Background: More than a century ago, experimental work and clinical observations revealed the functional communication between the brain and the peripheral immune system. This is documented on the one hand by studies first demonstrating the effects of catecholamines on the circulation of leukocytes in experimental animals and humans, and on the other hand via the work of Russian physiologist Ivan Petrovic Pavlov and his coworkers, reporting observations that associative learning can modify peripheral immune functions. This work later fell into oblivion since little was known about the endocrine and immune system’s function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. Summary: In this article, we embark on a fascinating exploration of the historical trajectory of behaviorally conditioned immune responses. Key Message: We will pay homage to the visionary scientists who laid the groundwork for this field of research, tracing its evolution from early theories of how associative learning can affect immunity to the modern-day insights that behavioral conditioning of pharmacological responses can be exploited to improve the efficacy of medical interventions for patients.

The history of psychoneuroimmunology can be traced back in general to various scientific developments and key milestones aiming at understanding the bidirectional connection between brain, behavior, and immunity. The concept of the mind-body connection has ancient roots with early philosophers and healers recognizing the influence of emotions and mental states on health. Hippocrates for examples already emphasized the importance of a balanced life style for overall well-being, and Plato stated in his text Charmides, 155–6: “…I replied that it was a kind of leaf, which required to be accompanied by a charm, and if a person would repeat the charm at the same time that he used the cure, he would be made whole; but that without the charm the leaf would be of no avail” [1].

The scientific approach toward the functional relationship between the central nervous system (CNS), the endocrine, and the immune systems started at the beginning of the last century at a time, when the American physiologist Walter Bradford Cannon introduced the concept of the “fight or flight” response, thereby highlighting the physiological changes that occur in response to stress. This early research investigating inter-system communications was in particular addressed by two independent research areas. One related to the discovery of adrenaline by von Fürth [2], the other by the observation of Russian physiologist Ivan Petrovich Pavlov and coworkers, demonstrating that autonomous physiological responses can be behaviorally conditioned [3]. Both researchers provided compelling evidence that the brain and the immune system are intimately connected, sharing a common chemical language and are continuously exchanging information [4, 5].

Interestingly, these two research areas, the catecholamine-induced leukocytosis as well as the reports that immune responses can be modified by associative learning, have two things in common: both observations were made in the first two–three decades of the last century and both not only fade into obscurity but were rejected as misleading because of lacking a sufficient scientific basis [6, 7] (Fig. 1).

Fig. 1.

The discovery of the two research areas, the “behavioral conditioning of immune responses” and the “catecholamine-induced leukocytosis” were made in the first three decades of the last century, with both subsequently fading into obscurity and were rediscovered more than four decades later.

Fig. 1.

The discovery of the two research areas, the “behavioral conditioning of immune responses” and the “catecholamine-induced leukocytosis” were made in the first three decades of the last century, with both subsequently fading into obscurity and were rediscovered more than four decades later.

Close modal

The adrenal glands were identified in 1563 by Italian doctor Bartolomeo Eustachi (1520–1574). The finding that adrenal gland extracts significantly raised blood pressure sparked widespread interest in the medical community. von Fürth [2] was the pioneer in extracting the active component from animal glands, naming this semi-purified substance “Suprarenin.” Adrenaline, the first hormone to be extracted from tissue, was soon chemically characterized and mass-produced [8, 9]. Three years afterward, Takamine and Aldrich independently succeeded in obtaining this component in a crystallized form. Takamine named it adrenaline, while Aldrich determined its chemical structure (C9H13NO3). In 1907, during adrenaline synthesis, a by-product was discovered. This substance, marketed as “arterenol” in 1908, was actually noradrenaline, which would be officially identified and extracted from organs four decades later. Since arterenol’s effects were milder compared to adrenaline, its production ceased in 1910 [10].

The availability of adrenaline for commercial use sparked numerous studies on its impact on white blood cells. In 1904, Loeper and Crouzon [11] first noted a significant increase (two to three times) in white blood cell count following a subcutaneous adrenaline injection of 1 mg in humans. Frey and Lury [12] observed a two-phase reaction to adrenaline injections in both animals and humans. The initial phase, lasting about 30 min, was marked by a rise in lymphocyte count, followed by an increase in granulocytes in the second phase. These findings were validated by other researchers [13, 14], although large individual variations were seen, particularly in the granulocyte count increase [15‒17]. These studies led to a consensus that the typical response to adrenaline includes an early increase in lymphocytes (peaking within 30 min) followed by a rise in various types of white blood cells with a relative decrease in lymphocytes with a peak response at 2–4 h [18]. Despite the recognition of this catecholamine-induced increase in white blood cells and its importance in hematological research, this early evidence of interaction between the neuroendocrine and immune systems did not gain widespread acceptance in the scientific and biomedical community. At the start of the 20th century, there was limited understanding of the immune system, its biochemical processes, and how these interacted with the central nervous and endocrine systems.

The terms “learning” and “memory” are commonly used in immunology to describe how T and B lymphocytes recognize antigens. However, immunological responses can also be learned and memorized by associative learning or Pavlovian conditioning (Table 1). From birth on, the human brain is continuously learning and storing new information. This information processing is not limited to cognitive factors, social interactions, or specific skills. It also applies to the interpretation of environmental and contextual clues. For instance, certain tastes or smells can trigger discomfort or even gastrointestinal problems if they are associated with eating spoiled or toxic food or beverages. This type of learned taste aversion or avoidance is considered as a particular form of learning with some of the fundamental mechanics of classical conditioning and an evolutionary adaptation to protect organisms from potential dangers in their environment [19‒22].

Table 1.

Chronological table on the history of conditioned immune responses

YearScientist/PhysicianContribution/DiscoveryReferences
1886 Mackenzie Coryza at the sight of an artificial rose [23
1925 Voronov and Riskin “Habitual rises” in leukocyte counts [24
1926 Metalnikov and Chorine Conditioned immune response to various bacterial substances [25, 26
1927 Pavlov and coworkers Conditioning of autonomous physiological responses [3
1928 Tapilskij First approaches to behaviorally condition immune responses in humans [27
1952 Pavlov’s successors Dolin, Krylov, Flerov, and Lukyanenko Conditioning immune-suppressive and immune-enhancing effects in a range of species [28‒32
1955 Garcia Conditioned taste aversion [19
1961 Lukyanenko Extinction of conditioned responses [6
1962 Kruglaya Exploring the mechanisms of conditioned immune responses [33
1975 Ader and Cohen Behaviorally conditioned immunosuppression [34
1982 Ader and Cohen Conditioned immunosuppression diminished symptoms of lupus [35
1993 Ader Drug intake as the concept of associative learning [36
2005 Pacheco-Lopez and Schedlowski Mediation of conditioned immunomodulation [37
2016 Hadamitzky and Schedlowski Systematic application of learned immunopharmacological placebo responses in animal disease models [38‒40
YearScientist/PhysicianContribution/DiscoveryReferences
1886 Mackenzie Coryza at the sight of an artificial rose [23
1925 Voronov and Riskin “Habitual rises” in leukocyte counts [24
1926 Metalnikov and Chorine Conditioned immune response to various bacterial substances [25, 26
1927 Pavlov and coworkers Conditioning of autonomous physiological responses [3
1928 Tapilskij First approaches to behaviorally condition immune responses in humans [27
1952 Pavlov’s successors Dolin, Krylov, Flerov, and Lukyanenko Conditioning immune-suppressive and immune-enhancing effects in a range of species [28‒32
1955 Garcia Conditioned taste aversion [19
1961 Lukyanenko Extinction of conditioned responses [6
1962 Kruglaya Exploring the mechanisms of conditioned immune responses [33
1975 Ader and Cohen Behaviorally conditioned immunosuppression [34
1982 Ader and Cohen Conditioned immunosuppression diminished symptoms of lupus [35
1993 Ader Drug intake as the concept of associative learning [36
2005 Pacheco-Lopez and Schedlowski Mediation of conditioned immunomodulation [37
2016 Hadamitzky and Schedlowski Systematic application of learned immunopharmacological placebo responses in animal disease models [38‒40

After the discovery that autonomous functions could be modified through associative learning, experimental work in the early part of the last century saw Pavlov’s colleagues focusing on the phenomenon itself. Given the limited knowledge of the immune system at the time, most experiments investigated the potential generalization of behaviorally conditioned immune functions. They tested the effects of various conditioned stimuli, drugs, and substances as unconditioned stimuli (UCS) across species. With the rediscovery of behaviorally conditioned immunosuppression by Ader and Cohen [34], initial experiments explored the basic mechanisms driving learned placebo responses in the immune system, such as glucocorticoid action and their potential clinical significance (Ader [36]). At the start of this decade, approaches started to analyze the efferent pathways through which reexposure to the conditioned stimulus (CS) modulates immune responses. These studies have identified brain areas like the insular cortex and the amygdala, which are responsible for the CS-UCS association, and provided evidence for the afferent pathways by which drugs used as UCS reach the brain. More recent empirical evidence confirmed the potential clinical relevance of learned immune functions in experimental animals, healthy volunteers, and patient populations, and introduced new concepts and learning protocols to safeguard conditioned immune responses from extinction, thereby paving the way for their use in clinical practice.

The behavioral conditioning of immunological responses usually involves the pairing of an immunomodulatory compound (unconditioned stimulus [UCS]) with a neutral (conditioned) stimulus (CS). Following several CS/UCS pairings, an association between the two is established, and the mere presentation of the CS induces immunopharmacological responses closely mimicking the effect of the UCS. However, when Russian scientists reported their first observations about the phenomenon of learned immune responses, these neuroanatomical and biochemical interactions were completely unknown (Fig. 2).

Fig. 2.

a Photograph from 1914 showing Ivan Pavlov together with his coworkers and his dog Bierka. b Schematical drawing of the experimental setup leading to the concept of classic conditioning.

Fig. 2.

a Photograph from 1914 showing Ivan Pavlov together with his coworkers and his dog Bierka. b Schematical drawing of the experimental setup leading to the concept of classic conditioning.

Close modal

One of the first documented cases of a learned immune response was reported in the late 19th century where a patient suffered from severe coryza at the sight of an artificial rose, which the presence of natural roses invariably elicited [23]. Without having a physiological explanation for this phenomenon, Mackenzie named this phenomenon “rose cold” rhinitis sympathetic and stated: “…this particular caseopens our eyes to the fact that the association of ideas sometimes plays a more important role in awakening the paroxysms of vasomotor coryza than the alleged vital property of the pollen granule” [41].

Beside this case of rather anecdotal character, the first scientific reports of behaviorally conditioned immune responses arose in the early 20th century from Pavlov’s contemporaries in St. Petersburg. The transformation of Pavlov’s theory into immunology tremendously expanded the knowledge about immune functions as one of the organisms’ physiological systems controlled by the CNS. A large scale of experimental approaches in the early and mid-20th century reported examples of conditioned immune functions, indicating that the rules applicable to conditioned reflexes such as salivation also apply to immune response [6]. Importantly, these findings changed the prevailing previous idea of Rudolf Virchow, who emphasized the importance of cells as the basic units of life and the origin of diseases, focusing on cellular pathology [28, 29, 42].

An early study by [24] documented conditioned increases in white blood cell counts (leukocytosis) in both humans and dogs. They found that in fasting humans, the number of leukocytes varied throughout the day, with changes ranging from 90 to 175%. Each participant showed a consistent, individual pattern of these fluctuations. Interestingly, these variations were linked to the usual times of eating, leading the researchers to describe them as “habitual rises”. The study also noted that conditioned changes were less pronounced in adults compared to children and experimental animals. In puppies that were fed multiple times a day, similar “habitual rises” in leukocyte counts were observed. Notably, at the start of the experiment, there was an additional increase in leukocyte count, which the authors believed was triggered by the stress of being removed from the cage and the anticipation of feeding. Thus, this spike was termed as the “conditioned rise,” indicating a conditioned change in leukocyte circulation.

In the 1920s, Metalnikov and Chorine conducted groundbreaking research at the Pasteur Institute in Paris showing that an immune response could be triggered solely by a CS without the need for an antigen (Fig. 3). They conditioned guinea pigs by pairing intraperitoneal injections of various bacterial substances (e.g., small doses of bacillus anthracis, staphylococcus filtrate, a tapioca emulsion, or vibrio cholera) as the UCS together with scratching or heating the skin with a warm metal plate as CS. Later, the presentation of the CS alone led to a significant and rapid increase in polymorphonuclear leukocytes [25, 26]. When vibrio cholera was used as the UCS, unconditioned guinea pigs typically died 7–8 h after being challenged with this pathogen. In contrast, after being reexposed to the CS, conditioned animals survived for up to 36 h post-challenge, with some even surviving long-term and withstanding subsequent challenges with streptococcus. Notably, animals that had been reexposed to the CS before facing the streptococcus challenge survived, while those animals that were not reexposed died. After publication of their experimental findings, Vygodchikov and Barykina [42] replicated the work of Metalnikov and Chorine with guinea pigs. They used intraperitoneal bouillon injections as the US and heating the belly as the CS. After 21 daily acquisition trials and a 12-day break, the experimental group was reexposed to just the CS, while the control group received bouillon injections during the retrieval phase. Both groups exhibited similar cellular immune responses in the abdominal fluid, showing an increase in polynuclear cells by the 5th hour and a rise in monocytes by the 24th hour from the start of the trial.

Fig. 3.

Copies of the original documents written in Cyrillic script (a, b) with the respective translation in German (c) and English (d) below.

Fig. 3.

Copies of the original documents written in Cyrillic script (a, b) with the respective translation in German (c) and English (d) below.

Close modal

In a subsequent study by Ostrovskaya [43], these results were not only confirmed but also expanded upon. The research involved using scratching and heating of the skin, as well as an electrical stimulus (CS), paired with intraperitoneal bouillon injection (UCS) in guinea pigs. However, a critical observation was made regarding the distinct effects of different CS; heating the skin was not neutral as it triggered leukocytosis on its own, whereas the electrical stimulus was partially neutral and scratching was entirely neutral. A separate experiment focused on conditioning antibody production in rabbits using a typhoid vaccine as the UCS. This study observed that the agglutination titer, a measure of antibody presence, increased in response to both the CS and the UCS in conditioned animals and controls, respectively. Although the study did not successfully condition the humoral (antibody-mediated) response, it demonstrated a successfully conditioned response at the cellular level. Shamboorov and Belikova [44] referenced that Shamboorov had conceptualized the idea of conditioned modulation of immune responses shortly before Metalnikov’s notable publication. In their experiments, they used either scratching of the ear or the sound of a bell as the CS and cholera vaccination as the UCS to induce conditioned leukocytosis in rabbits. It was observed that only those rabbits (2 in total) which had an atypical reaction to the vaccination showed no such conditioned response. Moreover, the rabbits’ behavior in response to the CS mirrored their reaction to the actual vaccination. This study also demonstrated conditioned inhibition of these learned effects. When new inhibitory stimuli such as the smell of camphor, liquid ammonia, and faradic currents were introduced alongside the CS during the retrieval phase, the conditioned response was either weakened or completely suppressed.

Reflecting on these early 20th century findings, Pavlov himself commented on the broad significance of nervous regulation in physiological functions. In 1928, he stated: “Nowadays - the conditionality - and it should be connected with the higher department of the CNS - is given wide biological significance, since conditioned leukocytosis, immunity, and various other organic processes have been proved, although we do not yet have precisely specified neural connections involved in this in a direct or some indirect way.” This highlighted the growing understanding of the CNS’s role in regulating diverse physiological processes through conditioned responses [45].

The first experimental approaches to behaviorally condition immune responses in humans were presented by Tapilskij [27]. He used hypnosis as the conditioned sleep and investigated changes in the leukocyte numbers in response to the feeling of satiety or hunger in different stages of hypnosis. Data showed that by the development of the conditioned reflex (deep stages of hypnosis – 3rd and 4th), the suggestion of satiety increased leukocytosis, while the suggestion of hunger decreased this parameter. If the conditioned reflex was not developed (1st or 2nd stage of hypnosis), the number of leucocytes upon suggestion of satiety or hunger changed in the opposite direction, presumably under the influence of autosuggestion that acted contrary to the experimenter’s suggestion. Additionally, patients in an excited or depressed state did not show conditioned changes in leukocyte numbers, confirming Pavlov’s statement that: “…the slightest hesitation of the external environment or inner state, often barely perceptible or completely unnoticed, drastically changes the course of phenomena” [46].

Due to methodological differences and errors, many early results in immune conditioning were not replicable by other researchers, leading to a near cessation of studies in this field. In 1950, the Soviet Union held a “Pavlovian” session at the Academy of Sciences and a meeting at the Academy of Medical Sciences in Moscow. The aim was to exert ideological control over Soviet scientific research and to shield it from Western influence. During these meetings, many scientists faced severe criticism for straying from Pavlov’s theories, which were then declared the only acceptable scientific approach [47]. This declaration negatively impacted Soviet science, resulting in its isolation and decline within the global scientific community. However, paradoxically, it also renewed interest in the study of classical conditioning of immune functions, leading to further research in this area [29, 30].

After a gap of nearly two decades, studies on immune conditioning resumed in the Soviet Union, led by Dolin (Pavlov’s successor at Leningrad University) and his students Krylov, Flerov, and Lukyanenko [28, 29, 31]. They explored both specific and nonspecific immune responses, including conditioned immunosuppressive and immunoenhancing effects. They used various substances as the UCS, including viruses, foreign red blood cells, albumin, malarial parasites, whole organisms, vaccines, and extracts from salmonellae, dysentery, typhoid, paratyphoid, diphtheria bacilli, Escherichia coli, and staphylococci [30, 32]. These studies were conducted on a range of species such as mice, rats, guinea pigs, rabbits, dogs, oxen, monkeys, and even humans.

In a series of experiments conducted in the 1950s, Dolin and colleagues [28] demonstrated the development of a conditioned reflex, as well as the dynamics of the extinction of conditioned responses [6, 28]. They observed a behaviorally conditioned increase in agglutinin levels in the peripheral blood of rabbits, when using a paratyphoid vaccine as UCS and the immunization procedure itself as the CS. During the extinction phase, rabbits were injected with saline instead of the vaccine. Remarkably, the evoked conditioned response on humoral agglutinin levels was more pronounced than the unconditioned responses and persisted for up to 240 days. In follow-up experiments, Dolin and colleagues investigated the phenomenon of the “dynamic stereotype”, discovering that saline injections inhibited the response to subsequent vaccine injections when given several times before immunization. Additionally, rabbits pre-immunized with a vaccine and later injected with a different vaccine displayed antibody production as a conditioned response following administration with the first vaccine, but not with the second. In their final series of experiments, rabbits were immunized with a mixture of horse, lamb, and guinea pig serums. However, a subsequent injection of just one type of serum induced antibody production to all three serums (horse, lamb, guinea pig) administered previously.

Other isolated studies from the early 1950s also documented behaviorally conditioned immune responses in humans. For instance, Strutsovskaya [48] reported that in children with scarlet fever, who had received four administrations of gamma globulin, a subsequent saline injection increased phagocytic activity compared to a control group that received only saline injections. Furthermore, numerous studies analyzed the effects of CS intensity and valence on the magnitude of the conditioned response. Doroshkevich [29] used intranasal administration of an isotonic saline solution as the CS and a paratyphoid vaccine as the UCS, reporting a conditioned increase in the titer of agglutinins in rabbits. To further explore the effect of CS valence on this learned immune response, subsequent experiments employed hyper- and hypotonic NaCl solutions as the CS. These studies found no influence of varying CS intensity on the conditioned immune response. In the next series of experiments, using just an NaCl injection as the CS also demonstrated a conditioned increase in agglutinin titer, although the magnitude of the conditioned response was lower than in previous experiments. Finally, merely “wrapping” a rabbit as a CS failed to induce a learned immune response in the evocation retrieval phase. This collection of experiments corroborated earlier findings that immune defensive reactions in organisms can be modulated through associative learning procedures, often exceeding the unconditioned responses induced by the compounds used as UCS [28].

In an attempt to behaviorally condition an antiviral immune response in rats, mechanical skin irritation was used as the CS, alongside the concurrent administration of the influenza virus as the UCS. When the CS was represented alone, an increase in antibody levels was observed in the experimental animals, in contrast to the control group, which showed no change in antibody levels. In a follow-up experiment, pairing pilocarpine administration (CS) with virus injection (UCS) demonstrated a conditioned increase in antibody production in response to pilocarpine alone. This protocol, when applied to rabbits, replicated the findings obtained in rats [49]. To further understand the role of the CS in learned immune responses, two experimental groups of rabbits (n = 4 in each group) received subcutaneous injections of either saline or acetyl chloride as the CS, paired with a dysentery vaccine as the US. During retrieval, two animals of each group were reexposed to either saline or acetyl chloride. The results showed a conditioned increase in agglutinin titer in those rabbits that received the same CS during both acquisition and retrieval, compared to the animals that received different CS at retrieval.

A distinct set of experiments in rabbits paired various CS – including needle injection, saline injection, and acetyl chloride – with a dysentery vaccine. Upon representation of each specific CS alone at retrieval, a conditioned increase in agglutinin titer was observed, lasting up to 2 months in each group. The authors concluded: “Multiple vaccinations with small doses can be used in anti-epidemic practice to maintain immunity for a longer period by repeated injections of acetylcholine chloride, used as a conditioned stimulus” [50]. Additionally, a behaviorally conditioned modulation of phagocytic activity in leukocytes was reported in dogs, using the ringing of a bell as the CS, associated with either a strong or mild electrical stimulus as the US. As a conditioned response, the representation of the bell ringing alone at retrieval enhanced phagocytic activity. Furthermore, the repetitive presentation of the CS (bell ringing) without the UCS (electrical stimulus) led to the inhibition of the learned response [51].

Despite the impressive array of sophisticated experimental studies, not only the functioning of the immune system but also the potential mechanisms guiding conditioned immune responses were still largely unknown at that time. Believing that the learned production of antibodies was triggered by a reflex mechanism, Russian researchers sought to elucidate this mystery. In one experimental approach, they explored the possibility of antigen binding to receptors in the afferent neural pathways. More specifically, the carotid sinus of rabbits was isolated and the antigen Breslau coli was introduced, with controls to prevent the antigen from entering the peripheral blood flow. The immune response, analyzed 7 days after surgery, showed a slight increase in antibody titer. The experimenters concluded that while antigenic stimulation was transmitted through nerve fibers, these stimuli were not sufficient to elicit intensive antibody production [52]. Another study examined the effect of diphtheria toxin vaccination on the conditioned reflex in rabbits [53]. Based on the results, it was hypothesized that defensive reflexes are more robust and less affected by antigen stimulation compared to alimentary reflexes. However, attempts to induce a conditioned immune response in rabbits using a pyrogenic reaction of pharmacological or bacterial origin as the CS and tularemia vaccine as the UCS were unsuccessful. The author speculated that the null results of this study might be attributed to the inappropriate choice of the CS, which, according to Pavlov’s theory, should not induce any physiological changes in the organism [54].

During the mid-1950s, experimental approaches also explored the impact of immunization on behaviorally conditioned salivation in dogs [55]. More specific, two dogs were subjected to a conditioning procedure, with one receiving an inhibitory signal to block the conditioned response. Both dogs then received 10 injections of typhoid vaccine during the retrieval phase. The dog without the inhibitory signal showed the most significant disturbance in higher nervous activity between the 4th and 5th vaccination, indicated by a reduced conditioned increase in salivation. This diminished response to the CS was accompanied by a disinhibition of inhibitory conditioned reflexes, which the authors termed the “ultra-paradoxical phase.” During the final 5 vaccinations, almost no changes in the conditioned salivation were observed. The second dog exhibited similar effects, with a severe inhibition of the conditioned salivation after the 4th and 5th vaccinations. Following the 10th vaccination and a 2-week rest period, both dogs received a saline injection under the same experimental conditions, but no conditioned antibody response was observed. In four baboons (Papio hamadryas), the experimental procedure and the “context” (immobilization of the animals for 2 h) served as the CS, with an injection of paratyphoid vaccine as the UCS. Reexposure to the combined CS led to a significant increase in antibody titers after 5 retrieval trials [30].

Ilyenko and Kovaleva [56] investigated behaviorally conditioned immune responses in dogs and rats using sheep erythrocytes, influenza virus, and E. coli vaccine as US in various combinations. Learned immune responses extinguished if they were not reinforced for an extended period and were restored upon reinforcement with vaccination. One of the dogs underwent a conditioning procedure using two antigens as UCS (influenza virus and sheep erythrocytes) but was subsequently reinforced with only sheep erythrocytes. Interestingly, the extinction of the conditioned response to the influenza virus also led to the extinction of the learned immune response against sheep erythrocytes, even though it was reinforced. This phenomenon was thought to be part of the “conditional reflex complex.”

The work of Dolin and Krylov [28] on the role of the dynamic stereotype in immune conditioning was expanded upon in 1960. Various conditioning protocols employing different UCS, such as local and generalized allergic reactions, tetanus intoxication, and antibody production, were utilized. The findings from these experiments indicated not only a learned suppression of immune functions but also alterations in the direction of immune responses, including a complete blockade of immune reactions. In some cases, the conditioned response even prevented the death of animals in response to toxin or allergen administration. The authors asserted that their data support the notion that unconditioned reactions to toxins or antigens are influenced by an experimental modification of the nervous system [57]. Kruglaya [33] also focused on exploring the mechanisms of conditioned immune responses in dogs, particularly the role of the autonomic nervous system in conditioned leukocytosis. After pairing a metronome sound (CS) with E. coli administration, an increase in leukocyte count was observed in these dogs when reexposed solely to the CS. However, the pharmacological blockade of autonomic ganglia with pentamine and dicoline at the beginning of the retrieval phase altered the conditioned response, leading to leukopenia instead of leukocytosis. Importantly, prolonged ganglionic blockade prior to the acquisition phase completely inhibited the formation of the reflex [33]. Romanian researchers around the same period documented the influence of immune activation on a conditioned salivary response as well as putatively conditioned enhancements in the phagocytic activity of polymorphonuclear cells in dogs’ peripheral blood [58, 59]. In parallel, Swiss scientists released a series of reports demonstrating conditioned asthma-like responses in guinea pigs using auditory CS [22, 60‒64]. This experiment was later replicated with human subjects [65]. Simultaneously, other experimental findings indicated that specific contexts as CS could trigger allergic response symptoms in guinea pigs [66]. These observations led to the suggestion that bronchoconstriction, at least in certain cases, might be a learned response resulting from a conditioning process [67].

However, it is important to note that many of these early studies conducted by Russian researchers did not adhere to current methodological standards (limited numbers of animals in experimental and control groups, error-prone or inconsistent experimental and laboratory conditions, inadequate or absent control conditions, etc.). Given the limited understanding of immune system functions at that time, many of these studies are likely to exhibit signs of “false positive” results and bias. Despite these limitations, these pioneering investigations indicated that peripheral immune functions could be influenced, by the CNS. Furthermore, they began to challenge the prevailing scientific view of an autonomously functioning immune system, solely activated by external pathogens, as early as the first half of the 20th century.

In 1975, Ader and Cohen [34] (Fig. 4) published a groundbreaking paper where they introduced the concept of “behaviorally conditioned immunosuppression” or “learned immunopharmacological placebo responses,” laying the groundwork for the field of psychoneuroimmunology. Their research involved conditioned taste aversion (CTA) experiments using saccharin as the CS and the immunosuppressive drug cyclophosphamide as the UCS. They observed that some animals in the conditioned group, which had consumed significant amounts of saccharin and demonstrated strong CTA, died [68]. This apparent direct link between mortality and the intensity of CTA led to the theory that the saccharin (CS) acquired immunosuppressive effects by being associated with the UCS (cyclophosphamide). Their hypothesis was confirmed when they found that rats exposed to both cyclophosphamide and saccharin not only exhibited expected CTA but also showed reduced antibody production in response to sheep red blood cells when presented alongside the CS [34]. Further validation of this phenomenon came from independent laboratories that replicated these results under similar conditions [69, 70]. These studies varied the doses of the UCS and the timing after inoculation, thereby solidifying its reliability and credibility. This has led to numerous reviews that summarize and examine various facets of the phenomenon of behaviorally conditioned immune modulation [41, 71].

Fig. 4.

Dr. Robert Ader and Dr. Nicholas Cohen, University of Rochester, USA (personal archive of Prof. Cobi J. Heijnen).

Fig. 4.

Dr. Robert Ader and Dr. Nicholas Cohen, University of Rochester, USA (personal archive of Prof. Cobi J. Heijnen).

Close modal

Well-controlled experimental preclinical research, as well as studies comprising healthy individuals and patient groups, have not only deepened our understanding of the communication between the brain and the peripheral immune system but also opened avenues for utilizing associative learning paradigms as alternative or rather substitution of immunopharmacological treatments [72]. Chronic inflammatory diseases, which often necessitate ongoing treatment with specific immunomodulatory medications, can lead to significant side effects that negatively impact patient quality of life [73‒76]. In this scenario, the application of associative learning paradigms has been effectively used in controlled strategies for reducing required drug doses but sustaining and amplifying the effectiveness of treatments [77].

Drug intake is seldom analyzed under the concept of associative learning, and viewing it as such presents a novel approach for enhancing treatment efficacy [36]. Nevertheless, the clinical relevance of associative learning paradigms has been debated since their reemergence in the mid-1970s, primarily due to arguments that this approach may not be viable if learned immune responses are quickly extinguished and are only short-lived. But, if the extinction of a learned immune response can be managed or even controlled through reinforcement strategies or memory updating, the potential of using associative learning paradigms as adjunct therapy alongside standard pharmacological treatments could be significant [77].

For many years, the mechanisms underlying behaviorally conditioned immune functions remained elusive. However, in the last two decades, significant strides have been made in understanding the basic neurobiological and immunological mechanisms behind these functions, though they are not yet fully comprehended in detail. By employing immunosuppressive substances such as the calcineurin inhibitor cyclosporine A, we, along with others, have demonstrated that behaviorally conditioned immunomodulation is centrally mediated via the insular cortex, the amygdala, and the ventromedial nucleus of the hypothalamus. Additionally, it involves the efferent pathway through the splenic nerve, utilizing noradrenaline and adrenoceptor-dependent mechanisms [37]. Furthermore, the potential clinical relevance of learned immune responses has been demonstrated in numerous experimental animal studies. These studies show that conditioned immunological responses can prolong the survival time of transplanted organs [38], attenuate chronic inflammatory diseases [39], and significantly diminish brain tumor growth [40]. Importantly, behaviorally conditioned immunosuppression has been documented in healthy volunteers and patient populations (summarized in [41]).

In associative learning, it is well established that repeated exposure to the CS without the UCS during a phase of transient lability can destabilize conditioned memory traces, leading to their extinction. In this context, Pavlov and his colleagues recognized that extinction is not merely forgetting or loss of information but rather a form of “new learning.” More recent research has shown that when a memory is reactivated, it enters a labile state, becoming prone to changes. This state, known as reconsolidation, requires protein synthesis and allows for the integration of new information into preexisting memories during an approximately 4-h time period (the reconsolidation window). Therefore, memories can be restabilized (reconsolidated), augmented by using memory enhancers, or pharmacologically inhibited [78‒81]. Notably, research has demonstrated that administering subeffective doses of the UCS in close temporal proximity to the CS at retrieval can prolong the persistence of conditioned responses [41]. Although the underlying mechanisms remain largely unclear, it is suggested that presenting such reminder cues can partly recreate the original encoding experience, thus allowing for the modification or reinforcement of memories [82]. In rodent studies, the use of these reminder cues (10–25% of the drug used as UCS) in conjunction with CS reexposure has been shown to not only sustain conditioned immune responses using various immunosuppressive drugs but also significantly influence the progression of chronic inflammatory diseases, extend the survival of transplanted organs, and inhibit the growth of brain tumors [38, 40]. These cues have also been effective in preventing the extinction of learned immunosuppressive effects in human studies [83]. To use an information technology analogy: if we consider the efferent and afferent communication pathways between the brain and the peripheral immune system as the hardware, and sophisticated associative learning protocols as the software, then behavioral conditioning of immunopharmacological responses could act as an activator of the body’s own pharmacy. This approach may become a highly valuable future supportive treatment tool for enhancing patient outcomes [72].

The authors have no conflicts of interest to declare.

This work was funded by center grants of the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) project number 316803389 – SFB 1280 (TP A18 to M.H. and M.S.).

Manfred Schedlowski and Martin Hadamitzky wrote and edited the manuscript. The submitted version of the manuscript has been approved by all authors.

1.
WRM
Lamb
.
Plato, Charmides Plato in twelve volumes
.
Cambridge, London
:
Harvard University Press; William Heinemann Ltd.
;
1955
.
Vol. 8
; p.
155
6
.
2.
von Fürth
O
.
Zur Kenntniss der brenzcatechinähnlichen Substanz der Nebennieren Mittheilung
.
Z Physiol Chem
.
1900
;
3
:
105
23
.
3.
Pavlov
I
.
Conditioned reflexes:an investigation of the physiological activity of the cerebral cortex
.
Cambridge
:
Oxford University Press
;
1927
.
4.
Dantzer
R
,
O’Connor
JC
,
Freund
GG
,
Johnson
RW
,
Kelley
KW
.
From inflammation to sickness and depression: when the immune system subjugates the brain
.
Nat Rev Neurosci
.
2008
;
9
(
1
):
46
56
.
5.
Tracey
KJ
.
Understanding immunity requires more than immunology
.
Nat Immunol
.
2010
;
11
(
7
):
561
4
.
6.
Lukyanenko
V
.
The problem of conditioned reflex regulation of immunobiological reactions
.
Zhurnal vysshei nervnoi deiatelnosti imeni IP Pavlova
.
1961
;
51
:
170
87
.
7.
Ziegler
K
.
Über die Verteilung der Blutzellen in der Blutbahn
.
Klin Wochenschr
.
1924
;
3
(
33
):
1481
2
.
8.
Rao
Y
.
The first hormone: adrenaline
.
Trends Endocrinol Metab
.
2019
;
30
(
6
):
331
4
.
9.
Weisser
U
. Das erste Hormon aus der Retorte: Arbeiten am synthetischen Adrenalin (Suprarenin) bei Hoechst; 1900–1908. Dokumente aus Hoechst Archiven (Farbwerke Hoechst AG, Frankfurt/M.); 1984.
10.
Benschop
RJ
,
Rodriguez-Feuerhahn
M
,
Schedlowski
M
.
Catecholamine-induced leukocytosis: early observations, current research, and future directions
.
Brain Behav Immun
.
1996
;
10
(
2
):
77
91
.
11.
Loeper
MC
.
O., l’Action de l’adre´naline sur le sang
.
Arch Med Exp Anat Pathol
.
1904
;
16
:
83
108
.
12.
Frey
WL
,
Lury
S
.
Adrenalin zur funktionellen Diagnostik der Milz? Untersuchungen an klinischem Material
.
Zeitschrift für die gesamte experimentelle Medizin
.
1914
;
2
(
1
):
50
64
.
13.
Hatiegan
J
.
Untersuchungen u¨ber die Adrenalinwirkung auf die weißen Blutzellen
.
Wiener Medizinische Wochenschrift
.
1917
;
30
:
1541
7
.
14.
Hess
O
.
Suprarenin und weißes Blutbild
.
Deutsches Archiv für klinische Medizin
.
1922
;
141
:
151
64
.
15.
Hoefer
PAH
.
Zur Beeinflussung des Blutbildes durch Adrenalin
.
Folia Haematolgoica
.
1921
;
27
.
16.
Walterhöfer
G
.
Die Veräderungen des weißen Blutbildes nach Adrenalininjektionen
.
Deutsches Archiv für klinische Medizin
.
1933
;
135
:
208
23
.
17.
Kägi
A
.
Studien und Kritik der Blutveränderung nach Adrenalin
.
Folia Haematologica
.
1920
;
25
:
107
19
.
18.
Samuels
AJ
.
Primary and secondary leucocyte changes following the intramuscular injection of epinephrine hydrochloride
.
J Clin Invest
.
1951
;
30
(
9
):
941
7
.
19.
Garcia
J
,
Kimeldorf
DJ
,
Koelling
RA
.
Conditioned aversion to saccharin resulting from exposure to gamma radiation
.
Science
.
1955
;
122
(
3160
):
157
8
.
20.
Bures
J
,
Bermúdez-Rattoni
F
,
Yamamoto
T
, editors.
Conditioned taste aversion: memory of a special kind
.
Oxford Univ Press
;
1998
.
Vol. 31
.
21.
Garcia
J
,
Lasiter
PS
,
Bermudez-Rattoni
F
,
Deems
DA
.
A general theory of aversion learning
.
Ann N Y Acad Sci
.
1985
;
443
:
8
21
.
22.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Das experimentelle Asthma bronchiale des Meerschweinchens. I. Mitteilung Methoden zur objektiven Erfassung (Registrierung) des Asthmaanfalles
.
Int Arch Allergy Immunol
.
1951
;
2
(
4
):
308
20
.
23.
Mackenzie
JN
.
The production of the so-called ‘‘rose cold’’ by means of an artificial rose
.
Am J Med Sci
.
1886
;
91
:
45
7
.
24.
Voronov
A
,
Riskin
I
.
About leukocytosis of healthy people and dogs
.
Russkaya Klinika
.
1925
;
3
:
483
512
.
25.
Metalnikov
S
,
Chorine
V
.
Role des reflexes conditionnels dans l’immunite
.
Ann L’inst Pasteur
.
1926
;
40
:
893
900
.
26.
Metalnikov
S
,
Chorine
V
.
Role des reflexes conditionnels dans la formation des anticorps
.
C R Soc Biol
.
1928
;
1
(
102
):
133
4
.
27.
Tapilskij
A
.
Change in the number of leukocytes upon inducing satiety or hunger in a condition of conditioned reflex sleep
.
Meditsinskie mysli Uzbekistana
.
1928
;
2
:
8
13
.
28.
Dolin
A
,
Krylov
V
.
Role of the cerebral cortex in immunologic reactions of the organism
.
Zh Vyssh Nerv Deiat Im I P Pavlova
.
1952
;
2
(
4
):
547
60
.
29.
Doroshkevich
A
.
Effect of conditioned stimuli on formation of immunological reactions
.
Zh Vyssh Nerv Deiat Im I P Pavlova
.
1954
;
4
(
1
):
108
15
.
30.
V
Lukyanenko
,
Concerning the conditioned reflex control of immunity
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1958
;
10
:
53
9
.
31.
Vygodchikov
G
.
Certain controversial questions in the theory of immunity
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1955
;
26
:
5
14
.
32.
Spector
NH
.
Neuroimmunomodulation: a brief review
.
Regul Toxicol Pharmacol
.
1996
;
24
(
1
):
S32
38
.
33.
Kruglaya
N
.
Effect of autonomic ganglionic block on the course of conditioned reflex leukocytosis
.
Zh Mikrobiol Epidemiol Immunobiol
.
1962
;
33
:
52
5
.
34.
Ader
R
,
Cohen
N
.
Behaviorally conditioned immunosuppression
.
Psychosom Med
.
1975
;
37
(
4
):
333
40
.
35.
Robert
Ader
,
Cohen
Nicholas
.
Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus.
.
Science
.
1982
;
215
(
4539
):
1534
1536
.
36.
Ader
R
.
Conditioned responses in pharmacotherapy research
.
Psychol Med
.
1993
;
23
(
2
):
297
9
.
37.
Pacheco-Lopez
G
,
Niemi
MB
,
Kou
W
,
Härting
M
,
Fandrey
J
,
Schedlowski
M
.
Neural substrates for behaviorally conditioned immunosuppression in the rat
.
J Neurosci
.
2005
;
25
(
9
):
2330
7
.
38.
Hadamitzky
M
,
Bösche
K
,
Wirth
T
,
Buck
B
,
Beetz
O
,
Christians
U
, et al
.
Memory-updating abrogates extinction of learned immunosuppression
.
Brain Behav Immun
.
2016
;
52
:
40
8
.
39.
Lückemann
L
,
Stangl
H
,
Straub
RH
,
Schedlowski
M
,
Hadamitzky
M
.
Learned immunosuppressive placebo response attenuates disease progression in a rodent model of rheumatoid arthritis
.
Arthritis Rheumatol
.
2020
;
72
(
4
):
588
97
.
40.
Hetze
S
,
Barthel
L
,
Lückemann
L
,
Günther
HS
,
Wülfing
C
,
Salem
Y
, et al
.
Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model
.
Brain Behav Immun
.
2022
;
106
:
270
9
.
41.
Hadamitzky
M
,
Lückemann
L
,
Pacheco-López
G
,
Schedlowski
M
.
Pavlovian conditioning of immunological and neuroendocrine functions
.
Physiol Rev
.
2020
;
100
(
1
):
357
405
.
42.
Vygodchikov
G
,
Barykina
O
.
Conditional reflex and protective cell responses
.
J Exp Biol Med
.
1927
;
6
:
538
642
.
43.
Ostrovskaya
O
.
The conditioned reflex and the immunologic reaction
.
J Exp Biol Med
.
1929
;
12
:
174
82
.
44.
Shamboorov
D
,
Belikova
O
.
The role of the nervous system in immunity
.
Soviet Psychoneurology
.
1936
;
12
:
57
63
.
45.
Pavlov
IP
.
Lectures on conditioned reflexes
. In:
Twenty years of objective study of the higher nervous activity (behavior of animals)
.
New York
:
International Publishers
;
1928
.
46.
Pavlov
IP
.
Lectures on the work of the cerebral hemisphere
.
Experimental Psychology and other essays
.
New York
:
Philosophical Library
;
1957
.
47.
Brushlinsky
A
.
The “Pavlovian” session of the two academies
.
Eur Psychol
.
1997
;
2
:
102
5
.
48.
Strutsovskaya
A
.
The experience of the formation of a conditional phagocytic reaction in children
.
Zhurnal vysshei nervnoi deiatelnosti imeni IP Pavlova
.
1953
;
3
:
238
46
.
49.
Zeitlenok
N
,
Bychkova
Y
.
About studying the role of higher nervous activity in infection and immunity
.
Zhurnal vysshei nervnoi deiatelnosti imeni IP Pavlova
.
1954
;
4
:
267
82
.
50.
Berezhnykh
DV
.
(Conditioned reflex restoration of immunogenesis)
.
Biull Eksp Biol Med
.
1955
;
40
(
8
):
49
52
.
51.
Pelts
D
.
Concerning the role of the cortex of the cerebral hemispheres in changing the phagocytic activity of animal blood leukocytes when applying electrocutaneous stimuli
.
Bull Exp Biolology Med
.
1955
;
40
:
55
63
.
52.
Avetikian
B
,
Totolian
A
,
Alaversian
M
.
On the role of the nervous system in immunological reactions. Results of experimental verification of Gordienko data on the reflex development of antibodies
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1956
;
27
:
54
9
.
53.
Amiantova
L
,
Mikrobiologii
Z
.
Concerning the effect of vaccination on conditioned reflex activity in animals
.
Epidemiologii i Immunobiologii
.
1958
;
29
:
108
.
54.
Maiskii
I
,
Suvorova
G
.
Concerning the conditioned reflex influence on immunogenesis
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1956
;
27
(
5
):
48
52
.
55.
Iakovleva
E
,
Kovaleva
N
.
On the role of higher structures of the central nervous system in the immune reactions of the organism
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1956
;
27
(
1
):
36
42
.
56.
Ilyenko
VI
,
Kovaleva
GA
.
Conditioned-reflex regulation of immunological reactions
.
Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii
.
1960
;
31
:
108
13
.
57.
Dolin
A
,
Krylov
V
,
Lukyanenko
V
,
Flerov
B
.
New experimental data on conditined reproduction and supression of immune and allergic reactions
.
Zh Vyssh Nerv Deiat Im I P Pavlova
.
1960
;
10
:
832
41
.
58.
Baciu
I
,
Sotuz
V
,
Stoica
N
,
Raducanu
N
.
Sur les centres nerveux re´gulateurs de l’erythropoie’se
.
Rev Roum Physiol
.
1965
:
123
33
.
59.
Benetato
G
.
Central nervous mechanism of the leukocytic and phagocytic reaction
.
J Physiol
.
1955
;
47
(
2
):
391
403
.
60.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Role of conditioned reflex in bronchial asthma; experimental investigation on the pathogenesis of bronchial asthma
.
Helv Med Acta
.
1951
;
18
(
2
):
142
58
.
61.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Das experimentelle Asthma bronchiale des Meerschweinchens. II. Mitteilung Die Rolle bedingter Reflexe in der Pathogenese des Asthma bronchiale
.
Int Arch Allergy Immunol
.
1951
;
2
(
4
):
321
9
.
62.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Das experimentelle Asthma bronchiale des Meerschweinchens
.
Int Arch Allergy Immunol
.
1952
;
3
(
4
):
302
23
.
63.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Das experimentelle Asthma bronchiale des Meerschweinchens
.
Int Arch Allergy Immunol
.
1952
;
3
:
207
17
.
64.
Noelpp
B
,
Noelpp-Eschenhagen
I
.
Das experimentelle Asthma bronchiale des Meerschweinchens
.
Int Arch Allergy Immunol
.
1952
;
3
(
2
):
108
36
.
65.
Dekker
E
,
Pelser
HE
,
Groen
J
.
Conditioning as a cause of asthmatic attacks; a laboratory study
.
J Psychosom Res
.
1957
;
2
:
97
108
.
66.
Ottenberg
P
,
Stein
M
,
Lewis
J
,
Hamilton
C
.
Learned asthma in the Guinea pig
.
Psychosom Med
.
1958
;
20
(
5
):
395
400
.
67.
Tsung
A
,
Sahai
R
,
Tanaka
H
,
Nakao
A
,
Fink
MP
,
Lotze
MT
, et al
.
The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion
.
J Exp Med
.
2005
;
201
(
7
):
1135
43
.
68.
Ader
R
.
Letter: behaviorially conditioned immunosuppression
.
Psychosom Med
.
1974
;
36
(
2
):
183
4
.
69.
Rogers
MP
,
Reich
P
,
Strom
TB
,
Carpenter
CB
.
Behaviorally conditioned immunosuppression: replication of a recent study
.
Psychosom Med
.
1976
;
38
(
6
):
447
51
.
70.
Wayner
EA
,
Flannery
GR
,
Singer
G
.
Effects of taste aversion conditioning on the primary antibody response to sheep red blood cells and Brucella abortus in the albino rat
.
Physiol Behav
.
1978
;
21
(
6
):
995
1000
.
71.
Schiller
M
,
Ben-Shaanan
TL
,
Rolls
A
.
Neuronal regulation of immunity: why, how and where
.
Nat Rev Immunol
.
2021
;
21
(
1
):
20
36
.
72.
Hadamitzky
M
,
Schedlowski
M
.
Harnessing associative learning paradigms to optimize drug treatment
.
Trends Pharmacol Sci
.
2022
;
43
(
6
):
464
72
.
73.
Storebø
OJ
,
Pedersen
N
,
Ramstad
E
,
Kielsholm
ML
,
Nielsen
SS
,
Krogh
HB
, et al
.
Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies
.
Cochrane Database Syst Rev
.
2018
;
5
:
CD012069
.
74.
Bosche
K
,
Weissenborn
K
,
Christians
U
,
Witzke
O
,
Engler
H
,
Schedlowski
M
, et al
.
Neurobehavioral consequences of small molecule-drug immunosuppression
.
Neuropharmacology
.
2015
;
96
(
Pt A
):
83
93
.
75.
Spahn
V
,
Del Vecchio
G
,
Labuz
D
,
Rodriguez-Gaztelumendi
A
,
Massaly
N
,
Temp
J
, et al
.
A nontoxic pain killer designed by modeling of pathological receptor conformations
.
Science
.
2017
;
355
(
6328
):
966
9
.
76.
Hawkshaw
NJ
,
Paus
R
.
Beyond the NFAT horizon: from cyclosporine A-induced adverse skin effects to novel therapeutics
.
Trends Pharmacol Sci
.
2021
;
42
(
5
):
316
28
.
77.
Schedlowski
M
,
Enck
P
,
Rief
W
,
Bingel
U
.
Neuro-bio-behavioral mechanisms of placebo and nocebo responses: implications for clinical trials and clinical practice
.
Pharmacol Rev
.
2015
;
67
(
3
):
697
730
.
78.
Nader
K
,
Schafe
GE
,
Le Doux
JE
.
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval
.
Nature
.
2000
;
406
(
6797
):
722
6
.
79.
Dudai
Y
.
The neurobiology of consolidations, or, how stable is the engram
.
Annu Rev Psychol
.
2004
;
55
(
1
):
51
86
.
80.
Tronson
NC
,
Taylor
JR
.
Molecular mechanisms of memory reconsolidation
.
Nat Rev Neurosci
.
2007
;
8
(
4
):
262
75
.
81.
Lee
JLC
,
Nader
K
,
Schiller
D
.
An update on memory reconsolidation updating
.
Trends Cogn Sci
.
2017
;
21
(
7
):
531
45
.
82.
Sinclair
AH
,
Barense
MD
.
Prediction error and memory reactivation: how incomplete reminders drive reconsolidation
.
Trends Neurosci
.
2019
;
42
(
10
):
727
39
.
83.
Albring
A
,
Wendt
L
,
Benson
S
,
Nissen
S
,
Yavuz
Z
,
Engler
H
, et al
.
Preserving learned immunosuppressive placebo response: perspectives for clinical application
.
Clin Pharmacol Ther
.
2014
;
96
(
2
):
247
55
.