Thèse (Ph. D.)--Université Laval, 2008. / Titre de l'écran-titre (visionné le 9 mai 2008). Bibliogr.

Thesis (Ph. D. in Psychology)--Vanderbilt University, May 2006. / Title from title screen. Includes bibliographical references.

Neuromodulatory systems, such as the locus coeruleus (LC) - norepinephrine (NE) system, are integral in the modulation of behavioral state, which in turn exerts a heavy influence on sensory processing, perception, and behavior. LC neurons project diffusely through the forebrain as the sole source of NE. LC tonic firing rate has been shown to correlate with arousal level and behavioral performance. As the LC-NE system innervates sensory pathways and NE has been shown to affect neuronal response, the LC-NE system could potentially allow for state-dependent modulation of sensory processing. However, the precise link between LC activation and sensory processing in the various stages of the sensory pathway that underly perception remained elusive. It is well established that thalamic relay nuclei play an essential role in gating the flow of sensory information to the neocortex, serving to establish cortical representation of sensory environment. Thalamocortical information transmission has been proposed to be strongly modulated by the dynamic interplay between the thalamic relay nuclei and the thalamic reticular nucleus (TRN). Neurons in the early stages of sensory pathways selectively respond to specific features of sensory stimuli. In the rodent vibrissa pathway, thalamocortical neurons in the ventral posteromedial nucleus (VPm) encode kinetic features of whisker movement, allowing stimuli to be encoded by distinctive, temporally precise firing patterns. Therefore, understanding feature selectivity is crucial to understanding sensory processing and perception. However, whether LC activation modulates this feature selectivity, and if it does, the mechanisms through which this modulation occurs, remained largely unknown. This work investigates LC modulation of thalamic feature selectivity through reverse correlation analysis of single-unit recordings from different stages of the rat vibrissa pathway. LC activation increased feature selectivity, drastically improving thalamic information transmission. This improvement was dependent on both local activation of α-adrenergic receptors and modulation of T-type calcium channels in the thalamus and was not due to LC modulation of trigeminothalamic feedforward or corticothalamic feedback inputs. LC activation reduced thalamic bursting, but this change in thalamic firing mode was not the primary cause of the improved information transmission as tonic spikes with LC stimulation carried three-times the information than tonic spikes without LC stimulation. Modelling confirmed NE regulation of intrathalamic circuit dynamics led to the improved information transmission as LC-NE modulation of either relay or reticular nucleus alone cannot account for the improvement. These results suggest a new sub-dimension within the tonic mode in which brain state can optimize thalamic sensory processing through modulation of intrathalamic circuit dynamics. Subsequent computational work was then performed to determine exactly how the encoding of sensory information by thalamic relay neurons was altered to allow for an increase in both information transmission efficiency and rate. The results show that LC-NE induced improvements in feature selectivity are not simply due to an increased signal-to-noise ratio, a shift from bursting to tonic firing, or improvements in reliability or precision. Rather, LC-NE-induced modulation of intrathalamic dynamics changed the temporal response structure thalamic neurons used to encode the same stimuli to a new structure that increased the information carried by both tonic and burst spikes. The shift in events times favors optimal encoding, as more events occur at ideal positions, i.e. when the stimulus most closely matches the neuron’s feature selectivity. Further, this work analyzed the ability to reconstruct the original stimulus using the evoked spike trains of multiple neurons and their recovered feature selectivity from an ideal observer point-of-view. The results showed that LC-activation improved the accuracy of this reconstruction, indicating it may improve the accuracy of perception of whisker stimuli. Finally, to make this work translatable, the use of vagus nerve stimulation (VNS) was investigated as a potential method for minimally invasive enhancement of thalamic sensory processing. The vagus nerve, which runs through the side of the neck, has long been known to have profound effects on brain-state and VNS has been shown to evoke LC firing. This work elucidates the previously uninvestigated short-term effects of VNS on thalamic sensory processing. Similar to direct LC stimulation, VNS enhanced the feature selectivity of thalamic neurons, resulting in a significant increase in the efficiency and rate of stimulus-related information conveyed by thalamic spikes. VNS-induced improvement in thalamic sensory processing also coincided with a decrease in thalamic burst firing, suggesting the same underlying mechanism as the improvements induced with direct LC stimulation.

This thesis provides insights into the mechanism by which thalamocortical axons (TCAs) approach the cortex from their origin in the thalamus. Previous studies suggested that the reciprocal projections from the prethalamus and the ventral telencephalon guide TCAs to descend through the prethalamus and cross the diencephalic-telencephalic boundary (DTB), after which TCAs navigate through permissive corridor cells in the ventral telencephalon and cross the pallial-subpallial boundary (PSPB) before reaching their final targets in the cortex. The ‘Handshake Hypothesis’ proposed that pioneer axons from cortical preplate neurons guide TCAs into corresponding cortical areas. However, there is a lack of convincing evidence on whether TCAs need any guidance to cross the PSPB. In the current study, Adenomatous polyposis (Apc) gene is conditionally deleted from the cortex, by using Emx1Cre-APCloxP recombination technology. Apc is widely expressed in the nervous system including the cortical plate of the cortex and regulates axonal growth and neuronal differentiation. Deleting Apc may block neurite extension and/or affect the formation of attractive or repulsive cues in the cortex. By using DiI tracing as well as L1 immunohistochemistry techniques, I showed that in the Apc mutants cortical axons are absent and that TCAs initially navigate into the ventral telencephalon normally but fail to complete their journey into the cortex. They stop as they approach the PSPB, although the PSPB doesn’t seem to be directly affected by the mutation of Apc in the cortex. Additionally, Ig-Nrg1 (Neuregulin-1), the secreted protein that was suggested to play long-range roles in attracting TCAs towards the cortex, is present in the Apc mutant. This implies that Ig-Nrg1 is not sufficient for guiding TCAs into the cortex, and that additional guidance factors are needed. Moreover, my in vitro explant culture experiments show that the mutant cortex neither repel nor inhibit thalamic axonal outgrowth, indicating that the failure of TCAs in reaching the cortex is not due to the change of repulsive cues secreted by the mutant cortex. It rather indicates that the guidance factors for TCAs are likely to function through cell-cell contact mediated mechanisms. The Apc mutant cortex lacks these guidance factors, which might be the cortical axons. In conclusion, my data reveal a choice point for TCAs at the PSPB. Guidance factors from the cortex are needed for TCAs to cross the PSPB, which are absent in the Apc mutant. TCAs may need the direct contact with cortical axons and use them as an axonal scaffold to navigate into the cerebral cortex.

Conventional theories of diencephalic amnesia have focused on a single thalamic region as a critical factor in the origins of anterograde amnesia. A more contemporary view is that different thalamic regions might contribute in unique ways to normal diencephalic functioning and therefore provide distinct contributions to the learning and memory. This study directly compared the effects of AT and MT lesions on a spatial pattern separation task, a spatial working memory task and a conditioned place preference task. AT lesions but not MT lesions produces deficits on the spatial working memory task on a cheeseboard. No group AT, MT or control rats acquired a conditioned place preference on the AT/MT lesion conditioned place preference task. Furthermore, this study determined the effect of systematic procedural variations on control rats in a conditioned place preference control task. The only variation that acquired a condition place preference was a separate arms conditioned place preference with one pre-exposure and three training trials. The results of this study provide new information regarding the role of thalamic lesions in spatial memory and suggests a revision of the current theories regarding learning and memory to incorporate the thalamic involvement that has been highlighted

Neural oscillations are a ubiquitous form of neural activity seen across scales and modalities. These neural rhythms correlate with diverse cognitive functions and brain states. One mechanism for changing the oscillatory dynamics of large neuronal populations is through neuromodulator activity. An intriguing phenomenon explored here is when local neuromodulation of a distinct neuron type within a single brain nucleus exerts a powerful influence on global cortical rhythms. One approach to investigate the impact of local circuits on global rhythms is through optogenetic techniques. My first project involves the statistical analysis of electrophysiological recordings of an optogenetically-mediated Parkinsonian phenotype. Empirical studies demonstrate that Parkinsonian motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the cortico-basal ganglia-thalamic network. However, the mechanism of these aberrant oscillatory dynamics is not well understood. A previous modeling study predicted that cholinergic neuromodulation of medium spiny neurons in the striatum of the basal ganglia may mediate the pathologic beta rhythm. Here, this hypothesis was tested using selective optogenetic stimulation of striatal cholinergic interneurons in normal mice; stimulation robustly and reversibly amplified beta oscillations and Parkinsonian motor symptoms. The modulation of global rhythms by local networks was further studied using computational modeling in the context of intrathalamic neuromodulation. While intrathalamic vasoactive intestinal peptide (VIP) is known to cause long-lasting excitation in vitro, its in vivo dynamical effects have not been reported. Here, biophysical computational models were used to elucidate the impact of VIP on thalamocortical dynamics during sleep and propofol general anesthesia. The modeling results suggest that VIP can form robust sleep spindle oscillations and control aspects of sleep architecture through a novel homeostatic mechanism. This homeostatic mechanism would be inhibited by general anesthesia, representing a new mechanism contributing to anesthetic-induced loss of consciousness. While the previous two projects differed in their use of empirical versus theoretical methods, a challenge common to both domains is the difficulty in visualizing and analyzing large multi-dimensional datasets. A tool to mitigate these issues is introduced here: GIMBL-Vis is a Graphical Interactive Multi-dimensional extensiBLe Visualization toolbox for Matlab. This toolbox simplifies the process of exploring multi-dimensional data in Matlab by providing a graphical interface for visualization and analysis. Furthermore, it provides an extensible open platform for distributed development by the community.

Es wurden insgesamt sieben Gallozyanin-gefärbte Schnittserien durch die rechte oder linke Hemisphäre von zwei Kontrollfällen (männlich, 28 Jahre, rechte Hemisphäre, weiblich, 65 Jahre, linke Hemisphäre), einem Fall mit Megalenzephalie (männlich, 48 Jahre, linke Hemisphäre), einem Fall von M. Little (65 Jahre, männlich, linke Hemisphäre), einem Fall von Alzheimerscher Krankheit (85 Jahre, weiblich, linke Hemisphäre) und einem Fall mit Huntingtonscher Krankheit (männlich, 49 Jahre, beide Hemisphären) verwendet. Die zentralen Anteile der Hemisphären mit den kompletten Schnittserien durch Thalami und Corpora striata wurden mit einer digitalen Kamera in Nahaufnahmetechnik aufgenommen, mit einem kommerziellen Bildbearbeitungs-programm (Adobe Photoshop 6.0®) aufbereitet und die derart aufbereiteten Bilder am Computer mit einer Computer gestützten 3D-Rekonstruktionssoftware (Amira®) verar-beitet. Ein wesentlicher Schritt in der Bearbeitung besteht in der Abgrenzung von Thalamus und Striatum von den benachbarten Strukturen. Die hohe Schnittdicke von 440 µm erleichterte dabei die zytoarchitektonische Abgrenzung beider Kerngebiete. Anders als erwartet unterliegen auch Serienschnitte mit einer Dicke von 440 µm Schrumpfungsartefakten, die nicht immer auf den ersten Blick erkennbar sind. Aus diesem Grund beschränken sich die 3D-Rekonstruktionen nicht auf das manuelle Abgrenzen von Strukturen. Vielmehr müssen alle Schnitte sorgfältig den Koordinaten des Raumes angepasst, hintereinander in der z-Achse angeordnet und bei Bedarf gedreht und verschoben werden. Die Rekonstruktionssoftware bietet für diese Prozedur eine halbautomatische Unterstützung. Einzelne stark verformte Schnitte mussten aber dennoch teilweise aufwändig der Serie angepasst werden. Amira® bietet vielseitige Möglichkeiten in der Darstellung der räumlich rekonstruierten Schnitte. Durch Interpolation werden die Rohdaten zum Teil stark verändert und die ursprünglich kantigen und eckigen Formen zunehmend geglättet. Diese Glättung ist der Erfahrung/Willkür des Untersuchers anheim gestellt und folglich werden die Grenzen zwischen einer realistischen 3D-Rekonstruktion und einer Fiktion fließend. Neben 3D-Rekonstruktionen lassen sich mit Amira auch die Volumina von Striatum und Thalamus berechnen. Diese Daten wurden mit den stereologisch bestimmten Kernvolumina und Nervenzellzahlen verglichen. Grundsätzlich liegen die mit Amira erhobenen Volumenwerte zwischen 1,4 und 6,65% unter den stereologisch geschätzten Werten. Diese Diskrepanz ist bei der bekannten biologischen Variabilität des menschlichen ZNS akzeptabel und im Vergleich mit Literaturangaben und -abbildungen dürften Form und Größe der rekonstruierten Thalami und Corpora striata der Wirklichkeit weitgehend entsprechen. Die Nervenzellzahlen schwanken dabei in einem weiten Bereich zwischen rund 71 Millionen im Striatum bei Megalenzephalie und weniger als 7 Millionen bei Chorea Huntington. Im Thalamus liegt die Nervenzellzahl zwischen rund 18 Millionen (Kontrollfall) und etwas mehr als 6 Millionen bei dem untersuchten Fall mit M. Little. Berücksichtigt man die vielfältigen physiologischen Verbindungen zwischen Thalamus und Striatum, so lassen die Schwankungen in den Nervenzellzahlen auf komplexe Interaktionen und Defizite bei den untersuchten Fällen schließen. Im Ergebnis unerwartet ist die weitgehende Konstanz in Form und Aussehen von Thalamus und Striatum im Endstadium von Alzheimerscher Demenz und bei einem Fall von M. Little. Offensichtlich stehen globale Atrophie- bzw. Degenerationsprozesse bei der Alzheimerschen Krankheit im Vordergrund mit der Folge, dass Thalamus und Striatum trotz deutlicher Nervenzellausfälle bei erhöhter Zahl von Gliazellen insgesamt nur wenig kleiner werden. Allerdings tat sich bei dem Fall mit M. Alzheimer an der Ventralseite des Thalamus eine Rinne auf, die bei den anderen untersuchten Fällen nicht gefunden und deren Ursache nicht geklärt werden konnte. Dramatisch erschienen die Größen- und Formveränderung des Striatum beim Chorea-Huntington-Fall. Nervenzell- und Gliazellausfälle im Striatum bei Chorea Huntington dürften die ausgeprägten makroskopischen Veränderungen erklären. Die Kombination von Serienschnitttechnik mit hoher Schnittdicke und einer Computer gestützten 3D-Rekonstruktion bietet bisher nie da gewesene und faszinierende Aspekte vom Bau des menschlichen ZNS. Nach Import in spezielle Computersoftware zur Animation von 3D-Modellen eröffnen die 3D-Rekonstruktionen auch neue Aspekte in der Präsentation der vermuteten Funktionsweise des ZNS. Dabei sollte aber in Anbetracht der komplexen methodischen Faktoren immer eine kritische Distanz zu vielfältigen Darstellungsformen am Bildschirm gewahrt bleiben. / In total we investigated seven gallocyanin stained slice series through the right and left hemisphere of two control cases (man, age 28, right hemisphere, female, age 65, left hemisphere), one case of Megalencephaly (man, age 48, left hemisphere), one case of M. Little (man, age 65, left hemisphere), one case of Alzheimers Disease (female, age 85, left hemisphere) and one case of Huntingtons Disease (man, age 49, both hemispheres). The central parts of the hemispheres with the complete slice series through thalamus and striatum were captured with a digital camera and processed with a commercial picture-processing-programme (Adobe Photoshop 6.0®) and the result was further processed to 3D-models with another software (Amira®). One fundamental step in this procedure is the demarcation between thalamus and striatum and their sourrounding cell groups. The high slice thickness of 440 µm makes this much easier. Different from our expactation we found shrinking artefacts even in slices with a thickness of 440 µm, which were not always visible at first sight. For this reason we had to do more than manual demarcation of the structures, e.g. arrangement of all slices in a row in z-axes and rotation of the slices when needed. The reconstruction software can do this semiautomatically, but in some cases we had to do this on our own in a very difficult procedure. Amira® has a lot of possibilities to show the reconstructed slices. The original database is transformated during the reconstruction procedure so that the models are influenced subjective. Besides 3D-reconstructions we can measure the volume of striatum and thalamus with Amira®. We compared this data with the volumes determined with stereological methods and can say that the volumes measured with Amira® lay 1,4-6,65% under the volumes determined with stereological methods. This different is acceptabel in the face of biological variability. The amount of neurons extend from 71 millions in striatum with Megalencephaly to 7 millions in striatum with Huntingtons Disease. In the thalamus it extends from18 millions in a control case to 6 millions in a M.Little case. Unexpected was the constant form and shape of thalamus and striatum in the late stages of neurodegenerative diseases like Alzheimers Disease. We suggest that the undergoing neurons are replaced by glia and so the macroscopical form remains nearly constant. On the other hand we could see dramatically changes in form and size of the striatum in the Huntingtons Disease case. The combination of serial slice technique with high sliche thickness and computer supported 3D-reconstruction offers new and fascinating aspects of the human central nervous system. Knowing the complex methods to get to this reconstructions one should always observe these models critical.

The development of the diencephalon can be summarised as a process in which cells that initially appear similar give rise to a complex structure that contains a variety of cell groups called nuclei. It involves two stages: the early patterning of the diencephalic prosomeres and the later formation of the individual nuclei. It has been shown that transcription factors and morphogens regulate the first stage but their further effects on the second stage remain unclear. The ventral lateral geniculate nucleus (vLGN) is involved in the visual system and is shown to have complex origins from the thalamus, the zona limitans intrathalamica (ZLI) and the prethalamus. The transcription factor Pax6 is involved in the development of brain structures including the cortex, the diencephalon and the major axonal tracts in the forebrain by playing a multifaceted role in patterning, proliferation, differentiation, migration and axon guidance. It is known that Pax6 is essential in setting up the prosomeric boundaries in the developing diencephalon but its role in the formation of individual nuclei has not yet been explored. By using a conditional Pax6 knock-out mouse driven by Zic4Cre with a green fluorescent protein (GFP) reporter showing the Cre activity, the formation of the thalamic nuclei vLGN, dorsal lateral geniculate nucleus (dLGN) and VP (ventral posterior nuclei) was examined in postnatal day 0 (P0) Pax6+/+, Pax6fl/+ and Pax6fl/fl pups. Using this mouse model, I found an increase in nuclear volume at the rostral level and a global decrease in cell density in the P0 Pax6fl/fl vLGN, whereas in the dLGN an increase of GFP+ve cell proportion was observed. In Pax6fl/+, I found an increase in GFP+ve cell proportion in the caudal part of the vLGN and across the dLGN. No significant change was observed in the VP in either the Pax6fl/+ or the Pax6fl/fl. The defects in the vLGN and dLGN could be caused by: 1. disruption of the expression of patterning factors such as Shh and Nkx2.2; 2. cell proliferation defcts and abnormal apoptosis; 3. ocular developmental defects; 4. failure in cell sorting/migration; 5. cell fate change. During my PhD, I tested the first three theories and explored the fourth but was not able to pursue the last due to the time limit of the project. To test the hypothesized mechanisms underlying those defects seen in the vLGN and dLGN, I performed BrdU labelling to study the time origin of cells that contribute to these two nuclei and discovered that E11.5 and E12.5 are the main ages when these cells and the GFP+ve subpopulation are born. Then I carried out experiments to examine the cell proliferation and cell apoptosis in the thalamus (pTH-R, rostral part of the progenitor zone of the thalamus, and pTH-C, caudal part of the progenitor zone of the thalamus) and the prethalamus (Pth) from E11.5 to E13.5 and found: 1. the proliferation rate decreased in the pTH-R in Pax6fl/+ at E11.5; 2. the growth fraction decreased in both pTH-C and pTH-R in E12.5 Pax6fl/fl; 3. there is no change in cell proliferation in the GFP+ve subpopulation; 4. no abnormal apoptosis is observed in either the whole cell population or the GFP+ve subpopulation. Judging by the amplitude of the change in proliferation in the pTH-R and pTH-C at E11.5 and E12.5, it is unlikely that these changes alone are responsible for the phenotypes seen in P0 vLGN and dLGN. Then I examined the expression patterns of Shh and Nkx2.2 and the expansion of both was observed in Pax6fl/fl at both E12.5 and E13.5, which could explain the volume change of the vLGN but not the change in the proportion of GFP+ve subpopulation in both the vLGN and dLGN. Then I continued to examine if the ocular input from the retinal ganglionic cells are severely affected by the deletion of Pax6 and found no gross change in the conditional mutants, which rejected the ocular developmental defects theory. At the end of my PhD, I performed a BrdU short-term survival experiment and a brain slice culture combined with live imaging experiment to explore the possibility of abnormal cell migration causing the vLGN and dLGN phenotypes and found that the cells moving along the border of the thalamus and prethalamus move faster in the Pax6fl/fl than in the Pax6fl/+, but rather than moving directly toward the lateral surface of the diencephalon, they take a detour. These findings indicate that the deletion of Pax6 causes minor changes in the proliferation of E11.5 to E13.5 diencephalon and expansion of regional marker expression such as Shh and Nkx2.2, which could potenially affect the volume and change the proportion of GFP+ve cells in P0 vLGN and dLGN. Migration defects caused by Pax6 could also contribute to the phenotype observed in those two nuclei. Potential cell fate change caused by Pax6 deletion could be another factor that contributes to the defects in the conditional mutants. More work needs to be done to test the migration defect and cell fate change hypotheses in future.

The nuclei of the midline thalamus are an important part of the brain’s limbic system. Previous work has described the presence of dopamine D2 receptors in the midline thalamus in humans, non-human primates, and rodents. A similar body of literature has also demonstrated dopaminergic innervation of the midline thalamus across these species. However, little is known regarding a) the source of dopaminergic innervation to the midline thalamus in rodents and b) the function of D2R in the midline thalamus in any species. I begin this thesis with a review of the literature examining the anatomy, electrophysiological properties, and role in behavior of the paraventricular nucleus of the thalamus (PVT), a region where D2R mRNA and protein is expressed. I next describe a series of three sets of experiments aimed toward examining the anatomical, electrophysiological, and behavioral role of D2R in the PVT in mice. In the first set of experiments, I used anatomical methods to show that D2R are particularly enriched in neurons of the PVT. I focused on D2R-expressing PVT neurons specifically and show their afferent and efferent projections throughout the brain. In addition, I describe a set of experiments aimed to establish a dopaminergic innervation to the PVT. In the second set of experiments, I used electrophysiological methods to study D2R-expressing PVT neurons. Here, I establish that tonic firing in D2R-expressing thalamic relay neurons in the PVT is inhibited by quinpirole, a D2R/D3R agonist, and increased by sulpiride, a D2R/D3R antagonist. In the third set of experiments, I assessed the behavioral function of D2R in PVT neurons since this has never been studied in any species. I directly manipulated PVT D2R in two directions: a) by overexpressing D2R, and b) by downregulating D2R. Here I show PVT D2R plays a role in both cocaine locomotor sensitization as well as contextual fear expression. Our findings demonstrate for the first time the role of D2R in the PVT and add to literature suggesting that the PVT is an important component of the neural circuitry underlying fear behavior and drug reward. I conclude this thesis with a discussion of the findings described in the three sets of experiments as well as a proposal for future experiments.

Intrazerebrale stereotaktische Eingriffe werden zu einem großen Teil ohne direkte Sichtkontrolle durchgeführt. Ein Operateur muss sich deshalb bei der räumlichen Festlegung von Strukturen und beim Anfahren dieser Strukturen auf Hilfsmittel wie stereotaktische Geräte und auf Atlanten, über welche die stereotaktischen Geräte gesteuert werden, verlassen. Trotz großer Fortschritte bei den bildgebenden Verfahren während der letzten dreißig Jahre, ist es gegenwärtig noch nicht möglich, zuverlässig alle subkortikalen Strukturen mit computertomographischen (CT) oder magnetresonanztomographischen (MRT) zu identifizieren oder begrenzen. Eine ganze Reihe zytoarchitektonischer beziehungsweise immunhistochemischer Atlanten wurde veröffentlicht. Dennoch ist es nicht gelungen, die Ergebnisse und Abbildungen dieser Atlanten mit bildgebenden Verfahren bis in die gewünschten Details zu kombinieren, um auf diese Weise das immer noch geringe Auflösungsvermögen radiologischer Methoden zu erhöhen. Deformationen bei der Gewebsentnahme des Gehirns, bei der anschließenden Einbettung, bei der alkoholischen Dehydrierung des Gewebes, Verformungen beim Schneiden und Färben der Schnitte überfordern selbst hoch komplexe mathematische Verfahren und Algorithmen beim Versuch, zytoarchitektonische und immunhistochemische Schnitte mit der gewünschten Präzision den radiologischen Ergebnissen und Bildern und damit indirekt auch den Verhältnissen in vivo anzupassen. Als Alternative verwendeten wir ungewöhnlich dicke (350 – 440 µm) Gallozyanin- (Nissl) gefärbte Serienschnitte durch die Gehirne (ZNS) von drei Personen im Alter von 56, 68 und 36 Jahren. Bei einem Fall wurde das ZNS post mortem mit einem Kernspintomographen vor der Entnahme gescannt. Die Serienschnitte durch dieses Gehirn und das eines zweiten und dritten nicht-gescannten Falles wurden mit Gallozyanin gefärbt, die zytoarchitektonischen Grenzen des Thalamuskomplexes und seiner Unterkerne wurden nach Hassler (1982) identifiziert, jede ihrer Grenzen mit dem Cursor eines Graphiktabletts umfahren und die Gestalt des Thalamuskomplexes und seiner Unterkerne mit Hilfe von Photoshop CS5® und eines computergestützten 3D-Rekonstruktionsprogramms (Amira®) dargestellt. Im Fall 3 ließen sich nach Dunkelfeldbeleuchten die Verteilung markhaltiger Fasern studieren und die zytoarchitektonischen mit myeloarchitektonischen Befunden erweitern und ergänzen. Zusätzlich konnten im Fall 1 die histologischen Serienschnitte und ihre 3D Rekonstruktion mit dem post mortem in cranio MRT registriert werden. Insgesamt kann dieser methodische Ansatz als eine robuste und relativ einfache wenn auch mit umfangreicherer manueller Tätigkeit verbundene Technik zur sehr detailreichen unverformten Korrelation zytoarchitektonischer und kernspinotomographsicher Darstellung des Thalamuskomplexus und seiner Unterkerne angesehen werden. Sie könnte als Grundlage für die Herausgabe eines multimedialen 3D stereotaktischen Atlas des menschlichen Gehirns dienen. / Stereotactic procedures are based on the precise spatial localization of targets within the human brain.Despite the great advance in neuroimaging in the last thirty years, it is still not possible to delineate or toreliably identify all the subcortical structures using computed tomography (CT) or magnetic resonance imaging (MRI).Although several cytoarchitectural- or immunohistochemical- maps have been proposed as parameters for correlating imaging results with anatomical location of these structures, technical limitations prevent a point-to-point correlation between imaging and anatomy. The main shortcoming of these maps is the lack of precise correction of post-mortem tissue deformations caused by fixation and processing. To date, even complex algorithms failed to completely correct these distortions. As an alternative, we present a 3D reconstruction of the human thalamic nuclei of 2 subjects (n=4), based on serial histological sections. We assessed the results of histology-based 3D reconstruction either with or without corregistration to post mortem in-situ MR images of the same brains. To this purpose a simple and reliable method to processthe tissue was used and a new tissue warping technique was developed, allowing outstanding three-dimensional coherence. The one-to-one correlation of the histology with the 3T MRI of the same subject warrants a better interpretation of MR images. This procedure compensates the inherent shortcomings of either methods. Our results render feasible the construction of an improvedthree-dimensional stereotactic atlas of the human brain.