Associative Conditioning Is a Robust Systemic Behavior in Unicellular Organisms: An Interspecies Comparison

The capacity to learn new efficient systemic behavior is a fundamental issue of contemporary biology. We have recently observed, in a preliminary analysis, the emergence of conditioned behavior in some individual amoebae cells. In these experiments, cells were able to acquire new migratory patterns and remember them for long periods of their cellular cycle, forgetting them later on. Here, following a similar conceptual framework of Pavlov’s experiments, we have exhaustively studied the migration trajectories of more than 2000 individual cells belonging to three different species: Amoeba proteus, Metamoeba leningradensis, and Amoeba borokensis. Fundamentally, we have analyzed several relevant properties of conditioned cells, such as the intensity of the responses, the directionality persistence, the total distance traveled, the directionality ratio, the average speed, and the persistence times. We have observed that cells belonging to these three species can modify the systemic response to a specific stimulus by associative conditioning. Our main analysis shows that such new behavior is very robust and presents a similar structure of migration patterns in the three species, which was characterized by the presence of conditioning for long periods, remarkable straightness in their trajectories and strong directional persistence. Our experimental and quantitative results, compared with other studies on complex cellular responses in bacteria, protozoa, fungus-like organisms and metazoans that we discus here, allow us to conclude that cellular associative conditioning might be a widespread characteristic of unicellular organisms. This new systemic behavior could be essential to understand some key principles involved in increasing the cellular adaptive fitness to microenvironments.

Computational Modelling of Cerebellar Magnetic Stimulation: The Effect of Washout

Nowadays, clinicians have multiple tools that they can use to stimulate the brain, by means of electric or magnetic fields that can interfere with the bio-electrical behaviour of neurons. However, it is still unclear which are the neural mechanisms that are involved and how the external stimulation changes the neural responses at network-level. In this paper, we have exploited the simulations carried out using a spiking neural network model, which reconstructed the cerebellar system, to shed light on the underlying mechanisms of cerebellar Transcranial Magnetic Stimulation affecting specific task behaviour. Namely, two computational studies have been merged and compared. The two studies employed a very similar experimental protocol: a first session of Pavlovian associative conditioning, the administration of the TMS (effective or sham), a washout period, and a second session of Pavlovian associative conditioning. In one study, the washout period between the two sessions was long (1 week), while the other study foresaw a very short washout (15 min). Computational models suggested a mechanistic explanation for the TMS effect on the cerebellum. In this work, we have found that the duration of the washout strongly changes the modification of plasticity mechanisms in the cerebellar network, then reflected in the learning behaviour.

Unicellular associative conditioning: an interspecies analysis

The capacity to learn new systemic behaviour is a fundamental issue to understand the adaptive mechanisms involved in cellular evolution. We have recently observed, in a preliminary analysis, the emergence of conditioned behaviour in individual amoebae cells. In these experiments, cells were able to acquire new migratory conduct and remember it for long periods of their cellular cycle, forgetting it later on. Here, following a similar conceptual framework of Pavlov’s experiments, we have exhaustively studied the migration trajectories of more than 2000 individual cells belonging to three different species: Amoeba proteus, Metamoeba leningradensis, and Amoeba borokensis. Fundamentally, we have analysed several properties of conditioned cells, such as the intensity of the responses, the directionality persistence, the total distance traveled, the directionality ratio, the average speed, and the persistence times. We have observed that these three species can modify the systemic response to a specific stimulus by associative conditioning. Our main analysis shows that such new behaviour is very robust and presents a similar structure of migration patterns in the three species, which was characterized by the presence of conditioning for long periods, remarkable straightness in their trajectories and strong directional persistence. Our quantitative results, compared with other studies on complex cellular responses in bacteria, protozoa, fungus-like organisms and metazoans, allow us to conclude that cellular associative conditioning might be a widespread characteristic of unicellular organisms. This finding could be essential to understand some key evolutionary principles involved in increasing the cellular adaptive fitness to microenvironments.

The complex genetics and biology of human temperament: a review of traditional concepts in relation to new molecular findings

Recent genome-wide association studies (GWAS) have shown that temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term learning and memory. The results were replicated in three independent samples despite variable cultures and environments. The identified genes were enriched in pathways activated by behavioral conditioning in animals, including the two major molecular pathways for response to extracellular stimuli, the Ras-MEK-ERK and the PI3K-AKT-mTOR cascades. These pathways are activated by a wide variety of physiological and psychosocial stimuli that vary in positive and negative valence and in consequences for health and survival. Changes in these pathways are orchestrated to maintain cellular homeostasis despite changing conditions by modulating temperament and its circadian and seasonal rhythms. In this review we first consider traditional concepts of temperament in relation to the new genetic findings by examining the partial overlap of alternative measures of temperament. Then we propose a definition of temperament as the disposition of a person to learn how to behave, react emotionally, and form attachments automatically by associative conditioning. This definition provides necessary and sufficient criteria to distinguish temperament from other aspects of personality that become integrated with it across the life span. We describe the effects of specific stimuli on the molecular processes underlying temperament from functional, developmental, and evolutionary perspectives. Our new knowledge can improve communication among investigators, increase the power and efficacy of clinical trials, and improve the effectiveness of treatment of personality and its disorders.

Uncovering the complex genetics of human temperament

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic–phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37–53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.