Anterior thalamic NMDA-induced damage impairs extrapolation relying on serial stimulus patterns, in rats.

Extrapolation of serial stimulus patterns seems to depend upon identification and application of patterns relating sequences of stimuli stored in memory, thus allowing prediction of pending events never experienced before. There have been proposals that such a "generator of predictions system" would include the subiculum, mammillary bodies, anteroventral thalamus and cingulate cortex (e.g., Gray, 1982). The anteroventral thalamus (AVT) seems to be in a strategic position, both hodologically and experimentally, to allow testing of this hypothesis. This study investigated the effect of NMDA-induced damage to the anteroventral thalamus [part of the anterodorsal (AD) thalamus was also damaged in some animals], following stereotaxic minute topic microinjections, on the ability of male Wistar rats to extrapolate relying on serial stimulus patterns. Corresponding sham-operated controls received phosphate-saline buffer microinjections at the same stereotaxic coordinates. The subjects were trained to run through a straight alleyway along 31 sessions, one session per day, to get rewarded. Each session included four successive trials. Subjects exposed to the monotonic serial pattern received 14, 7, 3, 1 sunflower seeds along trials. Subjects exposed to the non-monotonic serial pattern received 14, 3, 7, 1 sunflower seeds. On the 32nd testing session, a fifth trial, never experienced before, was included immediately after the fourth trial. Sham-operated control subjects exposed to the monotonic serial pattern were expected to exhibit longer running times, since the content of their prediction in the fifth trial should be "less than 1 sunflower seeds". In contrast, control subjects exposed to the non-monotonic serial pattern were expected to exhibit shorter running times, since the content of their prediction would be "more than 1 sunflower seeds". Confirming these predictions, control subjects exposed to the monotonic serial pattern exhibited longer running times as compared to both, their own running times in previous trials within the same session and control subjects exposed to the non-monotonic schedule, thus indicating the occurrence of extrapolation. In contrast, AVT/AD lesioned subjects exposed to the monotonic schedule did not exhibit this increase in running times on the fifth trial, indicating lack of extrapolation. These results indicate that extrapolation relying on serial stimulus patterns is disrupted following extensive NMDA-induced damage to AVT and part of the AD. This represents the first consistent demonstration that the anterior thalamic nuclei are required for extrapolation of serial stimulus patterns and generation of predictions.

The anterior and medial thalamic nuclei and the human limbic system: tracing the structural connectivity using diffusion-weighted imaging.

The limbic system is a phylogenetically old, behaviorally defined system that serves as a center for emotions. It controls the expression of anger, fear, and joy and also influences sexual behavior, vegetative functions, and memory. The system comprises a collection of tel-, di-, and mesencephalic structures whose components have evolved and increased over time. Previous animal research indicates that the anterior nuclear group of the thalamus (ANT), as well as the habenula (Hb) and the adjacent mediodorsal nucleus (MD) each play a vital role in the limbic circuitry. Accordingly, diffusion imaging data of 730 subjects obtained from the Human Connectome Project and the masks of six nuclei (anterodorsal, anteromedial, anteroventral, lateral dorsal, Hb, and MD) served as seed regions for a direct probabilistic tracking to the rest of the brain using diffusion-weighted imaging. The results revealed that the ANT nuclei are part of the limbic and the memory system as they mainly connect via the mammillary tract, mammillary body, anterior commissure, fornix, and retrosplenial cortices to the hippocampus, amygdala, medio-temporal, orbito-frontal and occipital cortices. Furthermore, the ANT nuclei showed connections to the mesencephalon and brainstem to varying extents, a pattern rarely described in experimental findings. The habenula-usually defined as part of the epithalamus-was closely connected to the tectum opticum and seems to serve as a neuroanatomical hub between the visual and the limbic system, brainstem, and cerebellum. Finally, in contrast to experimental findings with tracer studies, directly determined connections of MD were mainly confined to the brainstem, while indirect MD fibers form a broad pathway connecting the hippocampus and medio-temporal areas with the mediofrontal cortex.

The mammillothalamic tracts: Age-related conspicuity and normative morphometry on brain magnetic resonance imaging.

The mammillothalamic tract (MTT, bundle of Vicq d'Azyr) is a white-matter projection from each mammillary body to the anterior nucleus of the thalamus (ANT). Deep brain stimulation of the MTTs or ANTs is a treatment option for medically refractory focal epilepsy. Since the ANTs may be atrophied in epilepsy, targeting of the MTT terminations could be used as a proxy for ANT locations. However, MTT conspicuity and morphometry on MRI have not been evaluated to date. We investigated normative age- and sex-related MRI morphometrics of the MTTs in healthy individuals. We retrospectively analyzed magnified axial T2-weighted images of 80 subjects for bilateral MTT conspicuity, diameters, areas, shapes, precise locations, and symmetry. We statistically tested the effects of independent variables (sex and MTT side) on measured dependent variables using two-way ANOVA; and performed linear regressions with age as the independent variable for each of the dependent variables. Subjects were F:M = 44:36, with mean age 45.3 years. Only one (0.63%) MTT was inconspicuous. Mean MTT diameter was 1.8 mm, area was 2.0 mm2 , and distance from third ventricle was 3.1 mm. MTTs were mostly bilaterally symmetrical in shape, equally round, or ovoid. The right MTT diameter was larger than the left, and males had larger MTT areas than females. We found no statistical difference between MTT diameters and areas in young, middle-aged, and older adults. We report normative axial MRI morphometrics of the MTTs to guide neuromodulation treatments. Future detailed analyses will determine if the MTTs atrophy in proportion to the ANTs in refractory epilepsy.

Arterial Supply of the Thalamus: A Comprehensive Review.

The thalamus is a deep cerebral structure that is crucial for proper neurological functioning as it transmits signals from nearly all pathways in the body. Insult to the thalamus can, therefore, result in complex syndromes involving sensation, cognition, executive function, fine motor control, emotion, and arousal, to name a few. Specific territories in the thalamus that are supplied by deep cerebral arteries have been shown to correlate with clinical symptoms. The aim of this review is to enhance our understanding of the arterial anatomy of the thalamus and the complications that can arise from lesions to it by considering the functions of known thalamic nuclei supplied by each vascular territory.

Newly observed anterior thalamocortical fiber of the thalamus using 7.0T super-resolution magnetic resonance tractography and its implications for the classical Papez circuit.

Here, we have employed recently developed super-resolution tractography using 7.0T-MRI to analyze the fine structures involved in thalamocortical connections, something that has proved difficult using conventional techniques. We detail a newly observed thalamocortical pathway connecting the anterior nucleus of the thalamus and the cingulate cortex not via the internal capsule but via the septal area. The observed pathway is believed to be a classical pathway of the Papez circuit but had not been previously identified.

Variations in Thalamic Anatomy Affect Targeting in Deep Brain Stimulation for Epilepsy.

BACKGROUND: Thalamic size and shape vary significantly across patients - with changes specific to the anterior thalamus occurring with age and in the setting of chronic epilepsy. Such ambiguity raises concerns regarding electrode position and potential implications for seizure outcomes. METHODS: MRIs from 6 patients from a single center underwent quantitative analysis. In addition to direct measurements from postimplantation MRIs, the CRAnialVault Explorer suite was used to normalize electrode position to a common reference system. Relationships between thalamic dimensions, electrode location, and seizure outcome were analyzed. RESULTS: Although this study group was too small to sufficiently power statistical analysis, general trends were identified. There was a trend towards smaller thalamic volumes in nonresponders. Electrode locations demonstrated more variation after normalization. There was a trend towards a more lateral, posterior, and inferior electrode position in nonresponders. CONCLUSIONS: Variations in thalamic shape and volume necessitate direct targeting. Given that changes occur to thalamic anatomy with age and in the setting of epilepsy, improved methods for visualizing and targeting the anterior nucleus are necessary. Pronounced thalamic atrophy may preclude proper electrode placement and serve as a poor prognostic indicator. A greater understanding of thalamic anatomy and connectivity is necessary to optimize deep brain stimulation for epilepsy.

Complementary subicular pathways to the anterior thalamic nuclei and mammillary bodies in the rat and macaque monkey brain.

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 the 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 (septal hippocampus) and the more proximal subiculum (temporal hippocampus). In contrast, anterior thalamic inputs were largely confined to the dorsal (i.e. septal and intermediate) subiculum, where projections to the anteromedial nucleus favoured the proximal subiculum while those to the anteroventral nucleus predominantly arose in the distal subiculum. In the macaque, the corresponding diencephalic inputs were again distinguished by anterior-posterior topographies, as subicular inputs to the medial mammillary bodies predominantly arose from the posterior hippocampus while subicular inputs to the anteromedial thalamic nucleus predominantly arose from the anterior hippocampus. Unlike the rat, there was no clear evidence of proximal-distal separation as all of these medial diencephalic projections preferentially arose from the more distal subiculum.

Defining the anterior nucleus of the thalamus (ANT) as a deep brain stimulation target in refractory epilepsy: Delineation using 3 T MRI and intraoperative microelectrode recording.

BACKGROUND: Deep brain stimulation (DBS) is a minimally invasive and reversible method to treat an increasing number of neurological and psychiatric disorders, including epilepsy. Targeting poorly defined deep structures is based in large degree on stereotactic atlas information, which may be a major source of inconsistent treatment effects. AIM OF THE STUDY: In the present study, we aimed to study whether a recently approved target for epilepsy (anterior nucleus of thalamus, ANT) is visualized in clinically established 3 T MRI and whether ANT is delineated using intraoperative microelectrode recording (MER). We have especially focused on individual variation in the location of ANT in stereotactic space. We also aimed to demonstrate the role of individual variation in interpretation of MER data by projecting samples onto AC-PC (anterior and posterior commissure) and ANT-normalized coordinate systems. METHODS: Detailed analysis of ANT delineations in 3 T MRI short tau inversion recovery (STIR) images from eight patients undergoing DBS for refractory epilepsy was performed. Coronal and sagittal cross-sectional models of ANT were plotted in the AC-PC coordinate system to study individual variation. A total of 186 MER samples collected from 10 DBS trajectories and 5 patients were analyzed, and the location of each sample was calculated and corrected accordingly to the location of the final DBS electrode and projected to the AC-PC or coordinate system normalized to ANT. RESULTS: Most of the key structures in the anatomic atlas around ANT (mammillothalamic tract and external medullary lamina) were identified in STIR images allowing visual delineation of ANT. We observed a high degree of anatomical variation in the location of ANT, and the cross-sectional areas overlapped by study patients decreased in a linear fashion with an increasing number of patients. MER information from 10 individual trajectories correlated with STIR signal characteristics by demonstrating a spike-negative zone, presumably white matter layer, at the lateral aspect of ANT in ANT-normalized coordinate system as predicted by STIR images. However, MER information projected to the AC-PC coordinate system was not able to delineate ANT. CONCLUSIONS: ANT is delineated in 3 T MRI by visualization of a thin white matter lamina between ANT and other nuclear groups that lack spiking activity. Direct targeting in the anterior thalamic area is superior to indirect targeting due to extensive individual variation in the location of ANT. Without detailed imaging information, however, a single trajectory MER has little localizing value.

Thalamocortical projections of the anteroventral thalamic nucleus in the rabbit.

The anterior thalamic nuclei are one of the regions that play critical roles in behavioral learning and memory functions. A part of the anterior thalamic nuclei, the anteroventral nucleus (AV) is well developed and differentiated into the parvocellular (AVp) and magnocellular (AVm) division in the rabbit. The AV is crucial for learning discriminative avoidance conditioning. Although communication between the AV and cortex is considered important in learning, little is known about the neural connections of the AV in the rabbit. Thus, this study used anterograde tracer biotinylated dextran amine and the retrograde tracer cholera toxin B subunit to examine the organization of the thalamocortical projections of the AV. Our data show that each division of the AV provides a unique set of projections to restricted regions and layers of the retrosplenial cortex and presubiculum. In addition, the AVp projects to layers I and IV of retrosplenial areas 29 and 30 and to layers I and VI of the presubiculum. The dorsolateral AVm projects to layers I and IV of area 29 and to layers I, III, and V of the presubiculum. However, the ventromedial AVm only projects to layer I of area 29. These projections are generally organized such that the rostral-to-caudal axis of the AV corresponds to the caudal-to-rostral axis of the retrosplenial cortex and to the temporal-to-septal axis of the presubiculum. These findings suggest distinct functional roles played by each division of the AV in the learning and memory functions.

An anatomic review of thalamolimbic fiber tractography: ultra-high resolution direct visualization of thalamolimbic fibers anterior thalamic radiation, superolateral and inferomedial medial forebrain bundles, and newly identified septum pellucidum tract.

BACKGROUND: Images obtained through ultra-high-field 7.0-tesla magnetic resonance imaging with track-density imaging provide clear, high-resolution tractograms that have been hitherto unavailable, especially in deep brain areas such as the limbic and thalamic regions. This study is a largely pictorial description of the deep fiber tracts in the brain using track-density images obtained with 7.0-T diffusion-weighted imaging. METHODS: To identify the fiber tracts, we selected 3 sets of tractograms and performed interaxis correlation between them. These tractograms offered an opportunity to extract new information in areas that have previously been difficult to examine using either in vivo or in vitro human brain tractography. RESULTS: With this new technique, we identified 4 fiber tracts that have not previously been directly visualized in vivo: septum pellucidum tract, anterior thalamic radiation, superolateral medial forebrain bundle, and inferomedial forebrain bundle. CONCLUSIONS: We present the high-resolution images as a tool for researchers and clinicians working with neurodegenerative and psychiatric diseases, such as Parkinson disease, Alzheimer disease, and depression, in which the accurate positioning of deep brain stimulation is essential for precise targeting of nuclei and fiber tracts.

Anterior nucleus of the thalamus: functional organization and clinical implications.

The anterior nucleus of thalamus (ANT) is a key component of the hippocampal system for episodic memory. The ANT consist of 3 subnuclei with distinct connectivity with the subicular cortex, retrosplenial cortex, and mammillary bodies. Via its connections with the anterior cingulate and orbitomedial prefrontal cortex, the ANT may also contribute to reciprocal hippocampal-prefrontal interactions involved in emotional and executive functions. As in other thalamic nuclei, neurons of the ANT have 2 different state-dependent patterns of discharge, tonic and burst-firing; some ANT neurons also contribute to propagation of the theta rhythm, which is important for mechanisms of synaptic plasticity of the hippocampal circuit. Clinical and experimental evidence indicate that damage of the ANT or its inputs from the mammillary bodies are primarily responsible for the episodic memory deficit observed in Wernicke-Korsakoff syndrome and thalamic stroke. Experimental models also indicate that the ANT may have a role in the propagation of seizure activity both in absence and in focal seizures. Because of its central connectivity and possible role in propagation of seizure activity, the ANT has become an attractive target for deep brain stimulation (DBS) for treatment of medically refractory epilepsy. The ANT is one of the nuclei preferentially affected in prion disorders, such as fatal familial insomnia, but the relationship between ANT involvement and the clinical manifestations of these disorders remains unclear. The connectivity patterns and electrophysiology of the ANT have been the subject of several reviews.(1-4.)

Hippocampal-anterior thalamic pathways for memory: uncovering a network of direct and indirect actions.

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 stimulation studies showing how the properties of the direct hippocampal-anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal-anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.

Parallel but separate inputs from limbic cortices to the mammillary bodies and anterior thalamic nuclei in the rat.

The proposal that separate populations of subicular cells provide the direct hippocampal projections to the mammillary bodies and anterior thalamic nuclei was tested by placing two different fluorescent tracers in these two sites. In spite of varying the injection locations within the mammillary bodies and within the three principal anterior thalamic nuclei and the lateral dorsal thalamic nucleus, the overall pattern of results remained consistent. Neurons projecting to the thalamus were localized to the deepest cell populations within the subiculum while neurons projecting to the mammillary bodies consisted of more superficially placed pyramidal cells within the subiculum. Even when these two cell populations become more intermingled, e.g., in parts of the intermediate subiculum, almost no individual cells were found to project to both diencephalic targets. In adjacent limbic areas, i.e., the retrosplenial cortex, postsubiculum, and entorhinal cortex, populations of cells that project to the anterior thalamic nuclei and mammillary bodies were completely segregated. This segregated pattern included afferents to those nuclei comprising the head-direction system. The sole exception was a handful of double-labeled cells, mainly confined to the ventral subiculum, that were only found after pairs of injections in the anteromedial thalamic nucleus and mammillary bodies. The projections to the anterior thalamic nuclei also had a septal-temporal gradient with relatively fewer cells projecting from the ventral (temporal) subiculum. These limbic projections to the mammillary bodies and anterior thalamus comprise a circuit that is vital for memory, within which the two major components could convey parallel, independent information.

Fornix microstructure correlates with recollection but not familiarity memory.

The fornix is the main tract between the medial temporal lobe (MTL) and medial diencephalon, both of which are critical for episodic memory. The precise involvement of the fornix in memory, however, has been difficult to ascertain since damage to this tract in human amnesics is invariably accompanied by atrophy to surrounding structures. We used diffusion-weighted imaging to investigate whether individual differences in fornix white matter microstructure in neurologically healthy participants were related to differences in memory as assessed by two recognition tasks. Higher microstructural integrity in the fornix tail was found to be associated with significantly better recollection memory. In contrast, there was no significant correlation between fornix microstructure and familiarity memory or performance on two non-mnemonic tasks. Our findings support the idea that there are distinct MTL-diencephalon pathways that subserve differing memory processes.

Perinatal development of the mammillothalamic tract and innervation of the anterior thalamic nuclei.

Axonal projections originating from the mammillary bodies represent important pathways that are essential for spatial information processing. Mammillothalamic tract is one of the main efferent projection systems of the mammillary body belonging to the limbic "Papez circuit". This study was aimed to describe the schedule of the mammillothalamic tract development in the rat using carbocyanine dye tracing. It was shown for the first time that fibers of the mammillothalamic tract being the collaterals of the mammillotegmental tract axons start bifurcating from the mammillotegmental tract on E17. The axons of the mammillothalamic tract grow simultaneously and reach the ventral region of the anterior thalamus where they form first terminal arborizations on E20-E21. Ipsilateral projections from the medial mammillary nucleus to the anteromedial and anteroventral thalamic nuclei develop from E20 to P6. Bilateral projections from the lateral mammillary nucleus to the anterodorsal thalamic nuclei develop later, on P3-P6, after the formation of the thalamic decussation of the mammillary body axons. Unique spatial and temporal pattern of the perinatal development of ascending mammillary body projections to the anterior thalamic nuclei may reflect the importance of these connections within the limbic circuitry.

Hypothalamic sites responding to predator threats--the role of the dorsal premammillary nucleus in unconditioned and conditioned antipredatory defensive behavior.

In this study we provide a comprehensive analysis of the hypothalamic activation pattern during exposure to a live predator or an environment previously associated with a predator. Our results support the view that hypothalamic processing of the actual and the contextual predatory threats share the same circuit, in which the dorsal premammillary nucleus (PMd) plays a pivotal role in amplifying this processing. To further understand the role of the PMd in the circuit organizing antipredatory defensive behaviors, we studied rats with cytotoxic PMd lesions during cat exposure and examined the pattern of behavioral responses as well as how PMd lesions affect the neuronal activation of the systems engaged in predator detection, in contextual memory formation and in defensive behavioral responses. Next, we investigated how pharmacological blockade of the PMd interferes with the conditioned behavioral responses to a context previously associated with a predator, and how this blockade affects the activation pattern of periaqueductal gray (PAG) sites likely to organize the conditioned behavioral responses to the predatory context. Behavioral observations indicate that the PMd interferes with both unconditioned and conditioned antipredatory defensive behavior. Moreover, we have shown that the PMd influences the activation of its major projecting targets, i.e. the ventral part of the anteromedial thalamic nucleus which is likely to influence mnemonic processing, and PAG sites involved in the expression of antipredatory unconditioned and conditioned behavioral responses. Of particular relevance, this work provides evidence to elucidate the basic organization of the neural circuits integrating unconditioned and contextual conditioned responses to predatory threats.

Thalamic nuclei in the opossum Monodelphis domestica.

We investigated nuclear divisions of the thalamus in the gray short-tailed opossum (Monodelphis domestica) to gain detailed information for further developmental and comparative studies. Nissl and myelin staining, histochemistry for acetylcholinesterase and immunohistochemistry for calretinin and parvalbumin were performed on parallel series of sections. Many features of the Monodelphis opossum thalamus resemble those in Didelphis and small eutherians showing no particular sensory specializations, particularly in small murid rodents. However, several features of thalamic organization in Monodelphis were distinct from those in rodents. In the opossum the anterior and midline nuclear groups are more clearly separated from adjacent structures than in eutherians. The dorsal lateral geniculate nucleus (LGNd) starts more rostrally and occupies a large part of the lateral wall of the thalamus. As in other marsupials, two cytoarchitectonically different parts, alpha and beta are discernible in the LGNd of the opossum. Each of them may be subdivided into two additional bands in acetylcholinesterase staining, while in murid rodents the LGNd consists of a homogeneous mass of cells. Therefore, differentiation of the LGNd of the Monodelphis opossum is more advanced than in murid rodents. The medial geniculate body consists of three nuclei (medial, dorsal and ventral) that are cytoarchitectonically distinct and stain differentially for parvalbumin. The relatively large size of the MG and LGNd points to specialization of the visual and auditory systems in the Monodelphis opossum. In contrast to rodents, the lateral dorsal and lateral posterior nuclei in the opossum are poorly differentiated cytoarchitectonically.

A pathway for predation in the brain of the barn owl (Tyto alba): projections of the gracile nucleus to the "claw area" of the rostral wulst via the dorsal thalamus.

The Wulst of birds, which is generally considered homologous with the isocortex of mammals, is an elevation on the dorsum of the telencephalon that is particularly prominent in predatory species, especially those with large, frontally placed eyes, such as owls. The Wulst, therefore, is largely visual, but a relatively small rostral portion is somatosensory in nature. In barn owls, this rostral somatosensory part of the Wulst forms a unique physical protuberance dedicated to the representation of the contralateral claw. Here we investigate whether the input to this "claw area" arises from dorsal thalamic neurons that, in turn, receive their somatosensory input from the gracile nucleus. After injections of biotinylated dextran amine into the gracile nucleus and cholera toxin B chain into the claw area, terminations from the former and retrogradely labeled neurons from the latter overlapped substantially in the thalamic nucleus dorsalis intermedius ventralis anterior. These results indicate the existence in this species of a "classical" trisynaptic somatosensory pathway from the body periphery to the telencephalic Wulst, via the dorsal thalamus, one that is likely involved in the barn owl's predatory behavior. The results are discussed in the context of somatosensory projections, primarily in this and other avian species.

Distinct, parallel pathways link the medial mammillary bodies to the anterior thalamus in macaque monkeys.

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 to provide the source of projections to the rostral midline thalamic nuclei. In contrast, the labeled cells in the lateral mammillary nucleus were evenly spread across that nucleus, irrespective of injection site. In addition to the established projection to anterior dorsalis, the lateral mammillary nucleus appears to project lightly to a number of other thalamic nuclei, including lateralis dorsalis, anterior medialis, anterior ventralis, and the rostral midline nuclei, e.g. nucleus reuniens. These anatomical findings not only reveal novel ways of grouping the neurons within the medial mammillary nucleus, but also indicate that the mammillothalamic connections support cognition in multiple ways.