorsal part projecting most ventrally. A representation for the third, anterior-posterior (A-P), dimension was not evident since any cortical point within the field was supplied by a cylinder of cells extending the entire A-P extent of lateral MD. The medial half of MD, which does receive olfactory input, projected to the remaining rostral medical cortex, the lateral convexity and rhinal sulcal region. The inverse dorsoventral relationship was partially preserved and on overlapping A-P gradient was present with sulcal projections originating more caudally in medial MD and the rostral medial projection originating more rostrally.     

Involvement of the mediodorsal thalamic nucleus in mediating recollection and familiarity

The mediodorsal (MD) thalamic nucleus is thought to play an important role in memory processes. Distinct hippocampal-thalamic-prefrontal connections have been described as the potential neural substrate for both, recollection and familiarity. The aim of this study was to investigate whether the MD is part of the circuits underlying these two memory components.We assessed the effects of ischemic thalamic lesions with or without MD involvement on performance in a word list discrimination task and standard tests of memory and executive function. Estimates of recollection and familiarity were derived using the dual-process signal-detection model (DPSD).The results revealed impairments in both, recollection and familiarity, after unilateral thalamic damage, with recollection being more affected than familiarity. There were no significant differences in the memory performance of patients with MD lesions compared to patients with ventrolateral-thalamic lesions except for familiarity estimates, which were lower for the latter group. Lesions involving the MD led to recollection deficits, although inspection of individual cases suggested a decrease in both memory components after damage in the medial part of this nucleus. Executive dysfunction was associated with lateral MD lesions and also ventrolateral-thalamic damage.The findings suggest that MD contributes to recollection, with some preliminary evidence of a contribution of the medial MD to familiarity. The small sample size does, however, not yet allow any clear conclusions in this regard. Since damage in the ventrolateral thalamus leads to memory and executive dysfunction, further research is needed to elucidate the role of this thalamic region in cognition.     

Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia.

BACKGROUND: The thalamus is a brain region of interest in the study of schizophrenia because it provides critical input to brain regions such as the prefrontal, cingulate, and temporal cortices, where abnormalities have been repeatedly observed in patients with schizophrenia. Postmortem anatomic studies have rarely investigated the thalamus in this population. METHODS: Postmortem tissue was obtained from the left hemisphere of eight male schizophrenic patients and eight male age-matched control subjects. The optical dissector stereologic procedure was used to count neurons in the mediodorsal (MD) and anteroventral/anteromedial (AV/AM) nuclei of the thalamus. RESULTS: The number of neurons and volume of the MD were significantly reduced by 35% and 24%, respectively. The MD cell number reduction was a consistent finding; every control subject had more and every schizophrenic subject had fewer than 3.5 million neurons. Neuron number was also significantly reduced (16%) in the AV/AM nuclei. CONCLUSIONS: The present data indicate that schizophrenia is associated with robust reductions in nerve cell numbers in nuclei that communicate with the prefrontal cortex and limbic system. These thalamic anatomic deficits may be responsible, in part, for previous reports of such prefrontal cortical abnormalities as reduced synaptic density, reduced volume, and metabolic hypofunction.     

Effect of mediodorsal thalamic nucleus lesion on contextual fear conditioning in rats

Much evidence from animal and clinical studies has shown that the mediodorsal nucleus of the thalamus (MD) is related to various types of memory, such as visual recognition, object-reward association, spatial working, and reference memory; however, few studies have investigated its role in emotion-related learning and memory processes. This study compared the effect of pre- and posttraining bilateral lesions of the mediodorsal thalamic nucleus with those of the amygdala on contextual conditioned fear. Both pre- and posttraining amygdala lesions almost eliminated conditioned freezing, and significantly blocked postshock freezing when behavioral tests were performed immediately after footshocks, reconfirming previous studies that the amygdala is implicated in the learning of Pavlovian conditioning. Both pre- and posttraining lesions of the mediodorsal nucleus of the thalamus significantly attenuated conditioned freezing but had no effect on postshock freezing. In contrast to lesions of the amygdala, those of the mediodorsal thalamic nucleus failed to alter the increased defecation induced by conditioned fear stress. Our results suggest that the mediodorsal nucleus of the thalamus has an important role in acquisition, consolidation or retrieval in Pavlovian contextual fear conditioning. Possible neural circuits, incorporating the amygdala, MD, and hippocampus, and the functional similarity of the MD and hippocampus in contextual fear conditioning, are also discussed.     

Topographic organization of the brainstem afferents to the mediodorsal thalamic nucleus

The afferent projections from the brainstem to the mediodorsal thalamic nucleus (MD) were studied in the cat, by means of retrograde transport of horseradish peroxidase. A topographical arrangement of these projections is described. The medial part of MD is the area of the nucleus which receives fewer afferents from the brainstem. After injections in this part, labeled neurons were observed mainly in the interpeduncular nucleus, the ventral tegmental area and the substantia nigra. After injections of HRP in the intermediate part of the MD, labeled cells were seen mainly in the interpeduncular nucleus, substantia nigra, dorsal and centralis superior raphe nuclei, dorsal tegmental nucleus, and coeruleus complex. Less conspicuous was the number of labeled cells in the central gray and the dorsolateral portion of the tegmentum of the mesencephalon and pons. After injections in the lateral part of MD, labeled neurons were observed mainly in the deep layers of the superior colliculus, central gray, the oral paramedian pontine reticular tegmentum, and the interpeduncular nucleus. Labeled cells were also observed in the substantia nigra, locus coeruleus, dorsal tegmental nucleus, cuneiform area, and the mesencephalic reticular formation. These findings show the MD as a thalamic link of three different groups of brainstem structures projecting to different cortical areas with different functional significance.     

Cingulate cortex response to electrical stimulation of the mediodorsal thalamic nucleus

Electrical stimulation of the lateral, parvocellular part of the mediodorsal thalamic nucleus of the rabbit was found to evoke field potentials and drive single cells in the anterior cingulate cortex. Furthermore, the laminar distribution of the field responses and the population of effected cells were dependent on the frequency of the stimulation. Excitatory current sinks were produced in layers I and III (primary layers of mediodorsal input) only when the stimulus frequency was in the theta range (6 to 8 Hz); the majority of cells were reliably driven only by stimulation within this range. Lower-frequency stimulation, e.g., 0.5 Hz, produced a current sink in layer V. Cells that were driven at low frequencies might be antidromically activated. The study suggests that modulation of mediodorsal outflow in the theta range may be necessary for effective information transfer to the cortex.     

Afferents to prefrontal cortex from the thalamic mediodorsal nucleus in the rhesus monkey

Thalamic afferents to Macaque prefrontal cortex from the mediodorsal nucleus were examined by techniques specific for anterograde degeneration and axoplasmic transport. The sampling procedure employed permits establishing the extent of topographic projections to cortex from subcortical foci for the same brain which was surveyed subsequently in tracing specific neuronal connections by electron microscopy. Topographic and general laminar distribution of thalamic terminals are presented in terms of 3 subareas of prefrontal cortex.The dorsolateral and ventral (orbital) surfaces of prefrontal cortex receive respectively projections from the lateral and medial subdivision of the mediodorsal nucleus. In addition, the medial wall of the frontal lobe, including the dorsomedial part of the lateral convexity, heretofore regarded as athalamic, receives input from the caudal-dorsomedial aspect of the mediodorsal nucleus. Preliminary evidence suggests that axons from the mediodorsal nucleus terminate in the head of caudate nucleus, as Sachs⁸¹ described 65 years ago in the first orthograde study of thalamo-prefrontal cortex connections.     

The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat.

The mediodorsal nucleus of the rat thalamus has been divided into medial, central and lateral segments on the basis of its structure and axonal connections, and these segments have been shown by experiments using the autoradiographic method of demonstrating axonal connections to project to seven distinct cortical areas covering most of the frontal pole of the hemisphere. The position and cytoarchitectonic characteristics of these areas are described. The medial segment of the nucleus projects to the prelimbic area (32) on the medial surface of the hemisphere, and to the dorsal agranular insular area, dorsal to the rhinal sulcus on the lateral surface. The lateral segment projects to the anterior cingulate area (area 24) and the medial precentral area on the dorsomedial shoulder of the hemisphere, while the central segment projects to the ventral agranular insular area in the dorsal bank of the rhinal sulcus, and to a lateral part of the orbital cortex further rostrally. (The term "orbital" is used to refer to the cortex on the ventral surface of the frontal pole of the hemisphere.) A ventral part of this orbital cortex also receives fibers from the mediodorsal nucleus, possibly its lateral segment, but the medial part of the orbital cortex, and the ventrolateral orbital area in the fundus of the rhinal sulcus receive projections from the paratenial nucleus and the submedial nucleus, respectively. All of these thalamocortical projections end in layer III, and in the outer part of layer I. The basal nucleus of the ventromedial complex (the thalamic taste relay) has been shown to have a similar laminar projection (layer I and layers III/IV) to the granular insular area immediately dorsal to, but not overlapping, the mediodorsal projection field. However, the principal nucleus of the ventromedial complex appears to project to layer I, and possibly layer VI, of the entire frontal pole of the hemisphere. The anteromedial nucleus does not appear to project to layer III of the projection field of the mediodorsal nucleus, although it may project to layers I and VI, especially in the anterior cingulate and medial precentral areas. A thalamoamygdaloid projection from the medial segment of the mediodorsal nucleus to the basolateral nucleus of the amygdala has also been demonstrated, which reciprocates an amygdalothalamic projection from the basolateral nucleus to the medial segment. The habenular nuclei also appear to project to the central nucleus of the amygdala. These results are discussed in relation to the delineation and subdivision of the prefrontal cortex in the rat, and to amygdalothalamic and amygdalocortical projections which are described in a subsequent paper (Krettek and Price, '77).     

Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder

BACKGROUND: The importance of neuronal interactions in development, the cortical dependence of many thalamic nuclei, and the phenomenon of transsynaptic degeneration suggest possible abnormalities in thalamic nuclei with connections to other brain regions implicated in schizophrenia. Because frontal and temporal lobe volumes are diminished in schizophrenia, volume loss could characterize their primary thalamic relay nuclei (mediodorsal nucleus [MDN] and pulvinar). METHODS: Tracers delineated the thalamus, MDN, and pulvinar on contiguous 1.2-mm magnetic resonance images in 12 schizophrenic patients, 12 with schizotypal personality disorder (SPD), and 12 normal control subjects. The MDN and pulvinar were rendered visible by means of a Sobel intensity-gradient filter. RESULTS: Pixel overlap for delineation of all structures by independent tracers was at least 80%; intraclass correlations were r = 0.78 for MDN and r = 0.83 for pulvinar. Pulvinar volume was smaller in schizophrenic (1.22 +/- 0.24 cm(3)) and SPD (1.20 +/- 0.23 cm(3)) patients than controls (1.37 +/- 0.25 cm(3)). Differences for MDN were not statistically significant; however, when expressed as percentage of total brain volume, pulvinar and MDN together were reduced in SPD (0.14%) and schizophrenic (0.15%) patients vs controls (0.16%). Reductions were more prominent in the left hemisphere, with MDN reduced only in the schizophrenic group, and pulvinar in both patient groups. Total thalamic volume did not differ among the 3 groups. CONCLUSIONS: Measurement of MDN and pulvinar in magnetic resonance images is feasible and reproducible. Schizophrenic and SPD patients have volume reduction in the pulvinar, but only schizophrenic patients show reduction relative to brain volume in MDN.     

Post-stimulation excitability of mediodorsal thalamic self-stimulation

The post-stimulation excitability of the substrate for brain stimulation reward in the mediodorsal thalamus was assessed using equal- and unequal-pulse procedures. In 3 rats, refractory periods were found to begin no earlier than 1 ms and to end as late as 10 ms. Using test (T) pulses 1.5 times the amplitude of condition (C) pulses, the contribution of absolute and relative refractory periods was determined in one subject. No change in the slope of the recovery function was obtained in this condition, suggesting that several populations of neurons with different absolute refractory periods compose the behaviorally relevant substrate. A large supernormal contribution, evaluated by increasing the C amplitude to 1.5T, occurred between 3 and 10 ms with a peak at 7.5 ms. These results suggest that mediodorsal thalamic self-stimulation is mediated by a wide range of small, probably unmyelinated fibers.     

The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making

Recent evidence from monkey models of cognition shows that the magnocellular subdivision of the mediodorsal thalamus (MDmc) is more critical for learning new information than for retention of previously acquired information. Further, consistent evidence in animal models shows the mediodorsal thalamus (MD) contributes to adaptive decision-making. It is assumed that prefrontal cortex (PFC) and medial temporal lobes govern these cognitive processes so this evidence suggests that MD contributes a role in these cognitive processes too. Anatomically, the MD has extensive excitatory cortico-thalamo-cortical connections, especially with the PFC. MD also receives modulatory inputs from forebrain, midbrain and brainstem regions. It is suggested that the MD is a higher order thalamic relay of the PFC due to the dual cortico-thalamic inputs from layer V (‘driver’ inputs capable of transmitting a message) and layer VI (‘modulator’ inputs) of the PFC. Thus, the MD thalamic relay may support the transfer of information across the PFC via this indirect thalamic route. This review summarizes the current knowledge about the anatomy of MD as a higher order thalamic relay. It also reviews behavioral and electrophysiological studies in animals to consider how MD might support the transfer of information across the cortex during learning and decision-making. Current evidence suggests the MD is particularly important during rapid trial-by-trial associative learning and decision-making paradigms that involve multiple cognitive processes. Further studies need to consider the influence of the MD higher order relay to advance our knowledge about how the cortex processes higher order cognition.