Studying the Brain Monoaminergic Systems and Neurotrophic Factors in Minipigs with High and Low Tolerance to the Presence of Human.

Here, we present the first evidence for brain adaptation in pigs tolerant to the human presence, as a behavioral trait favoring domestication. The study was carried out on minipiglets from population bred at the Institute of Cytology and Genetics (Novosibirsk, Russia). We compared the behavior, metabolism of monoaminergic neurotransmitter systems, and functional activity of the hypothalamic-pituitary-adrenal system, as well as neurotrophic markers in the brain of minipigs differing by tolerance to human presence (HT and LT - high and low tolerance). The piglets did not differ in the levels of activity in the open field test. However, the concentration of cortisol plasma was significantly higher in minipigs with a low tolerance to the presence of humans. Moreover, LT minipigs demonstrated a decreased level of serotonin in the hypothalamus and augmented levels of serotonin and its metabolite 5-HIAA in the substantia nigra as compared to HT animals. In addition, LT minipigs showed increased content of dopamine and its metabolite DOPAC in the substantia nigra and decreased dopamine level in the striatum as well as reduced content of noradrenaline in the hippocampus. Increased mRNA levels of two markers of the serotonin system - TPH2 and HTR7 genes - in the raphe nuclei and in the prefrontal cortex, respectively, were associated in minipigs with a low tolerance to human presence. However, the expression of genes regulating a dopaminergic system (COMT, DRD1, and DRD2) in HT and LT animal groups varied depending on brain structure. In addition, a decrease in the expression of genes encoding BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) was revealed in LT minipigs. The results may contribute to our understanding of the initial stage of domestication in pigs.

Serotonin 5-HT7 receptor overexpression in the raphe nuclei area produces antidepressive effect and affects brain serotonin system in male mice.

Heterodimerization between 5-HT7 and 5-HT1A receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between 5-HT1A /5-HT7 hetero- and 5-HT1A /5-HT1A homodimers in presynaptic neurons toward 5-HT1A /5-HT1A homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT7 receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT7 receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT7 receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT7 receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT7 receptor overexpression resulted in the reduction of 5-HT1A receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT7 receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT7 receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT7 receptor in the mechanisms underlying depressive behavior.

Spatial learning in the Morris water maze in mice genetically different in the predisposition to catalepsy: the effect of intraventricular treatment with brain-derived neurotrophic factor.

Hereditary catalepsy in mice is accompanied with volume reduction of some brain structures and high vulnerability to inflammatory agents. Here an association between hereditary catalepsy and spatial learning deficit in the Morris water maze (MWM) in adult mouse males of catalepsy-resistant AKR, catalepsy-prone CBA and AKR.CBA-D13Mit76 (D13) strains was studied. Recombinant D13 strain was created by means of the transfer of the CBA-derived allele of the major gene of catalepsy to the AKR genome. D13 mice showed a low MWM performance in the acquisition test and high expression of the gene coding proinflammatory interleukin-6 (Il-6) in the hippocampus and cortex compared with mice of the parental AKR and CBA strains. An acute ivc administration of 300 ng of brain derived neurotrophic factor (BDNF) normalized the performance in the MWM, but did not decrease the high Il-6 gene expression in the brain of D13 mice. These results indicated a possible association between the hereditary catalepsy, MWM performance, BDNF and level of Il-6 mRNA in the brain, although the relation between these characteristics seems to be more complex. D13 recombinant mice with deficit of spatial learning is a promising model for study of the genetic and molecular mechanisms of learning disorders as well as for screening potential cognitive enhancers.

On the association between lipopolysaccharide induced catalepsy and serotonin metabolism in the brain of mice genetically different in the predisposition to catalepsy.

The study of the interaction between nervous and immune systems in the mechanism of psychopathology is an important problem of neuroscience. Catalepsy (freezing reaction) is a passive defensive strategy in response to threatening stimuli. An exaggerated form of catalepsy is a syndrome of some grave mental disorders. Both the brain serotonin (5-HT) and immune systems were shown to be involved in the mechanism of catalepsy. Here we compared the effects of two doses (50 or 200 µg/kg, ip) of innate immune system activator, bacterial lipopolysaccharide (LPS), on catalepsy, 5-HT and its main metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the hippocampus, striatum, and midbrain of mice of catalepsy-prone (CBA/Lac and AKR.CBA-D13Mit76) and catalepsy-resistant (AKR/J) strains. The expression of LPS-induced catalepsy as well as 5-HIAA/5-HT ratio in the midbrain and striatum were significantly higher in mice of the catalepsy-prone strains compared with animals of the catalepsy-resistant strains. These results indicated an involvement of the brain 5-HT system in the cataleptogenic effect of LPS and open up new vistas for understanding the nervous-immune mechanism of behavioral disorders.

Hereditary catalepsy in mice is associated with the brain dysmorphology and altered stress response.

Catalepsy is a passive defensive strategy in response to threatening stimuli. In exaggerated forms it is associated with brain dysfunctions. The study was aimed to examine (1) possible association of the hereditary catalepsy with neuroanatomical characteristics and (2) sensitivity of the catalepsy expression, HPA and brain serotonin (5-HT) systems to restraint stress (for one hour) in mice of catalepsy-prone (CBA/Lac, ASC (Antidepressant Sensitive Catalepsy), congenic AKR.CBA-D13M76) and catalepsy-resistant (AKR/J) strains. Magnetic resonance imaging showed that the catalepsy-prone mice were characterized by the smaller size of the pituitary gland and the larger size of the thalamus. In ASC mice, diencephalon region (including hypothalamus) and striatum were significantly reduced in size. Restraint stress provoked catalepsy in AKR mice and enhanced it in the catalepsy-prone mice. Stress-induced corticosterone elevation was diminished, while 5-HT metabolism (5-HIAA level or 5-HIAA/5-HT ratio) in the midbrain was significantly augmented by stress in the catalepsy-prone mice. The multivariate factor analysis revealed interactions between the basal levels and the stress-induced alterations of 5-HT metabolism in the hippocampus and midbrain suggesting the interaction between multiple alterations in 5-HT neurotransmission in several brain structures in the regulation of hereditary catalepsy. The study indicated an association between the hereditary catalepsy, neuroanatomical characteristics, and neurochemical responses to emotional stress. The catalepsy-prone genotypes seem to be more susceptible to stress that suggests them as the adequate models to study the genetic predisposition to stress-based neuropathology. The data support the association of hereditary catalepsy with the inherited brain dysfunction of a neurodegenerative nature.