In JoVE (1)

Other Publications (23)

Articles by Carsten R. Bjarkam in JoVE

Other articles by Carsten R. Bjarkam on PubMed

Distribution and Morphology of Serotonin-immunoreactive Axons in the Hippocampal Region of the New Zealand White Rabbit. I. Area Dentata and Hippocampus

Hippocampus. 2003  |  Pubmed ID: 12625454

This study provides a detailed light microscopic description of the morphology and distribution of immunohistochemically stained serotonergic axons in the hippocampal region of the New Zealand white rabbit. The serotonergic axons were segregated morphologically into three types: beaded fibers, fine fibers, and stem-axons, respectively. Beaded fibers were thin serotonergic axons with large varicosities, whereas thin axons with small fusiform or granular varicosities were called fine fibers. Finally, thick straight non-varicose axons were called stem-axons. Beaded fibers often formed large conglomerates with numerous boutons (pericellular arrays) in close apposition to the cell-rich layers in the hippocampal region, e.g., the granular and hilar cell layers of the dentate area and the pyramidal cell layer ventrally in CA3. The pericellular arrays in these layers were often encountered in relation to small calbindin-D2BK-positive cells, as shown by immunohistochemical double staining for serotonin and calbindin-D28K. The beaded and fine serotonergic fibers displayed a specific innervation pattern in the hippocampal region and were encountered predominantly within the terminal field of the perforant path, e.g., the stratum moleculare hippocampi and the outer two-thirds of the dentate molecular layer. These fibers were also frequently seen in the deep part of the stratum oriens and the alveus, forming a dense plexus in relation to large multipolar calbindin-D28K-positive cells and their basal extensions. Stem-axons were primarily seen in the fimbria and alveus. This innervation pattern was present throughout the entire hippocampal formation, but there were considerable septotemporal differences in the density of the serotonergic innervation. A high density of innervation prevailed in the ventral/temporal part of the hippocampal formation, whereas the dorsal/septal part received only a moderate to weak serotonergic innervation. These results suggest that the serotonergic system could modulate the internal hippocampal circuitry by way of its innervation in the terminal field of the perforant path, the hilus fasciae dentatae, and ventrally in the zone closely apposed to the mossy fiber layer and the pyramidal cells of CA3. This modulation could be of a dual nature, mediated directly by single serotonergic fibers traversing the hippocampal layers or indirectly by the pericellular arrays and their close relation to the calbindin-D28K-positive cells. The marked septotemporal differences in innervation density point toward a difference between the ventral and dorsal parts of the hippocampal formation with respect to serotonergic function and need for serotonergic modulation.

The Anatomy of the Porcine Subthalamic Nucleus Evaluated with Immunohistochemistry and Design-based Stereology

Anatomy and Embryology. Jun, 2004  |  Pubmed ID: 15168115

This study provides a light-microscopic description of the organization, morphology and number of neurons in the subthalamic nucleus (STN) of the Göttingen minipig. It is based on histological material stained with Nissl, Golgi and autometallographic techniques, and employs design-based stereological estimation of the total neuron number. The organization of several neurotransmitters in the STN has been evaluated in histological preparations stained for acetylcholinesterase (AChE) and immunostained for choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD) and glutamate. In all of the stained preparations the STN appeared as a distinct lens-shaped structure located in the caudal diencephalon, medial to the internal capsule and ventrolateral to the zona incerta. Rostrally, the STN approached the globus pallidus pars interna, whereas caudally the ventromedial part of the STN was adjacent to the rostral part of the substantia nigra pars compacta (SNc), where some of the neurons of the two nuclei merged. The neurons in the STN had medium-sized (25-40 microm) ovoid or fusiform cell bodies, from which three to six large dendrites emanated in a direction predominantly parallel to the long axis of the STN. Immunohistochemistry revealed that most of the subthalamic neurons were glutamatergic and differed significantly in appearance from the large stellate TH-positive cells of the adjacent SNc. Numerous TH-positive bouton-rich fibers traversed the STN. The GAD-staining revealed a large number of terminals within the boundaries of the STN. The STN was highly AChE-positive, reflecting a prominent innervation by ChAT-positive terminals. The total number of subthalamic neurons in one hemisphere was estimated to be approximately 56,000. We conclude that the neuroarchitecture of the porcine STN is similar to primates, including humans, and appears well-suited for further studies examining the role of the STN in movement disorders.

Therapeutic Strategies for Neurodegenerative Disorders: Emerging Clues from Parkinson's Disease

Biological Psychiatry. Aug, 2004  |  Pubmed ID: 15312807

Our knowledge of Parkinson's disease pathophysiology has greatly expanded during the last century, resulting in successful new medical and neurosurgical approaches toward this common neurodegenerative disorder. These approaches might also be useable in the treatment of psychiatric disorders, which often are linked to atrophic and degenerative processes in the brain; however, the successful application of these techniques in psychiatry requires thorough elucidation of disease pathophysiology to identify proper intervention sites. Likewise, awareness of the differences between the parkinsonian and psychiatric patient populations in terms of age, disease course, and life expectancy, as well as ethical considerations might in the end determine the appropriateness of these therapeutic strategies in psychiatry.

Stereotactic Electrical Stimulation of the Pontine Micturition Centre in the Pig

BJU International. Apr, 2005  |  Pubmed ID: 15794803

To apply stereotactic electrical stimulation of the pig brainstem and thus identify a pontine micturition centre.

Distribution and Morphology of Serotonin-immunoreactive Axons in the Retrohippocampal Areas of the New Zealand White Rabbit

Anatomy and Embryology. Oct, 2005  |  Pubmed ID: 16170538

This study provides a detailed light microscopic description of the morphology and distribution of serotonin-immunoreactive axons in the paleocortical retrohippocampal areas, viz. the subiculum, presubiculum, parasubiculum and entorhinal area, and the adjoining neocortical perirhinal and retrosplenial cortices of the New Zealand white rabbit. Serotonergic axons could be segregated into three different fiber types named fine fibers, beaded fibers and stem-axons. Fine fibers were evenly distributed thin axons with small fusiform/granular varicosities. Beaded fibers were thin axons with large varicosities, predominantly located in the retrohippocampal supragranular layers, where they often formed pericellular arrays. Stem-axons were thick straight, nonvaricose axons seen in the white matter of psalterium dorsale, alveus and the plexiform layer. The paleocortical retrohippocampal areas had a dense supragranular innervation with numerous tortuous fine and beaded fibers, intermingled in conglomerates with conspicuous varicosities forming pericellular arrays. In contrast, the neocortical area 17 and the lateral part of the perirhinal cortex (area 36) were innervated by evenly distributed fine fibers with a moderate number of small varicosities and few ramifications, whereas, the retrosplenial cortex (areas 29e, 29ab and 29cd), and the medial part of the perirhinal cortex (area 35) displayed an intermediate innervation pattern, probably reflecting the transitional nature of these areas being located between the paleo- and the neocortex. The described dualistic innervation pattern may functionally enable the serotonergic system to exert a strong influence on the supragranular layers of the retrohippocampal areas and thus on the neural input entering these areas from the perirhinal and neighboring polymodal association neocortices, whereas the innervation pattern in the adjoining neocortical areas points towards a more diffuse and general modulation of neural activity herein.

Deep Brain Stimulation Electrode Anchoring Using BioGlue((R)), a Protective Electrode Covering, and a Titanium Microplate

Journal of Neuroscience Methods. Feb, 2008  |  Pubmed ID: 17953993

The authors present an easily applicable deep brain stimulation (DBS) electrode anchoring technique for use in human and experimental animals. The anchoring technique combines the use of fibrin glue, a two-component surgical adhesive (BioGlue), a protective electrode covering, and a titanium microplate. The BioGlue (CryoLife International, Inc., Kennesaw, GA, USA) hinders unwanted electrode movement during the electrode fixation step and seals the burr hole, while the protective electrode covering protects the electrode under the titanium microplate which keeps the electrode in a permanent position. The described technique further has the advantage of being cosmetically acceptable to the human patient, and furthermore it perfectly adapts to the smaller and irregular-shaped skull in experimental animals. The described technique has clinically been used to implant DBS-electrodes in the subthalamic nucleus for Parkinson disease and is the preferred DBS-electrode anchoring technique for our experimental DBS-studies in the Göttingen minipig.

Long-term Meditation is Associated with Increased Gray Matter Density in the Brain Stem

Neuroreport. Jan, 2009  |  Pubmed ID: 19104459

Extensive practice involving sustained attention can lead to changes in brain structure. Here, we report evidence of structural differences in the lower brainstem of participants engaged in the long-term practice of meditation. Using magnetic resonance imaging, we observed higher gray matter density in lower brain stem regions of experienced meditators compared with age-matched nonmeditators. Our findings show that long-term practitioners of meditation have structural differences in brainstem regions concerned with cardiorespiratory control. This could account for some of the cardiorespiratory parasympathetic effects and traits, as well as the cognitive, emotional, and immunoreactive impact reported in several studies of different meditation practices.

Long-term Implantation of Deep Brain Stimulation Electrodes in the Pontine Micturition Centre of the Göttingen Minipig

Acta Neurochirurgica. Jul, 2009  |  Pubmed ID: 19404572

To implant deep brain stimulation (DBS) electrodes in the porcine pontine micturition centre (PMC) in order to establish a large animal model of PMC-DBS.

Autometallographic Enhancement of the Golgi-Cox Staining Enables High Resolution Visualization of Dendrites and Spines

Histochemistry and Cell Biology. Sep, 2009  |  Pubmed ID: 19504264

We present a method for autometallographic (AMG) enhancement of the Golgi-Cox staining enabling high resolution visualization of dendrites and spines. The method is cheaper and more flexible than conventional enhancement procedures performed with commercial photographic developers. The staining procedure is thoroughly described and we demonstrate with qualitative and quantitative data, how histological tissue sectioning, Golgi-Cox immersion time and different AMG enhancement length may influence the staining of dendrites and spines in the rat hippocampus. The described method will be of value for future behavioural-anatomical studies, examining changes in dendrite branching and spine density caused by brain diseases and their subsequent treatment.

MRI-guided Stereotaxic Targeting in Pigs Based on a Stereotaxic Localizer Box Fitted with an Isocentric Frame and Use of SurgiPlan Computer-planning Software

Journal of Neuroscience Methods. Oct, 2009  |  Pubmed ID: 19559051

We present a stereotaxic procedure enabling MRI-guided isocentric stereotaxy in pigs. The procedure is based on the Leksell stereotaxic arch principle, and a stereotaxic localizer box with an incorporated fiducial marking system (sideplates) defining a stereotaxic space similar to the clinical Leksell system. The obtained MRIs can be imported for 3D-reconstruction and coordinate calculation in the clinical stereotaxic software planning system (Leksell SurgiPlan, Elekta AB, Sweden). After MRI the sideplates are replaced by a modified Leksell arch accommodating clinical standard manipulators for isocentric placement of DBS-electrodes, neural tracers and therapeutics in the calculated target coordinates. The mechanical accuracy of the device was within 0.3-0.5 mm. Stereotaxic MRIs were imported to the stereotaxic software planning system with a mean error of 0.4-0.5 mm and a max error of 0.8-0.9 mm. Application accuracy measured on a phantom and on inserted skull markers in nine pigs was within 1 mm in all planes. The intracerebral application accuracy found after placement of 10 manganese trajectories within the full extent of the intracerebral stereotaxic space in two minipigs was equally randomly distributed and within 0.7+/-0.4; 0.5+/-0.4; and 0.7+/-0.3mm in the X, Y, and Z plane. Injection of neural tracers in the subgenual gyrus of three minipigs and placement of encapsulated gene-modified cells in four minipigs confirmed the accuracy and functionality of the described procedure. We conclude that the devised technique and instrumentation enable high-precision stereotaxic procedures in pigs that may benefit future large animal neuroscience research and outline the technical considerations for a similar stereotaxic methodology in other animals.

Neurite Density from Magnetic Resonance Diffusion Measurements at Ultrahigh Field: Comparison with Light Microscopy and Electron Microscopy

NeuroImage. Jan, 2010  |  Pubmed ID: 19732836

Due to its unique sensitivity to tissue microstructure, diffusion-weighted magnetic resonance imaging (MRI) has found many applications in clinical and fundamental science. With few exceptions, a more precise correspondence between physiological or biophysical properties and the obtained diffusion parameters remain uncertain due to lack of specificity. In this work, we address this problem by comparing diffusion parameters of a recently introduced model for water diffusion in brain matter to light microscopy and quantitative electron microscopy. Specifically, we compare diffusion model predictions of neurite density in rats to optical myelin staining intensity and stereological estimation of neurite volume fraction using electron microscopy. We find that the diffusion model describes data better and that its parameters show stronger correlation with optical and electron microscopy, and thus reflect myelinated neurite density better than the more frequently used diffusion tensor imaging (DTI) and cumulant expansion methods. Furthermore, the estimated neurite orientations capture dendritic architecture more faithfully than DTI diffusion ellipsoids.

The Anatomy of the Göttingen Minipig Hypothalamus

Journal of Chemical Neuroanatomy. May, 2010  |  Pubmed ID: 20043984

The microscopic organization of the Göttingen minipig (sus scrofa) hypothalamus was studied using Nissl stain, acetylcholinesterase histochemistry, and immunohistochemical staining for calretinin, tyrosin hydroxylase, oxytocin, vasopressin, and orexin A. Mediolaterally the minipig hypothalamus can be divided into three cytoarchitectonic distinct longitudinal zones. The periventricular longitudinal zone comprises the supraoptic, paraventricular, median preoptic, anteroventral periventricular, suprachiasmatic and arcuate nuclei. The medial longitudinal zone includes the prominent medial preoptic, ventromedial, dorsomedial and medial mammillary nuclei. Together with the anterior hypothalamic area, they can be further divided into distinct subregions. The dorsal and posterior hypothalamic areas and the retromammillary and lateral mammillary nuclei are cyto- and chemoarchitectonically distinct but cannot be further divided into subregions. The cell sparse, fiber rich lateral longitudinal zone comprises the lateral preoptic and lateral hypothalamic area as well as the perifornical, lateral tuberal and tuberomammillary nuclei. The findings presented here indicate that the cyto- and chemoarchitecture of the Göttingen minipig hypothalamus is comparable to that of rat, landrace pig, monkey, and human and that the Göttingen minipig may be well suited for future, non-primate, large mammal, hypothalamic research.

Safety and Function of a New Clinical Intracerebral Microinjection Instrument for Stem Cells and Therapeutics Examined in the Göttingen Minipig

Stereotactic and Functional Neurosurgery. 2010  |  Pubmed ID: 20051711

A new intracerebral microinjection instrument (IMI) allowing multiple electrophysiologically guided microvolume injections from a single proximal injection path in rats has been adapted to clinical use by coupling the IMI to an FHC microTargeting Manual Drive, designed to be used with standard stereotactic frame-based systems and FHC frameless microTargeting Platforms.

Long-term Delivery of Nerve Growth Factor by Encapsulated Cell Biodelivery in the Göttingen Minipig Basal Forebrain

Molecular Therapy : the Journal of the American Society of Gene Therapy. Dec, 2010  |  Pubmed ID: 20664524

Nerve growth factor (NGF) prevents cholinergic degeneration in Alzheimer's disease (AD) and improves memory in AD animal models. In humans, the safe delivery of therapeutic doses of NGF is challenging. For clinical use, we have therefore developed an encapsulated cell (EC) biodelivery device, capable of local delivery of NGF. The clinical device, named NsG0202, houses an NGF-secreting cell line (NGC-0295), which is derived from a human retinal pigment epithelial (RPE) cell line, stably genetically modified to secrete NGF. Bioactivity and correct processing of NGF was confirmed in vitro. NsG0202 devices were implanted in the basal forebrain of Göttingen minipigs and the function and retrievability were evaluated after 7 weeks, 6 and 12 months. All devices were implanted and retrieved without associated complications. They were physically intact and contained a high number of viable and NGF-producing NGC-0295 cells after explantation. Increased NGF levels were detected in tissue surrounding the devices. The implants were well tolerated as determined by histopathological brain tissue analysis, blood analysis, and general health status of the pigs. The NsG0202 device represents a promising approach for treating the cognitive decline in AD patients.

A Surgical Device for Minimally Invasive Implantation of Experimental Deep Brain Stimulation Leads in Large Research Animals

Journal of Neuroscience Methods. Aug, 2011  |  Pubmed ID: 21723320

Deep brain stimulation (DBS) in experimental animals has promoted new indications and refined existing treatments. Implantation of downscaled clinical DBS leads directly compatible with commercially available implantable pulse generators can however be challenging. Accordingly, we have developed a lead implantation device (LID) and technique for minimally invasive implantation of experimental multicontact DBS leads in large research animals.

Diffusion-weighted MRI and Quantitative Biophysical Modeling of Hippocampal Neurite Loss in Chronic Stress

PloS One. 2011  |  Pubmed ID: 21747929

Chronic stress has detrimental effects on physiology, learning and memory and is involved in the development of anxiety and depressive disorders. Besides changes in synaptic formation and neurogenesis, chronic stress also induces dendritic remodeling in the hippocampus, amygdala and the prefrontal cortex. Investigations of dendritic remodeling during development and treatment of stress are currently limited by the invasive nature of histological and stereological methods. Here we show that high field diffusion-weighted MRI combined with quantitative biophysical modeling of the hippocampal dendritic loss in 21 day restraint stressed rats highly correlates with former histological findings. Our study strongly indicates that diffusion-weighted MRI is sensitive to regional dendritic loss and thus a promising candidate for non-invasive studies of dendritic plasticity in chronic stress and stress-related disorders.

A Simple Reproducible and Time Saving Method of Semi-automatic Dendrite Spine Density Estimation Compared to Manual Spine Counting

Journal of Neuroscience Methods. Jul, 2012  |  Pubmed ID: 22595026

Estimation of spine number and spine density by manual counting under the assumption that all dendrite protrusions equal spines are often used in studies on neuroplasticity occurring during health, brain diseases, and different experimental paradigms. Manual spine counting is, however, time consuming and biased by inter-observer variation. We present accordingly a quick, reproducible and simple non-stereological semi-automatic spine density estimation method based on the irregularity of the dendrite surface. Using the freeware ImageJ program, microphotographs of Golgi impregnated hippocampal dendrites derived from a previously performed study on the impact of chronic restrained stress were binarized, skeletonized, and the skeleton endings assumed to represent spine positions were counted and the spine densities calculated. The results based on 754 dendrite fragments were compared to manual spine counting of the same dendrite fragments using the Bland-Altman method. The results from both methods were correlated (r=0.79, p<0.0001), The semi-automatic counting method gave a statistically higher (approx. 4%) spine density number, but both counting methods showed similar significant differences between the groups in the CA1 area, and no differences between the groups in the CA3 area. In conclusion, the presented semi-automatic spine density estimation method yields consistently a higher spine density number than manual counting resulting in similar significance between groups. The proposed method may therefore be a reproducible time saving and useful non-stereological approach to spine counting in neuroplasticity studies requiring analysis of hundreds of dendrites.

PiB Fails to Map Amyloid Deposits in Cerebral Cortex of Aged Dogs with Canine Cognitive Dysfunction

Frontiers in Aging Neuroscience. 2013  |  Pubmed ID: 24416017

Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control group (n = 4) of healthy dogs with radioactively labeled PiB ([(11)C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [(11)C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [(11)C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [(11)C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [(11)C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

Pig Models of Neurodegenerative Disorders: Utilization in Cell Replacement-based Preclinical Safety and Efficacy Studies

The Journal of Comparative Neurology. Aug, 2014  |  Pubmed ID: 24610493

An important component for successful translation of cell replacement-based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large-scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (naïve noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed.

SorCS2 Regulates Dopaminergic Wiring and is Processed into an Apoptotic Two-chain Receptor in Peripheral Glia

Neuron. Jun, 2014  |  Pubmed ID: 24908487

Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.

The Telencephalon of the Göttingen Minipig, Cytoarchitecture and Cortical Surface Anatomy

Brain Structure & Function. Oct, 2016  |  Pubmed ID: 27778106

During the last 20 years pigs have become increasingly popular in large animal translational neuroscience research as an economical and ethical feasible substitute to non-human primates. The anatomy of the pig telencephalon is, however, not well known. We present, accordingly, a detailed description of the surface anatomy and cytoarchitecture of the Göttingen minipig telencephalon based on macrophotos and consecutive high-power microphotographs of 15 μm thick paraffin embedded Nissl-stained coronal sections. In 1-year-old specimens the formalin perfused brain measures approximately 55 × 47 × 36 mm (length, width, height) and weighs around 69 g. The telencephalic part of the Göttingen minipig cerebrum covers a large surface area, which can be divided into a neocortical gyrencephalic part located dorsal to the rhinal fissure, and a ventral subrhinal part dominated by olfactory, amygdaloid, septal, and hippocampal structures. This part of the telencephalon is named the subrhinal lobe, and based on cytoarchitectural and sulcal anatomy, can be discerned from the remaining dorsally located neocortical perirhinal/insular, pericallosal, frontal, parietal, temporal, and occipital lobes. The inner subcortical structure of the minipig telencephalon is dominated by a prominent ventricular system and large basal ganglia, wherein the putamen and the caudate nucleus posterior and dorsally are separated into two entities by the internal capsule, whereas both structures ventrally fuse into a large accumbens nucleus. The presented anatomical data is accompanied by surface renderings and high-power macrophotographs illustrating the telencephalic sulcal pattern, and the localization of the identified lobes and cytoarchitectonic areas. Additionally, 24 representative Nissl-stained telencephalic coronal sections are presented as supplementary material in atlas form on and referred to as S1-S24 throughout the manuscript.

The Retrograde Connections and Anatomical Segregation of the Göttingen Minipig Nucleus Accumbens

Frontiers in Neuroanatomy. 2016  |  Pubmed ID: 27994542

Nucleus accumbens (NAcc) has been implicated in several psychiatric disorders such as treatment resistant depression (TRD), and obsessive-compulsive disorder (OCD), and has been an ongoing experimental target for deep brain stimulation (DBS) in both rats and humans. In order to translate basic scientific results from rodents to the human setting a large animal model is needed to thoroughly study the effect of such therapeutic interventions. The aim of the study was, accordingly, to describe the basic anatomy of the Göttingen minipig NAcc and its retrograde connections. Tracing was carried out by MRI-guided stereotactic unilateral fluorogold injections in the NAcc of Göttingen minipigs. After 2 weeks the brains were sectioned and subsequently stained with Nissl-, autometallographic (AMG) development of myelin, and DARPP-32 and calbindin immunohistochemistry. The minipig NAcc was divided in a central core and an outer medial, ventral and lateral shell. We confirmed the NAcc to be a large and well-segregated structure toward its medial, ventral and lateral borders. The fluorogold tracing revealed inputs to NAcc from the medial parts of the prefrontal cortex, BA 25 (subgenual cortex), insula bilaterally, amygdala, the CA1-region of hippocampus, entorhinal cortex, subiculum, paraventricular and anterior parts of thalamus, dorsomedial parts of hypothalamus, substantia nigra, ventral tegmental area (VTA), the retrorubral field and the dorsal and median raphe nuclei. In conclusion the Göttingen minipig NAcc is a large ventral striatal structure that can be divided into a core and shell with prominent afferent connections from several subrhinal and infra-/prelimbic brain areas.

Cerebral 5-HT Release Correlates with [(11)C]Cimbi36 PET Measures of 5-HT2A Receptor Occupancy in the Pig Brain

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Feb, 2017  |  Pubmed ID: 26825776

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [(11)C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [(11)C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [(11)C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [(11)C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [(11)C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.

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