The In-Vitro Reinforcement WebPage.

This page is intended to inform people about an important mechanism of neural plasticity (the basis of learning in the brain) understood in terms of a laboratory procedure and the evidence obtained thereby: In-Vitro Reinforcement or IVR. The following material is included:

a definition of IVR (with links to a glossary)
a bibliography of IVR research
contact information for obtaining hardcopy reprints
links to online and downloadable documents and related sites

Neural plasticity, the alteration of brain systems at a neural level that systematically affects behavior, is key to understanding the relationship between biology and psychology. Behavior evidences the mysteries of the mind by virtue of its adaptivity to circumstances. Presumably, this adaptivity is due to systematic changes in brain function that are sensitive to the environment.

Few mechanisms for neural plasticity are known and even fewer are understood. The best-known is Long-Term Potentiation (LTP), which involves the increased conductivity of synaptic connections between neurons due to increased activity over time. LTP is presumed to produce learning by differentially facilitating the associations between stimuli and responses. The role of LTP, if any, in producing those more complex behaviors less closely tied to specific stimuli and more indicative of cognition is not well-understood. LTP is best understood as underlying associative processes in behavior.

In-Vitro Reinforcement, by way of contrast, involves increases and decreases in intrinsic burst rates of individual neurons. IVR is presumed to produce learning by differentially reinforcing activity by those neurons involved in generating more adaptive behavior. An artificial neural network with a computational model of learning based on a simulation of IVR has demonstrated that complex, independently-generated behaviors can be learned by a network of IVR-sensitive neurons. Thus, In-Vitro Reinforcement may provide a key to understanding how complex, cognitive behaviors are learned.

Hardcopy reprints:

Prof. Larry Stein and Prof. James Belluzzi, both of the University of Calfornia at Irvine, are the discoverers of IVR. A bibliography of their work on IVR is included below. Prof. Stein has compiled a packet of IVR-related reprints in hardcopy, which he will be happy to send out to anyone interested. In order to obtain copies, write to him at:

Prof. Larry Stein
Dept of Pharmacology
UCI College of Medicine
University of California, Irvine
Irvine, CA 92697-4625
USA

and ask for the "IVR packet." Please enclose a self-addressed mailing label if possible.

Definition of In-Vitro Reinforcement:

Included as another part of this WebSite is an online paper on the neural network research connected with In-Vitro Reinforcement. That paper includes a hyperlinked glossary, which contains the following definition of IVR (slightly expanded):

In-Vitro Reinforcement (IVR): Results of a standard experimental procedure (Stein, 1997; Stein, Xue, & Belluzzi, 1993a; 1994; Stein & Belluzzi, 1989) that demonstrates changing neural activity due to the infusion of the neuromodulator, dopamine. A neuron (usually a pyramidal cell from the CA1 area of the hippocampus) that exhibits a characteristic multi-spike burst (mediated by activity of L-type Ca²⁺ channels) is monitored in-vitro. Whenever a Ca²⁺ burst is detected, dopamine is injected around the cell via pipette. The burst rate is observed to increase. The basic notion is that initially random activity, when regularly followed by a biologically important event, will come to occur more often. This idea is credited to Skinner (1951).

This increase has been demonstrated not to be the result of the effects of dopamine alone. Only the close temporal sequence of a calcium burst followed by dopamine results in increased burst rate. Dopamine delivered at other times results in a slight decrease in burst rate. Likewise, bursts not followed by dopamine cause a decrease of the burst rate in vitro. It is the delivery of dopamine contingent upon bursting that causes the increase in burst rate.

Details of a proposed molecular mechanism that may underly IVR are given in Appendix B of the online paper.

Bibliography on In-Vitro Reinforcement:

This bibliography is complete as of March, 1998. Please report any errors or ommissions.

Black, J., Belluzzi, J.D., & Stein, L. (1986). Operant conditioning of neuronal activity in anesthetized rat. Society for Neuroscience Abstracts, 12, 523.

Belluzzi, J. D. & Stein, L. (1983). Operant conditioning: Cellular or systems property? Neuroscience Abstracts, 9, 478.

Belluzzi, J. D. & Stein, L. (1986). Operant conditioning of hippocampal neurons: Role of dopamine D2 receptors. Society for Neuroscience Abstracts, 12, 706.

Belluzzi, J. D. & Stein, L. (1987). Operant conditioning of hippocampal CA1 neurons requires immediately-contingent activation of dopamine D2 receptors. Society for Neuroscience Abstracts, 13, 834.

Stein, L. (1994). In-vitro reinforcement of hippocampal bursting: Possible cellular and molecular mechanism of drug reward. Regulatory Peptides, 54, 285-286.

Stein, L. (1995, May). Skinner's behavioral atom: A cellular analogue of operant conditioning and its implications. Paper presented at the 21st annual meeting of the Association for Behavior Analysis, Washington, DC.

Stein, L. (1997). Biological substrates of operant conditioning and the operant-respondent distinction. Journal of the Experimental Analysis of Behavior, 67, 246-253.

Stein, L. (1997). Neuropsychopharmacology of mind and behavior. In O. S. Ray (Ed.), ACNP: First 35 Years (pp. 86-91). American College of Neuropsychopharmacology.

Stein, L. & Belluzzi, J. D. (1982). Beyond the reflex arc: A neuronal model of operant conditioning. In A. R. Morrison & P. L. Strick (Eds.), Changing concepts of the nervous system (pp. 651-665). New York: Academic Press.

Stein, L. & Belluzzi, J. D. (1982). Cellular mechanisms of reinforcement: An hypothesis. In B. G. Hoebel & D. Novin (Eds.), The Neural Basis of Feeding and Reward (pp. 129-136). Brunswick, ME: Haer Institute Press.

Stein, L. & Belluzzi, J. D. (1985). Operant conditioning of hippocampal neurons: Chlorpromazine blocks reinforcing actions of dopamine. Society for Neuroscience Abstracts, 11, 873.

Stein, L. & Belluzzi, J. D. (1987). Cellular basis of positive reinforcement. In D. C. Clark & J. Fawcett (Eds.), The Neural Basis of Feeding and Reward (pp. 129-146). New York: PMA Publishing.

Stein, L. & Belluzzi, J. D. (1987). Reinforcement, neurochemical substrates. In G. Adelman (Ed.), Encyclopedia of Neuroscience (pp. 1686-1689). Cambridge, MA: Birkhauser Boston.

Stein, L. & Belluzzi, J. D. (1987). Reward transmitters and drugs of abuse. In J. Engel & L. Oreland (Eds.), Berzelius Symposium VII: Brain Reward Systems and Abuse (pp. 19-33).

Stein, L. & Belluzzi, J. D. (1988). Operant conditioning of individual neurons. In M. L. Commons, R. M. Church, J. R. Stellar, & A. R. Wagner (Eds.), Quantitative Analyses of Behavior, Vol. VII (pp. 249-264). Hillsdale, NJ: Lawrence Erlbaum Associates.

Stein, L. & Belluzzi, J. D. (1989). Cellular investigations of behavioral reinforcement. Neuroscience and Biobehavioral Reviews, 13, 69-80.

Stein, L. & Belluzzi, J. D. (in press). Reinforcement, neurochemical substrates. Encyclopedia of Neuroscience.

Stein, L., Lander, A. D., Xue, B. G., & Belluzzi, J. D. (1997). Type VIII adenylyl cyclase: Putative molecular coincidence detector for in vitro (and behavioral) reinforcement. Society for Neuroscience Abstracts, 23, 238.

Stein, L., Xue, B.G., & Belluzzi, J. D. (1993a). A cellular analogue of operant conditioning. Journal of the Experimental Analysis of Behavior, 60, 41-53.

Stein, L., Xue, B.G., & Belluzzi, J. D. (1993b). Brain mechanisms: Cellular targets of brain reinforcement systems. Annals of the New York Academy of Sciences, 702, 41-60.

Stein, L., Xue, B. G., & Belluzzi, J. D. (1994). In vitro reinforcement of hippocampal bursting: A search for Skinner's atoms of behavior. Journal of the Experimental Analysis of Behavior, 61, 155-168.

Stein, L., Xue, B. G., & Belluzzi, J. D. (1996). Anandamide: In vitro reinforcement of hippocampal bursting by the natural ligand of the cannabinoid receptor. Society for Neuroscience Abstracts, 22, 165.

Xue, B. G., Belluzzi, J. D., & Stein, L. (1993). In vitro reinforcement of hippocampal bursting by the cannabinoid receptor agonist (-)-CP-55, 940. Brain Research, 626, 272-277.

Xue, B. G., Belluzzi, J. D., & Stein, L. (1997). In vitro reinforcement of CA1 neurons in mouse hippocampus by dopamine. Society for Neuroscience Abstracts, 23, 226.

Xue, B. G. & Stein, L. (1990). Opposite action of dopamine and glutamate in operant conditioning of hippocampal CA1 cells. Society for Neuroscience Abstracts, 16, 261.

Xue, B. G. & Stein, L. (1991). Reinforcement of hippocampal CA1 bursting by cannabinoid receptor activation. Society for Neuroscience Abstracts, 17, 872.

Xue, B. G. & Stein, L. (1992). The dopamine D1 agonist SKF82958 reinforces operant conditioning of hippocampal CA1 cellular bursting. Society for Neuroscience Abstracts, 18, 522.

Links for In-Vitro Reinforcement:

Over and above the paper on this WebSite about the neural network research connected with In-Vitro Reinforcement and its hyperlinked glossary, here are links to IVR-related stuff on other sites.

In the March, 1997 issue, the Journal of the Experimental Analysis of Behavior published a paper by Donahoe, Palmer, & Burgos on issues related to how to study the biological bases of behavior together with open peer commentary. One of the commentators was Larry Stein, who presented his molecular hypothesis of IVR. The entire collection is downloadable from the JEAB WebSite. JEAB makes its articles available in PDF format. In order to view the PDF files, you must first download the FREE Adobe Acrobat Reader 3.0. If you are using an earlier version of the Reader, please get 3.0, which is much faster.