Janet Dubinsky - Academia.edu (original) (raw)

Papers by Janet Dubinsky

Experimental Neurology, Oct 1, 2004

Since excitotoxicity is hypothesized to contribute to cell death in Huntington's disease (HD), we... more Since excitotoxicity is hypothesized to contribute to cell death in Huntington's disease (HD), we examined the susceptibility of striatal and hippocampal neurons to glutamate-induced cell death. Striatal cultures were more susceptible to glutamate-triggered toxicity than sister hippocampal cultures. Dose-response curves were equivalent when secondary toxicity was blocked with application of the NMDA receptor antagonist, MK801, or enhanced with the pan-specific glutamate transport blocker, TBOA, following excitotoxin removal. TBOA failed to alter the dose-response characteristics of striatal excitotoxicity, ruling out reverse operation of glutamate transporters. Striatal cultures expressed less EAAC1and less membrane-associated EAAC1, GLT1, and GLAST than hippocampal cultures. Antisense down-regulation of EAAC1 increased the sensitivity of hippocampal cultures to glutamate, indicating that this transporter can act as an important neuroprotectant. Thus, the relative expression levels of glutamate transporters, even in parts of the brain where they are considered adequately expressed, appear to influence the sensitivities of different neuronal populations to excitotoxicity.

Journal of Cerebral Blood Flow and Metabolism, Nov 2, 2011

To improve the ability to move from preclinical trials in mouse models of Huntington's disease (H... more To improve the ability to move from preclinical trials in mouse models of Huntington's disease (HD) to clinical trials in humans, biomarkers are needed that can track similar aspects of disease progression across species. Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been suggested as potential biomarkers in HD. In this study, the R6/2 transgenic mouse model of HD was used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to anticipate the disease progression. Magnetic resonance imaging (MRI) and 1 H MRS data were acquired at 9.4 T from the R6/2 mice and wild-type littermates at 4, 8, 12, and 15 weeks. Brain shrinkage was detectable in striatum, cortex, thalamus, and hypothalamus by 12 weeks. Metabolite changes in cortex paralleled and sometimes preceded those in striatum. The entire set of metabolite changes was compressed into principal components (PCs) using Partial Least Squares-Discriminant Analysis (PLS-DA) to increase the sensitivity for monitoring disease progression. In comparing the efficacy of volume and metabolite measurements, the cortical PC1 emerged as the most sensitive single biomarker, distinguishing R6/2 mice from littermates at all time points. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models.

The Journal of Neuroscience, Jun 16, 2010

Editor's Note: In 2003, the Society for Neuroscience initiated the Science Educator Award to reco... more Editor's Note: In 2003, the Society for Neuroscience initiated the Science Educator Award to recognize an outstanding neuroscientist who has made significant contributions to the education of the public. For a description of the award, see http://www. sfn.org/sea. The Journal asked the 2009 winner, Janet M. Dubinsky, to give us her views on the importance of teaching teachers of kindergarten through 12th grade students about neuroscience.

The FASEB Journal, Apr 1, 2013

The present study was conducted to establish whether chronic salt loading alone, or in combinatio... more The present study was conducted to establish whether chronic salt loading alone, or in combination with the mineralocorticoid deoxycorticosterone acetate (DOCA), alters the content of sodium (Na+), potassium (K+) and calcium (Ca2+) in the brain. Male Sprague Dawley rats were implanted with a silicone pellet containing 0 (n=6) or 100 (n=6) mg DOCA and given 0.9% saline to drink ad libitum. The control group received 0mg DOCA and water ad libitum (n=6). After 21 days of treatment rats were anesthetized and brains were excised. The brainstem was removed and the remainder of the brain was bisected midsagitally. The right half of the brain was weighed intact and the left half was dissected into hypothalamus and cortex. Samples were analyzed for Na+/K+/Ca2+ content (ppm/gram) by inductively coupled argon plasma optical emission spectrometry. Compared to the control group, saline loading alone had no effect on Na+/K+/Ca2+ in any brain region. However, DOCA‐salt treatment increased Na+ (p < 0.05), and tended to decrease K+ content (p >; 0.05), in the hypothalamus but had no effect in the cortex or brainstem. DOCA‐salt treatment also increased hypothalamic (p < 0.05), but not cortical or brainstem, Ca2+ content. We conclude that regulation of hypothalamic Na+/K+/Ca2+ content is unique compared to the cortex and brainstem. HL64176–05

PLOS ONE, Feb 5, 2018

Educators are increasingly interested in applying neuroscience findings to improve educational pr... more Educators are increasingly interested in applying neuroscience findings to improve educational practice. However, their understanding of the brain often lags behind their enthusiasm for the brain. We propose that educational psychology can serve as a bridge between basic research in neuroscience and psychology on one hand and educational practice on the other. We evaluated whether taking an educational psychology course is associated with increased neuroscience literacy and reduced belief in neuromyths in a sample of South Korean pre-service teachers. The results showed that taking an educational psychology course was associated with the increased neuroscience literacy, but there was no impact on belief in neuromyths. We consider the implications of these and other findings of the study for redesigning educational psychology courses and textbooks for improving neuroscience literacy.

Kluwer Academic Publishers eBooks, Mar 7, 2006

Mitochondrial dysfunction and induction of the mitochondrial permeability transition (MPT) are ca... more Mitochondrial dysfunction and induction of the mitochondrial permeability transition (MPT) are candidate intermediate steps in both necrotic and apoptotic cell death pathways (Dubinsky and Levi, 1998; Hirsch et al., 1998; Schinder et al., 1996). In its classic definition (referred to here as the high-conductance MPT), the MPT is a nonselective, multiconductance pore in the inner mitochondrial membrane whose activation causes mitochondrial swelling and dysfunction (Nieminen et al., 1996; Schinder et al., 1996; Zoratti and Szabo, 1995). In liver and heart mitochondria, accumulation of excess matrix calcium combined with phosphate or with an oxidative event leads to opening of the high conductance MPT pore (Zoratti and Szabo, 1995). Induction of the MPT is modulated by mitochondrial membrane potential , matrix free fatty acids, redox status of mitochondrial protein thiols, and surface potential generated by the largely anionic phospholipids of the inner mitochondrial membrane (Zoratti and Szabo, 1995). Pharmacological inhibition of the MPT can be accomplished with the immunosuppressant cyclosporin and some of its analogs, adenine nucleotides, and the adenine nucleotide transporter inhibitor bongkrekic acid (Zoratti and Szabo, 1995). Mitochondrial swelling as measured by changes in absorbance has typically been studied in mitochondria after loading. High loads alone, or lower plus phosphate, uncoupler, or pro-oxidants, initiates transition, a process thought to propagate through the mitochondrial population (Bernardi, 1992; Broekemeier et al., 1989). When ruthenium red (RR) is added after to prevent its loss through reverse operation of the uniporter, application of

The Science Teacher, 2020

bioRxiv (Cold Spring Harbor Laboratory), Mar 12, 2018

Introduction: Comparisons of hypothalamic dysfunction between Huntington's Disease (HD) patients ... more Introduction: Comparisons of hypothalamic dysfunction between Huntington's Disease (HD) patients and rodent models of HD have not always yielded similar results. Cortisol levels in HD patients have been contradictory, with reports ranging from hypo-to hypercorticoidism of morning measurements. Initial reports of major elevations in circulating corticosterone levels in the R6/2 mouse model of HD have only been followed up in one other closely related model, the R6/1 mouse, and the results were not perfectly congruent. To determine if abnormal stress hormones were a characteristic of disease, we examined diurnal and stress-induced corticosterone levels in multiple HD mouse models. Methods: We analyzed serum corticosterone levels from R6/2, Q140 and BACHD mice either diurnally (R6/2) or after restraint stress and subsequent recovery (all 3 models). Glucocorticoid secretion was also examined (R6/2) following dexamethasone suppression and ACTH stimulation. Blood samples were collected either by submandibular puncture or as trunk blood at sacrifice. Plasma corticosterone levels were assayed by RIA. Regional brain glucocorticoid receptor (GR) levels were visualized using immunofluorescence. Results: In the R6/2 mouse, basal levels of corticosterone, exhibited normal, sexually dimorphic diurnal rhythms but eventually became elevated towards end of life, after 13 weeks. The ability of the adrenal gland to produce corticosterone was not altered and the adrenal response to ACTH stimulation was only elevated in male R6/2 mice compared to littermates. Down regulation of GR receptors was only observed in the PVN at 16 weeks. R6/2 mice at both 6 and 12 weeks responded equivalently to littermates in the initial corticosterone response to restraint stress but serum corticosterone recovered from stress significantly more slowly. No differences were found in the initial stress response or in the recovery from stress for Q140 or BACHD mice, examined at 12 and 9 months, respectively. Conclusions: We did not find evidence of major disruption in glucocorticoid signaling in HD mouse models. A significantly slowed recovery from stress observed in the R6/2 mouse suggests such disruptions are context dependent. These results suggest that disruption of the HPA axis was subtle and occurred only at advanced stages of disease represented by comparisons among these HD mouse models. .

Cambridge University Press eBooks, Oct 8, 2013

Journal of Bioenergetics and Biomembranes, Aug 1, 2004

Mitochondria benefit their host cells by generating ATP, detoxifying oxygen, maintaining cellular... more Mitochondria benefit their host cells by generating ATP, detoxifying oxygen, maintaining cellular redox potential, and detoxifying reactive oxygen species and xenobiotics. These beneficial roles are in stark contrast to mitochondrial participation in both necrotic and apoptotic degenerative pathways. However, cellular stresses do not always result in deleterious mitochondrial changes. Decreases in the calcium sensitivity of the permeability transition may be initial mitochondrial responses to stress that act to preserve mitochondrial function and prolong normal functioning of the host cell.

Journal of Neurobiology, Apr 1, 1990

We have found that the incidence of functionally connected neuron‐myotube pairs in chick ciliary‐... more We have found that the incidence of functionally connected neuron‐myotube pairs in chick ciliary‐myotube cultures increases from 58% to more than 90% when the cells are treated for several hours with 8‐bromo‐cyclic adenosine monophosphate (8‐br‐cAMP) or with agents known to increase intracellular cAMP. The increase in connectivity was not accompanied by a change in neuron survival, or in the length of neurite‐myotube contact. Moreover, there was no change in the shape of the presynaptic action potential, in mean end plate potential (epp) amplitude or in the sensitivity of postsynaptic acetylcholine receptors (AChRs). One interpretation of these results is that a cAMP‐dependent phosphorylation acts as a trigger to activate a previously “silent” synapse.

Journal of comparative neurology, Jan 15, 1994

The principle neuronal output of the neostriatum comes from medium spiny neurons that project fro... more The principle neuronal output of the neostriatum comes from medium spiny neurons that project from the caudate/putamen to the globus pallidus and substantia nigra. Although current evidence generally indicates that y-aminobutyric acid (GABA) is the principal neurotransmitter in this pathway, this cannot account for the excitatory synaptic activity present among cultures of striatal neurons or the short latency excitatory postsynaptic potentials which often proceed or obscure inhibitory activity evoked by striatal stimulation. In this study, retrograde transport of [3H]~-aspartate has been used to demonstrate striatopallidal and striato-nigral neurons that possess a high-affinity uptake system for glutamate and aspartate and are therefore putatively glutamatergic. Injections of [3H]D-aspartate into the globus pallidus or substantia nigra, pars reticularis of the rat retrogradely labeled mediumsized neurons throughout the rostral-caudal extent of the neostriatum. To characterize this population further, adjacent sections were immunoreacted with antibodies to either GABA, glutamic acid decarboxylase (GAD), calbindin, or parvalbumin prior to autoradiographic processing. Under these conditions, autoradiographically labeled neurons displayed positive immunoreactivity for GABA, GAD, or calbindin. Autoradiographic label did not colocalize with parvalbumin immunoreactivity. The colocalization of anatomical markers of GABAergic and glutamatergic neurotransmission raises the possibility that both neurotransmitters are functionally expressed within single striatal projection neurons.

Educational Researcher, Aug 1, 2013

Bruer (1997) advocated connecting neuroscience and education indirectly through the intermediate ... more Bruer (1997) advocated connecting neuroscience and education indirectly through the intermediate discipline of psychology. We argue for a parallel route: the neurobiology of learning, and in particular the core concept of plasticity, have the potential to directly transform teacher preparation and professional development, and ultimately to affect how students think about their own learning. We present a case study of how the core concepts of neuroscience can be brought to in-service teachers-the BrainU workshops. We then discuss how neuroscience can be meaningfully integrated into pre-service teacher preparation, focusing on institutional and cultural barriers.

The Journal of Neuroscience, 2000

Isolated brain mitochondria were examined for their responses to calcium challenges under varying... more Isolated brain mitochondria were examined for their responses to calcium challenges under varying conditions. Mitochondrial membrane potential was monitored by following the distribution of tetraphenylphosphonium ions in the mitochondrial suspension, mitochondrial swelling by observing absorbance changes, calcium accumulation by an external calcium electrode, and oxygen consumption with an oxygen electrode. Both the extent and rate of calcium-induced mitochondrial swelling and depolarization varied greatly depending on the energy source provided to the mitochondria. When energized with succinate plus glutamate, after a calcium challenge, CNS mitochondria depolarized transiently, accumulated substantial calcium, and increased in volume, characteristic of a mitochondrial permeability transition. When energized with 3 mM succinate, CNS mitochondria maintained a sustained calciuminduced depolarization without appreciable swelling and were slow to accumulate calcium. Maximal oxygen consumption was also restricted under these conditions, preventing the electron transport chain from compensating for this increased proton permeability. In 3 mM succinate, cyclosporin A and ADP plus oligomycin restored potential and calcium uptake. This low conductance permeability was not effected by bongkrekic acid or carboxyatractylate, suggesting that the adenine nucleotide translocator was not directly involved. Fura-2FF measurements of [Ca 2ϩ ] i suggest that in cultured hippocampal neurons glutamate-induced increases reached tens of micromolar levels, approaching those used with mitochondria. We propose that in the restricted substrate environment, Ca 2ϩ activated a low-conductance permeability pathway responsible for the sustained mitochondrial depolarization.

Science and Engineering Ethics, Aug 1, 2021

User defined missing values are treated as missing. Statistics for each analysis are based on the... more User defined missing values are treated as missing. Statistics for each analysis are based on the cases with no missing or out-of-range data for any variable in the analysis. T-TEST GROUPS=Class ('NSCI' 'EDHD') /MISSING=ANALYSIS /VARIABLES=TimeSec Encouraged Required Regulate Free Age NeuroCourses PsychCourses PhysBiolCourses /CRITERIA=CI(.95).

Journal of Neurochemistry, 1992

During development, neural crest-derived sensory neurons require nerve growth factor (NGF) for su... more During development, neural crest-derived sensory neurons require nerve growth factor (NGF) for survival, but lose this dependency postnatally. Similarly, dissociated embryonic sensory neurons lose their NGF dependence during the first 3 weeks in cell culture. It has been hypothesized that, in sympathetic neurons, intracellular levels of calcium are related to trophic factor dependence. In vitro during the period in which embryonic-day-15 sensory neurons become independent of NGF, intracellular calcium concentrations progressively increased in parallel to the decline in NGF dependence. This elevation of intracellular calcium was directly related to the absolute age of the neurons, not to the length of time in culture. Without NGF, immature sensory, i.e., dependent, neurons survived in the presence of high extracellular potassium, a condition that produces elevated intra-cellular calcium. In another paradigm, measurements of intracellular calcium were determined in NGF-dependent neurons "committed to die" after NGF withdrawal. These measurements were determined prior to the time that extensive morphological changes, consistent with cell death, were noted by phase-contrast microscopy. No elevation in intracellular calcium was found in these dying neurons, but rather, a small decrease was observed prior to the disintegration of the neurons. These findings support the hypothesis that trophic factor dependence of neurons may be inversely related to levels of intracellular calcium. Key Words: Nerve growth factor-Intracellular calcium-Sensory neurons. Eichler M. E. et al. Relationship of intracellular calcium to dependence on nerve growth factor in dorsal root ganglion neurons in cell culture.

Proceedings of the National Academy of Sciences of the United States of America, Jun 1, 1985

Transmembrane electrical activity in pituitary tumor cells can be altered by substances that eith... more Transmembrane electrical activity in pituitary tumor cells can be altered by substances that either stimulate or inhibit their secretory activity. Using patch recording techniques, we have measured the resting membrane potentials, action potentials, transmembrane macroscopic ionic currents, and single Ca2+-activated K channel currents of GH3 and GH4/C1 rat pituitary tumor cells in response to Abbreviations: TRH, thyrotropin-releasing hormone; TTX, tetrodotoxin.

Electroencephalography and Clinical Neurophysiology, Apr 1, 1980

Journal of Biological Chemistry, Aug 1, 2001

Journal of Science Education and Technology, Aug 24, 2018

Disclosure of conflicts of interest: HSS, ACS, MM are employees of the company that owns the app ... more Disclosure of conflicts of interest: HSS, ACS, MM are employees of the company that owns the app and may benefit from its sale. KBS has multiple affiliations, and was eventually hired as an employee of the company that owns the app. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.