Yanai, Joseph                  

Biography:

Ph.D. 1972, Univ. of Colorado; Lect. 1978; Senior Lecturer ; Associate Professor; Professor. Professor (Adjunct); Department of Pharmacology, Duke University Medical School, Durham, North Carolina, USA, 1991.

Research Interests:

Ascertaining in the mouse model the mechanisms of neural and behavioral birth defects induced by drugs of abuse and other agents and their reversal utilizing various techniques, mainly stem cell therapy - understanding the path by which the neural progenitors exert their therapeutic action. The study of the mechanism focuses on behaviors related to the septohippocampal cholinergic innervation. Our hypothesis is that abolishment in the hippocampus of cholinergic receptor-induced translocation/activation of PKCg represents a principal component in the mechanism by which various substances induce neurobehavioral birth defects.

Our parallel neurobehavioral birth defects model, which controls for maternal confounds, involves perturbation of imprinting in the chick related to defects in translocation/activation of PKCg in the IMHV nucleus. 

Recent Findings:

Pregnant female mice were exposed to heroin or other substances (e.g., nicotine or alcohol). Their offspring showed, upon maturity, an abolishment of cholinergic receptor-induced translocation/activation of PKCg in the septohippocampal cholinergic innervation, paralleled with defects in the hippocampus-related eight-arm maze behavior.

Understanding the synaptic mechanism of the behavioral defects enabled reversal of the neurobehavioral teratogenicity using the following therapies: a. manipulating the regulating pathways of the septohippocampal cholinergic innervation b. grafting of normal embryonic cholinergic cells into the impaired hippocampus c. clinically feasible nicotine therapy d. grafting of stem cells (neural progenitors) into the impaired hippocampus.

The mouse findings were confirmed in studies using the chick model, incubating eggs were injected with heroin or other substances. The hatching chicks suffered marked defects in their imprinting behavior, which was correlated with abolishment of cholinergic-induced translocation/activation of PKCg in their IMHV nucleus.

The study of the reversal of heroin neurobehavioral teratogenicity will serve as an example: Neural progenitors derived from normal developing brain were grafted into the hippocampus of mice offspring who were exposed prenatally to heroin and showed hippocampus related defects in behavior and PKC translocation/activation. The grafted cells grew in the host hippocampus as shown in the following figure.

Grafted BrdU-labeled neural precursors identified in the brain of the teratogen-impaired brain by immunofluorescent staining. Some of the transplanted cells acquire markers of specific neural lineages. In the present case double labeling BrdU+, GFAP+ astrocytes (confocal microscopy).

 

Grafting of neural progenitors reversed the desensitization of hippocampal PKCg to the cholinergic agonist carbachol as can be seen in the following Figure.

Effect of prenatal treatment with heroin on cholinergic receptor-induced hippocampal PKCg activity and the effect of transplantation of neural progenitors on the heroin induced PKCg changes. 

C-C = Prenatal control – postnatal medium.	H-C = Prenatal heroin - postnatal medium.
C-N = Prenatal control - postnatal neural progenitors.	H-NP = Prenatal heroin - postnatal neural progenitors.

 

Furthermore, grafting of neural progenitors restored maze behavior to normal levels as can be seen in the following Figure.

 

Effects of prenatal heroin exposure and subsequent grafting of neural progenitors on performance in the Morris water maze. Numbers represent the time spent to reach the platform (mean±SEM)

 

Control (pooled) = Offspring who were exposed prenatally to control injections and were sham grafted postnatally with medium (C-C) or with neural progenitors (C-NP).
H-C = Offspring exposed prenatally to heroin and were grafted postnatally with neural progenitors.
H-NP = Offspring exposed prenatally to heroin and were grafted postnatally with neural progenitors.
 

H-C  required more time than Control reach the platform (p=0.0336).

H-NP differed from H-C (p=0.0043) and did not from C-C and C-NP (p=0.29).

All interactions, prenatal-exposure X test-day, prenatal-exposure X day were not statistically significant.

Sample sizes (number of animals) are: Control, n=28; H-C, n=22; H-NP, n=23.

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Number of newly born cells (BrdU-labeled) in prenatal heroin-exposed mice grafted with neural progenitors as compare to those injected with media only and control mice.

† p<0.043 for the reduction of Heroin+sham from control levels.

* p<0.0128  for the difference of Heroin+NP from Heroin+sham levels.

Control (pooled)- offspring exposed prenatally to saline and grafted with media (n=4) or neural progenitors (n=3).

Heroin+sham- offspring exposed prenatally to heroin and grafted with media (n=8).

Heroin+NP- offspring exposed prenatally to heroin and grafted with neural progenitors (n=9).

 

 

Research Projects:

1.	Stem cells therapy: ascertaining in the mouse and chick models the mechanisms of neural and behavioral birth defects induced by drugs of abuse and other agents and their reversal utilizing various techniques, mainly stem cell therapy.
2.	Mechanisms of neurobehavioral teratogenicity: cholinergic receptor regulation of translocation and activation of  PKC isoforms in the hippocampus and the possible involvement of this process in the mechanism of neurobehavioral birth defects.

Recent Selected Publications :

1.	Yanai, J., Y. Rogel-Fuchs, C. G. Pick, T. Slotkin, F. J. Seidler, E. A. Zahalka and E. Newman. Septohippocampal cholinergic changes after destruction of the A10-septal dopaminergic pathways. Neuropharmacology 32:113-117 (1993).
2.	Rogel-Fuchs, Y, E. Zahalka, and J. Yanai.  Reversal of early phenobarbital-induced cholinergic and related behavioral deficits by neuronal grafting. Brain Research Bulletin, 33:273-279 (1994).
3.	Rogel-Fuchs, Y, E. Zahalka, and J. Yanai. Reversal of early phenobarbital-induced cholinergic and related behavioral deficits by neuronal grafting. Brain Research Bulletin 33: 273-9 (1994).
4.	Yanai, J., T. Doetchman, N. Laufer, J. Maslaton, S. Mor-Yosef, M. Shani and D. Sofer. Embryonic cultures but not zygotes transplanted to the mouse's brain grow rapidly without immunosuppression. Int. Journal of Neuroscience 81:21-26 (1995).
5.	Yanai, J., W. Silverman and D. Shamir. An avian model for the reversal of 6-hydroxydopamine induced rotating behavior by neural grafting. Neuroscience Letters 187:153-156 (1995).
6.	Yanai, J. and C.G. Pick. Yanai, J. and C.G. Pick. Neuron transplantation into mice hippocampus alters sensitivity to barbital narcosis. Brain Research Bulletin 38: 93-98 (1995).
7.	Abu-Roumi, M., M. E. Newman and J. Yanai. Muscarinic receptor related inositol phosphate formation in mice prenatally-exposed to drugs. Brain Research Bulletin 40:183-186 (1996).
8.	Steingart, R.A., Abu-Roumi, M., Newman, M.E., Silverman, W.F., Slotkin, T.A. and Yanai, J., Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts, Dev. Brain. Research, 122:125-133 (2000).
9.	Steingart, R. A., W. F. Silverman, S. Barron, Y. Awad and J. Yanai. Reversal of Prenatal Drug Induced Alterations in Hippocampal PKC and Correlated Behavioral Deficits By Neural Grafting. Dev. Brain. Research, 125:9-19 (2000).
10.	Slotkin T. A., F. J. Seidler, E. C. McCook, and J. Yanai Heroin Neuroteratogenicity:  Targeting adenylyl cyclase as an underlying biochemical mechanism. Dev. Brain Research, 132: 69-79 (2001).
11.	Yanai, J., R. Huleihel, M. Izrael, S. Metsuyanim, H. Shahak, O. Vatury and S. P. Yaniv. Functional changes after prenatal opiates exposure related to alteration in opiate receptors and in cholinergic innervation. Int. J. Neuropsychopharmacology, 6: 1-13 (2003).
12.	Shahak, H., T. A. Slotkin and J. Yanai. Alterations in PKCg in the mouse hippocampus after prenatal exposure to heroin: a link from cell signaling to behavioral outcome. Dev. Brain Research, 140: 117-125 (2003).
13.	Yaniv, S. P., Z. Naor and J. Yanai. Prenatal heroin exposure alters cholinergic receptor stimulated translocation and basal levels of the PKCbII and PKCg isoforms. Brain Research Bulletin, 63: 339–349 (2004).
14.	Beer, A., T. A. Slotkin, F. J. Seidler and J. Yanai. Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital. Neuropsychopharmacology, 30: 156–165 (2005).
15.	Izrael, M., E. A. Van der Zee, T. A. Slotkin and J. Yanai. Cholinergic Synaptic Signaling Mechanisms Underlying Behavioral Teratogenicity:  Effects of Nicotine, Chlorpyrifos and Heroin Converge on PKC Translocation in the IMHV and on Imprinting Behavior in an Avian Model  J. Neuroscience Research, 78:499–507 (2004).
16.	Wormser, U., M. Izrael, E.A. Van der Zee and J. Yanai. A chick model for the mechanisms of mustard gas neurobehavioral teratogenicity. Neurotoxicology and Teratology, 27:65–71(2005).
17.	Katz S., T. Ben-Hur , T. L. Ben-Shaanan, and J. Yanai. Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors. Journal of Neurochemistry, in press.
18.	Tamar L. Ben-Shaanan T. L., T. Ben-Hur, and J. Yanai. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Molecular Psychiatry, in press.

Email:
josephy@ekmd.huji.ac.il

jyanai@duke.edu

Phone:
Telephone: 972-2-675-8439

Cell: 972-52-428-2638
Fax: 972-2-675-8443

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