Correlated Quantitative Studies of the Neostriatum, Nucleus Accumbens, Substantia Nigra, and Ventral Tegmental Area in Normal and Weaver Mutant Mice
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Characterization of Substantia Nigra
Mourtzi et al. Stem Cell Research & Therapy (2021) 12:335 https://doi.org/10.1186/s13287-021-02398-3 RESEARCH Open Access Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20 Theodora Mourtzi1,2*, Dimitrios Dimitrakopoulos2†, Dimitrios Kakogiannis2†, Charalampos Salodimitris2, Konstantinos Botsakis1, Danai Kassandra Meri2, Maria Anesti2,3, Aggeliki Dimopoulou1, Ioannis Charalampopoulos4,5, Achilleas Gravanis4,5, Nikolaos Matsokis3, Fevronia Angelatou1† and Ilias Kazanis2*† Abstract Background: Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson’s disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the “weaver” mouse model of PD. Here, we assessed its potential effects on neurogenesis. Methods: We quantified total numbers of dopaminergic neurons in the SNpc of wild-type and “weaver” mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20. * Correspondence: [email protected]; [email protected]; [email protected] †Dimitrios Dimitrakopoulos and Dimitrios Kakogiannis contributed equally to this work. -
Prominent Activation of Brainstem and Pallidal Afferents of the Ventral Tegmental Area by Cocaine
Neuropsychopharmacology (2008) 33, 2688–2700 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org Prominent Activation of Brainstem and Pallidal Afferents of the Ventral Tegmental Area by Cocaine 1,3 2 1 1 1 Stefanie Geisler , Michela Marinelli , Beth DeGarmo , Mary L Becker , Alexander J Freiman , 2 2 ,1 Mitch Beales , Gloria E Meredith and Daniel S Zahm* 1 2 Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO, USA; Department of Cellular & Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA Blockade of monoamine transporters by cocaine should not necessarily lead to certain observed consequences of cocaine administration, including increased firing of ventral mesencephalic dopamine (DA) neurons and accompanying impulse-stimulated release of DA in the forebrain and cortex. Accordingly, we hypothesize that the dopaminergic-activating effect of cocaine requires stimulation of the dopaminergic neurons by afferents of the ventral tegmental area (VTA). We sought to determine if afferents of the VTA are activated following cocaine administration. Rats were injected in the VTA with retrogradely transported Fluoro-Gold and, after 1 week, were allowed to self-administer cocaine or saline via jugular catheters for 2 h on 6 consecutive days. Other rats received a similar amount of investigator- administered cocaine through jugular catheters. Afterward, the rats were killed and the brains processed immunohistochemically for retrogradely transported tracer and Fos, the protein product of the neuronal activation-associated immediate early gene, c-fos. Forebrain neurons exhibiting both Fos and tracer immunoreactivity were enriched in both cocaine groups relative to the controls only in the globus pallidus and ventral pallidum, which, together, represented a minor part of total forebrain retrogradely labeled neurons. -
Chronic Amphetamine Exposure Causes Long Term Effects on Dopamine Uptake in Cultured Cells Nafisa Ferdous
University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects January 2016 Chronic Amphetamine Exposure Causes Long Term Effects On Dopamine Uptake In Cultured Cells Nafisa Ferdous Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Ferdous, Nafisa, "Chronic Amphetamine Exposure Causes Long Term Effects On Dopamine Uptake In Cultured Cells" (2016). Theses and Dissertations. 2016. https://commons.und.edu/theses/2016 This Thesis is brought to you for free and open access by the Theses, Dissertations, and Senior Projects at UND Scholarly Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UND Scholarly Commons. For more information, please contact [email protected]. CHRONIC AMPHETAMINE EXPOSURE CAUSES LONG TERM EFFECTS ON DOPAMINE UPTAKE IN CULTURED CELLS By Nafisa Ferdous Bachelor of Science, North South University, Bangladesh 2012 A Thesis submitted to the Graduate Faculty of the University of North Dakota in partial fulfillment of the requirements for the degree of Master of Science Grand Forks, North Dakota December 2016 ii PERMISSION Title Chronic amphetamine exposure causes long term effects on dopamine uptake in cultured cells Department Biomedical Sciences Degree Master of Science In presenting this thesis in partial fulfillment of the requirements for a graduate degree from the University of North Dakota, I agree that the library of this University shall make it freely available for inspection. I further agree that permission for extensive copying for scholarly purposes may be granted by the professor who supervised my thesis work or, in his absence, by the Chairperson of the department or the Dean of the School of Graduate Studies. -
Dopaminergic Microtransplants Into the Substantia Nigra of Neonatal Rats with Bilateral 6-OHDA Lesions
The Journal of Neuroscience, May 1995, 15(5): 3548-3561 Dopaminergic Microtransplants into the Substantia Nigra of Neonatal Rats with Bilateral 6-OHDA Lesions. I. Evidence for Anatomical Reconstruction of the Nigrostriatal Pathway Guido Nikkhah,1,2 Miles G. Cunningham,3 Maria A. Cenci,’ Ronald D. McKay,4 and Anders Bj6rklund’ ‘Department of Medical Cell Research, University of Lund, S-223 62 Lund, Sweden, *Neurosurgical Clinic, Nordstadt Hospital, D-301 67 Hannover, Germany, 3Harvard Medical School, Boston, Massachusetts 02115, and 4 Laboratory of Molecular Biology, NINDS NIH, Bethesda, Maryland 20892 Reconstruction of the nigrostriatal pathway by long axon [Key words: target reinnervation, axon growth, neural growth derived from dopamine-rich ventral mesencephalic transplantation, tyrosine hydroxylase immunohistochem- (VM) transplants grafted into the substantia nigra may en- istry, Fos protein, Fluoro-Gold] hance their functional integration as compared to VM grafts implanted ectopically into the striatum. Here we report on In the lesioned brain of adult recipients dopamine-rich grafts a novel approach by which fetal VM grafts are implanted from fetal ventral mesencephalon (VM) are unable to reinner- unilaterally into the substantia nigra (SN) of 6-hydroxydo- vate the caudate-putamen unless they are placed close to, or pamine (SOHDA)-lesioned neonatal pups at postnatal day within, the denervated target structure (BjGrklund et al., 1983b; 3 (P3) using a microtransplantation technique. The results Nikkhah et al., 1994b). The failure of regenerating dopaminergic demonstrate that homotopically placed dopaminergic neu- axons to reinnervate the striatum from more distant implantation rons survive and integrate well into the previously sites, including their normal site of origin, the substantia nigra 6-OHDA-lesioned neonatal SN region. -
Mapping the Populations of Neurotensin Neurons in the Male Mouse Brain T Laura E
Neuropeptides 76 (2019) 101930 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep Mapping the populations of neurotensin neurons in the male mouse brain T Laura E. Schroeder, Ryan Furdock, Cristina Rivera Quiles, Gizem Kurt, Patricia Perez-Bonilla, ⁎ Angela Garcia, Crystal Colon-Ortiz, Juliette Brown, Raluca Bugescu, Gina M. Leinninger Department of Physiology, Michigan State University, East Lansing, MI 48114, United States ARTICLE INFO ABSTRACT Keywords: Neurotensin (Nts) is a neuropeptide implicated in the regulation of many facets of physiology, including car- Lateral hypothalamus diovascular tone, pain processing, ingestive behaviors, locomotor drive, sleep, addiction and social behaviors. Parabrachial nucleus Yet, there is incomplete understanding about how the various populations of Nts neurons distributed throughout Periaqueductal gray the brain mediate such physiology. This knowledge gap largely stemmed from the inability to simultaneously Central amygdala identify Nts cell bodies and manipulate them in vivo. One means of overcoming this obstacle is to study NtsCre Thalamus mice crossed onto a Cre-inducible green fluorescent reporter line (NtsCre;GFP mice), as these mice permit both Nucleus accumbens Preoptic area visualization and in vivo modulation of specific populations of Nts neurons (using Cre-inducible viral and genetic tools) to reveal their function. Here we provide a comprehensive characterization of the distribution and relative Abbreviation: 12 N, Hypoglossal nucleus; -
Striatal and Midbrain Connectivity with the Hippocampus Selectively Boosts Memory for Contextual Novelty
HIPPOCAMPUS 25:1262–1273 (2015) Striatal and Midbrain Connectivity with the Hippocampus Selectively Boosts Memory for Contextual Novelty Alexandros Kafkas* and Daniela Montaldi ABSTRACT: The role of contextual expectation in processing familiar of the new information (Kakade and Dayan, 2002). and novel stimuli was investigated in a series of experiments combining eye The ability to discriminate potentially salient familiar tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detec- and novel information, in a context abundant with tion at retrieval was used. The detection of unexpected familiar and novel old and new stimuli, becomes crucial for ensuring stimuli, which were characterized by lower probability, engaged activity in effective contextual learning. Efficient discrimination midbrain and striatal structures. Specifically, detecting unexpected novel may trigger an orienting response toward the new stimuli, relative to expected novel stimuli, produced greater activity in the unexpected information and may therefore enhance substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity memory formation (Tulving and Kroll, 1995). Indeed, in the striatum/globus pallidus (GP). An effective connectivity analysis the brain’s dopaminergic system, including striatal and showed greater functional coupling between these two seed areas (GP and midbrain structures, has been shown to respond to SN/VTA) and the hippocampus, for unexpected than for expected stimuli. reward anticipation and to prediction errors as well as Within this network of midbrain/striatal–hippocampal interactions two having an effect on memory formation (Adcock et al., pathways are apparent; the direct SN–hippocampal pathway sensitive to unexpected novelty and the perirhinal–GP–hippocampal pathway sensitive 2006; Wittmann et al., 2011). -
Opiate Influences on Nucleus Accumbens Neuronal Electrophysiology: Dopamine and Non-Dopamine Mechanisms
The Journal of Neuroscience, October 1969, 9(10): 35363546 Opiate Influences on Nucleus Accumbens Neuronal Electrophysiology: Dopamine and Non-Dopamine Mechanisms Ft. L. Hakan and S. J. Henriksen Department of Neuropharmacology, Research Institute of the Scripps Clinic, La Jolla, California 92037 Single-unit recordings of nucleus accumbens septi (NAS) abuse potential for humans such as the opiate alkaloids (Goeders neurons in halothane-anesthetized rats revealed that mi- et al., 1984; Vaccarino et al., 1985; Corrigal and Vaccarino, croinfusions of morphine into the ventral tegmental area (VTA) 1988; Koob and Goeders, 1989). Although there is controversy primarily inhibited spontaneously active NAS units. These regarding the precise neuropharmacological mechanism(s) un- inhibitory effects were reversed by alpha-flupenthixol (s.c.), derlying opiate actions on the NAS and on NAS-related brain suggesting a role for dopamine (DA) in the observed opiate- circuitry (e.g., see Wise, 1987), behavioral research has indicated induced effect. VTA opiate microinfusions also inhibited the that these drugs may exert pharmacological influence over NAS evoked (driven) responses of silent cells (spontaneously function via dopamine (DA)-dependent and DA-independent inactive) in the NAS elicited by stimulation of hippocampal projections from the DA containing cell bodies of the midbrain afferents to the NAS. In addition, this inhibition of driven ventral tegmental area (VTA) (Bozarth and Wise, 198 l), the response was reversed by naloxone (s.c.) but not by alpha- cellular origin of the DA-ergic input to the NAS (see Kelly et flupenthixol, implying a VTA-mediated non-DA mechanism. al., 1980; Stinus et al., 1980; Kalivas et al., 1983; Pettit et al., Morphine applied iontophoretically to cells within the NAS 1984; Amahic and Koob, 1985; Vaccarino et al., 1986; Wise, inhibited spontaneous activity but not fimbria-driven cellular 1987; Di Chiara and Imperato, 1988; Koob and Goeders, 1989). -
Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping
Article Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping Graphical Abstract Authors Kevin T. Beier, Elizabeth E. Steinberg, Katherine E. DeLoach, ..., Eric J. Kremer, Robert C. Malenka, Liqun Luo Correspondence [email protected] (R.C.M.), [email protected] (L.L.) In Brief A combination of state-of-the-art viral- genetic tools shows that dopaminergic neurons in the ventral tegmental area (VTA-DA) employ biased-input/discrete- output circuit architecture, allowing the construction of an input-output map for further investigation of the neural circuits underlying the different functions of these neurons in psychological processes and brain diseases. Highlights d VTA dopamine (DA) and GABA neurons receive similar inputs from diverse sources d VTA-DA neurons projecting to different output sites receive biased input d VTA-DA neurons projecting to lateral and medial NAc innervate non-overlapping targets d A top-down anterior cortex/VTA-DA/lateral NAc circuit is reinforcing Beier et al., 2015, Cell 162, 622–634 July 30, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.cell.2015.07.015 Article Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping Kevin T. Beier,1,2 Elizabeth E. Steinberg,2 Katherine E. DeLoach,1 Stanley Xie,1 Kazunari Miyamichi,1,5 Lindsay Schwarz,1 Xiaojing J. Gao,1,6 Eric J. Kremer,3,4 Robert C. Malenka,2,* and Liqun Luo1,* 1Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA 2Nancy Pritzker Laboratory, -
Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain: Comparison with D2 Receptor Expressing Neurons Eugenia V
Distribution of Dopamine D3 Receptor Expressing Neurons in the Human Forebrain: Comparison with D2 Receptor Expressing Neurons Eugenia V. Gurevich, Ph.D., and Jeffrey N. Joyce, Ph.D. The dopamine D2 and D3 receptors are members of the D2 important difference from the rat is that D3 receptors were subfamily that includes the D2, D3 and D4 receptor. In the virtually absent in the ventral tegmental area. D3 receptor rat, the D3 receptor exhibits a distribution restricted to and D3 mRNA positive neurons were observed in sensory, mesolimbic regions with little overlap with the D2 receptor. hormonal, and association regions such as the nucleus Receptor binding and nonisotopic in situ hybridization basalis, anteroventral, mediodorsal, and geniculate nuclei of were used to study the distribution of the D3 receptors and the thalamus, mammillary nuclei, the basolateral, neurons positive for D3 mRNA in comparison to the D2 basomedial, and cortical nuclei of the amygdala. As revealed receptor/mRNA in subcortical regions of the human brain. by simultaneous labeling for D3 and D2 mRNA, D3 mRNA D2 binding sites were detected in all brain areas studied, was often expressed in D2 mRNA positive neurons. with the highest concentration found in the striatum Neurons that solely expressed D2 mRNA were numerous followed by the nucleus accumbens, external segment of the and regionally widespread, whereas only occasional D3- globus pallidus, substantia nigra and ventral tegmental positive-D2-negative cells were observed. The regions of area, medial preoptic area and tuberomammillary nucleus relatively higher expression of the D3 receptor and its of the hypothalamus. In most areas the presence of D2 mRNA appeared linked through functional circuits, but receptor sites coincided with the presence of neurons co-expression of D2 and D3 mRNA suggests a functional positive for its mRNA. -
Using High-Resolution MR Imaging at 7T to Evaluate the Anatomy of the Midbrain ORIGINAL RESEARCH Dopaminergic System
Using High-Resolution MR Imaging at 7T to Evaluate the Anatomy of the Midbrain ORIGINAL RESEARCH Dopaminergic System M. Eapen BACKGROUND AND PURPOSE: Dysfunction of DA neurotransmission from the SN and VTA has been D.H. Zald implicated in neuropsychiatric diseases, including Parkinson disease and schizophrenia. Unfortunately, these midbrain DA structures are difficult to define on clinical MR imaging. To more precisely evaluate J.C. Gatenby the anatomic architecture of the DA midbrain, we scanned healthy participants with a 7T MR imaging Z. Ding system. Here we contrast the performance of high-resolution T2- and T2*-weighted GRASE and FFE J.C. Gore MR imaging scans at 7T. MATERIALS AND METHODS: Ten healthy participants were scanned by using GRASE and FFE se- quences. CNRs were calculated among the SN, VTA, and RN, and their volumes were estimated by using a segmentation algorithm. RESULTS: Both GRASE and FFE scans revealed visible contrast between midbrain DA regions. The GRASE scan showed higher CNRs compared with the FFE scan. The T2* contrast of the FFE scan further delineated substructures and microvasculature within the midbrain SN and RN. Segmentation and volume estimation of the midbrain SN, RN, and VTA showed individual differences in the size and volume of these structures across participants. CONCLUSIONS: Both GRASE and FFE provide sufficient CNR to evaluate the anatomy of the midbrain DA system. The FFE in particular reveals vascular details and substructure information within the midbrain regions that could be useful for examining -
MR Findings in Patients with Subacute Necrotizing Encephalomyelopathy (Leigh Syndrome): Correlation with Biochemical Defect
379 MR Findings in Patients with Subacute Necrotizing Encephalomyelopathy (Leigh Syndrome): Correlation with Biochemical Defect 1 2 L. Medina · MR studies were correlated with biochemical results in nine children who presented 1 3 T. L. Chi · with lactic acidosis andjor abnormal MR findings in the basal ganglia. Neurologic D. C. DeVivo4 development was delayed in all nine children. Seven of these patients were diagnosed S. K. Hilal 1 as having subacute necrotizing encephalomyelopathy (SNE, or Leigh syndrome) on the basis of history, clinical findings, and biochemical studies; of the remaining two, one had congenital lactic acidosis and the other had familial bilateral striatal necrosis with no known biochemical correlate. Although the clinical presentation of these patients was similar, we found distinctive MR abnormalities in characteristic locations in the seven patients with SNE, with or without detectable specific mitochondrial enzyme deficiency in cultured skin fibroblast assays. In our case studies of SNE patients with detectable enzyme deficiency states, defects in pyruvate dehydrogenase complex and cytochrome c oxidase have been found. The MR finding of note in SNE is the remarkably symmetrical involvement, most frequently of the putamen. In our study, lesions were also commonly found in the globus pallidus and the caudate nucleus, but never in the absence of putamina! abnormalities. Other areas of involvement included the paraven tricular white matter, corpus callosum, substantia nigra, decussation of superior cere bellar peduncles, periaqueductal region, and brainstem. In patients who present with lactic acidosis and whose MR findings show symmetrical abnormalities in the brain, but with sparing of the putamen, the diagnosis of SNE is in doubt. -
Substantia Nigra and Parkinson's Disease
HISTORICAL REVIEW Substantia Nigra and Parkinson’s Disease: A Brief History of Their Long and Intimate Relationship Martin Parent, André Parent ABSTRACT: The substantia nigra was discovered in 1786 by Félix Vicq d’Azyr, but it took more than a century before Paul Blocq and Georges Marinesco alluded to a possible link between this structure and Parkinson’s disease. The insight came from the study of a tuberculosis patient admitted in Charcot’s neurology ward at la Salpêtrière because he was suffering from unilateral parkinsonian tremor. At autopsy, Blocq and Marinesco discovered an encapsulated tumor confined to the substantia nigra, contralateral to the affected side, and concluded that tremor in that particular case resulted from a midbrain lesion. This pioneering work, published in 1893, led Edouard Brissaud to formulate, in 1895, the hypothesis that the substantia nigra is the major pathological site in Parkinson’s disease. Brissaud’s hypothesis was validated in 1919 by Constantin Trétiakoff in a remarkable thesis summarizing a post-mortem study of the substantia nigra conducted in Marinesco’s laboratory. Despite highly convincing evidence of nigral cell losses in idiopathic and post-encephalitic Parkinsonism, Trétiakoff’s work raised considerable doubts among his colleagues, who believed that the striatum and pallidum were the preferential targets of parkinsonian degeneration. Trétiakoff’s results were nevertheless confirmed by detailed neuropathological studies undertaken in the 1930s and by the discovery, in the 1960s, of the dopaminergic nature of the nigrostriatal neurons that degenerate in Parkinson’s disease. These findings have strengthened the link between the substantia nigra and Parkinson’s disease, but modern research has uncovered the multifaceted nature of this neurodegenerative disorder by identifying other brain structures and chemospecifc systems involved in its pathogenesis.