Life Sciences, Vol. 50, pp. 2067-2074 Pergamon Press Printed in the USA ACQUISITION OF ENHANCED NATURAL KII J +ER CI~.I J. ACTIVITY UNDER ANESTHESIA Chi-Mei Hsueh 1, Joan F. Lorden 2, Raymond N. Hiramoto3, and Vithal K. Ghantal, 3 Departments of 1Biology, 2psychology, and 3Microbiology, University of Alabama at Birmingham, University Station, Birmingham, Alabama 35294-0007 (Received in final form April 20, 1992) Sulnmalw An increase in natural killer (NK) cell activity can be conditioned with a one trial learning paradigm to demonstrate the interaction between the central nervous system (CNS) and the immune system. In order to demonstrate learning possibilities during 'non-conscious' state, mice were anesthetized with a ketamin/rompun mixture and underwent one trial learning with odor cue as the conditioned stimulus (CS) preceding the unconditioned stimulus (US). The results indicated that mice that were exposed to camphor odor cue under the influence of anesthesia can associate the signal with the poly I:C unconditioned stimulus and were able to recall the conditioned response upon reexposure to the CS. Secondly, the conditioned association made in a conscious state can be recalled by exposure to the same olfactory odor cue in a 'non-conscious' state. The increase in the conditioned change in NK cell activity of both situations was significantly higher than the control group. The results demonstrate that learning can take place and the learned response can be recalled under the reduced awareness caused by anesthesia. The findings we report are unusual and novel in that they demonstrate that the CNS can learn new associations under conditions where the host is apparently unaware of the signals being linked. Anesthesia combined with the long interstimulus interval indicates that certain neuronal pathways in the CNS are receptive to second signals (elicited by the US) even when the second signal is separated by one day. This means the conditioned learning of a physiological response can take place unconsciously at a separate level and under situations where the host is totally unaware of the events which the brain is processing and linking as incoming information. Much evidence exists that the CNS communicates with the immune system. The pathways by which the CNS and the immune system maintain this communication with one another can be identified using conditioning paradigms which are easy to perform and which produce conditioned animals with high reliability. We have chosen the NK cell system for our conditioning studies because NK cells are a first line of defense in that they lyse tumor cells or virus-infected cells without the need for prior immunization. They play a significant role in natural immunity to tumors (1, 2), antibacterial resistance (3), and anfiviral response (4). We have used the pairing of camphor odor (CS) and the injection of poly I:C (US) to condition the increase in NK cell activity in a Pavlovian conditioning paradigm. Camphor alone has no effect on NK cell activity (5). Poly I:C, the unconditioned stimulus is a double stranded synthetic RNA that mimics infection by double stranded RNA virus. Poly I:C induces the expression and secretion of interferons (IFN) alpha and beta (6). The IFN in turn directly 0024-3205/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd All rights reserved.