The use of conditioning to probe for CNS pathways that regulate fever and NK cell activity. R. Hiramoto  C. Rogers  S. Demissie  C.M. Hsueh  N. Hiramoto  J. Lorden  V. Ghanta   Int J Neurosci  February, 1996; 84(1-4):229-45   Review PMID: 0008707485;  UI: 96234713

Efferent signal(s) responsible for the conditioned augmentation of natural killer cell activity. C.M. Hsueh  S.K. Tyring  R.N. Hiramoto  V.K. Ghanta   Neuroimmunomodulation  January, 1994; 1(1):74-81   PMID: 0008528888;  UI: 96053015

A simple, single, trial-learning paradigm for conditioned increase in natural killer cell activity. H.B. Solvason  V.K. Ghanta  S.J. Soong  C.F. Rogers  C.M. Hsueh  N.S. Hiramoto  R.N. Hiramoto   Proc Soc Exp Biol Med  February, 1992; 199(2):199-203   PMID: 0001741412;  UI: 9215908

A behavioral augmentation of natural immunity: odor specificity supports a Pavlovian conditioning model. H.B. Solvason  V.K. Ghanta  J.F. Lorden  S.J. Soong  R.N. Hiramoto   Int J Neurosci  December, 1991; 61(3-4):277-88   PMID: 0001824390;  UI: 92406360

Role of immune cells in the Pavlovian conditioning of specific resistance to cancer. R.N. Hiramoto  N.S. Hiramoto  M.E. Rish  S.J. Soong  D.M. Miller  V.K. Ghanta   Int J Neurosci  July, 1991; 59(1-3):101-17   PMID: 0001774131;  UI: 92129064

A new approach to immunotherapy. V.K. Ghanta  N.S. Hiramoto  H.B. Solvason  S.J. Soong  R.N. Hiramoto   Cancer Res  July, 1990; 50(14):4295-9   PMID: 0002364386;  UI: 90304782

Conditioning the elevation of body temperature, a host defensive reflex response. R.N. Hiramoto  V.K. Ghanta  C.F. Rogers  N.S. Hiramoto   Life Sci  ; 49(2):93-9   PMID: 0002062174;  UI: 91287471

Acquisition of enhanced natural killer cell activity under anesthesia. C.M. Hsueh  J.F. Lorden  R.N. Hiramoto  V.K. Ghanta   Life Sci  ; 50(26):2067-74   PMID: 0001608290;  UI: 92301243

Conditioned enhancement of natural killer cell activity, but not interferon, with camphor or saccharin-LiCl conditioned stimulus. V.K. Ghanta  N.S. Hiramoto  H.B. Solvason  S.K. Tyring  N.H. Spector  R.N. Hiramoto   J Neurosci Res  ; 18(1):10-5   PMID: 0002824798;  UI: 88062806

Identification of specific pathways of communication between the CNS and NK cell system. R. Hiramoto  V. Ghanta  B. Solvason  J. Lorden  C.M. Hsueh  C. Rogers  S. Demissie  N. Hiramoto   Life Sci  ; 53(7):527-40   Review PMID: 0008350666;  UI: 93354007

Augmentation of natural immunity and regulation of tumor growth by conditioning. V.K. Ghanta  T. Miura  N.S. Hiramoto  R.N. Hiramoto   Ann N Y Acad Sci  ; 521():29-42   PMID: 0003377365;  UI: 88239299

Influence of conditioned natural immunity on tumor growth. V. Ghanta  R.N. Hiramoto  B. Solvason  N.H. Spector   Ann N Y Acad Sci  ; 496():637-46   PMID: 0003474995;  UI: 87269176

Psychoneuroendocrine immunology: perception of stress can alter body temperature and natural killer cell activity. R.N. Hiramoto  H.B. Solvason  C.M. Hsueh  C.F. Rogers  S. Demissie  N.S. Hiramoto  D.K. Gauthier  J.F. Lorden  V.K. Ghanta   Int J Neurosci  ; 98(1-2):95-129   Review PMID: 0010395364;  UI: 99321287

  Psychoneuroendocrine immunology: site of recognition, learning and memory in the immune system and the brain. R.N. Hiramoto  C.F. Rogers  S. Demissie  C.M. Hsueh  N.S. Hiramoto  J.F. Lorden  V.K. Ghanta  INTERNATIONAL JOURNAL OF NEUROSCIENCE Dec 1997; 92(3-4):259-85 Department of Microbiology, University of Alabama at Birmingham 35294, USA. PMID: 0009522270   UI: 98182739

How the interaction between the brain and immune system takes place has not been clearly defined. Because multiple changes are occurring simultaneously in all organ systems (e.g., cardiovascular, gastrointestinal, reproductive, renal, respiratory, immune, CNS), how many single systems interacts with the brain becomes extraordinarily difficult to understand. The problem boils down to developing an approach that not only allows one to study the whole organism and define the mediators of the interacting systems, but also permit one to establish the connection and physiologic relevance of the responses that are being evaluated.

  Conditioning, a phenomenon made popular by the work of Pavlov (1906, 1927), may provide insight into the pathways of communication between the brain and possibly any organ system of the body. Conditioning allows one to separate the afferent from the efferent circuits. That is, signals from the immune system to the CNS (IS-->CNS) can be effectively separated from signals from the CNS to immune system (CNS-->IS). This permits one to study each pathway individually. Simple, single association trial models to condition fever, natural killer (NK) cell and cytotoxic lymphocyte (CTL) activities have been developed to evaluate the pathways. Single trial learning is not new. Pavlov has observed that "The electric buzzer set going before administration of food established a conditioned alimentary reflex after only a single combination," whereas the reverse order of presentation failed to condition the animal (Pavlov 1927 p. 27). Thus, conditioning can be used to train the brain to activate the immune system and other organ systems participating in the response. During the course of the conditioned response, presumably the CNS via the hypothalamus integrates in a cohesive orderly fashion all input and output signals and coordinates the responses made by the brain to the organ systems.

  The odor of camphor, the conditioned stimulus (CS) can be associated with the response produced by an unconditioned stimulus (US). The unconditioned stimuli used are poly I:C to raise fever and nonimmunospecific NK cell activity or alloantigens to raise immunospecific CTL activity. The unconditioned stimulus serves only as a means to activate the immune system and unbalance the homeostasis so that a transient but new bidirectional communication loop can be established between the immune system and the CNS (IS<-->CNS). The expression of the conditioned response (i.e., elevation of fever, NK cell, or CTL activity) induced with the CS (odor stimulus) is an outcome of neural activity (CNS-->IS). This infers that during conditioning, the signals generated by the CS and US imprints a neural pathway located within the central nervous system and leaves behind a CS/US memory of the association.

The immune activity (NK cell or CTL activity) which is modulated indicate that the memory pathway was activated in the brain of the animal expressing the conditioned response. The immune cells that are modulated can be considered to be casual bystander cells. These cells however must be in the proper (ready) state of activation to receive salient signals from the brain. Along with changes in the indicator cell population, other complex physiological processes are altered by the brain via sympathetic and neuroendocrine pathways to raise the fever response.