Effects of the Cc2d1a/Freud-1 Knockdown in the Hippocampus of BTBR Mice on the Autistic-Like Behavior,Expression of Serotonin 5-HT1A and D2 Dopamine Receptors,and CREB and NF-kB Intracellular Signaling

Biochemistry (Moscow) - The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the...     

The relationship between different types of genetically defined aggressive behavior

Aggressive behavior is not a unitary trait, and different stimuli/situations elicit different kinds of aggressive behavior. According to numerous data the genotype plays a significant role in the expression of aggressive behavior. However, it remains unclear how genetic predisposition to one kind of aggression is linked with other kinds of aggressive behavior, especially pathological aggression (infanticide). Here, we report on our investigation of the expression of defensive, offensive, predatory and asocial aggression in wild rats selectively bred for 85 generations for either a high level or a lack of aggression towards humans. We found that those rats genetically predisposed to a high level of defensive aggression showed decreased social behavior and increased pathological aggressive behavior towards juvenile males. The highly aggressive rates showed a reduced latency time of attack and an increased latency time of the first social contact. Rats genetically predisposed to defensive aggression demonstrated increased predatory aggression—latency time of muricide was shorter in highly aggressive than in tame animals. At the same time, both lines of rats did not differ significantly in intermale aggression. We conclude that the data indicate a close relation between defensive, predatory and pathological aggressive behavior that allows us to suggest that similar genetic mechanisms underlie these types of aggressive behavior.     

Neurotrophic factors (BDNF and GDNF) and the serotonergic system of the brain

Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system–those coding tryptophan hydroxylase-2 and 5-HT_1A and 5-HT_2A receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT2A receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.     

Expression of apoptosis genes in the brain of rats with genetically defined fear-induced aggression

The programmed cell death (or apoptosis) plays an important role both in developing and mature brains. Multiple data indicate the involvement of processes of apoptosis in mechanisms of different psychopathologies. At the same time, nothing is known about the role of apoptosis in the regulation of genetically defined aggression. In the present work, the expression of the genes that encode main pro- and antiapoptotic BAX and BCL-XL proteins, as well as caspase 3 (the main effector of apoptosis), in different brain structures of rats that were selected on a high aggression towards human (or its absence) was studied. A significant increase in the expression of the gene encoding caspase 3 was detected in the hypothalamus. This was accompanied by a significant decrease in the expression of proapoptotic Bax gene in the hippocampus and increase in mRNA level of antiapoptotic Bcl-xl gene in the raphe nuclei area of midbrain in highly aggressive rats. An increase in the ratio Bcl-xl: Bax was found in the midbrain and amygdala; a trend towards an increase in the ratio was also found in hippocampus of aggressive animals compared to tame animals. Thus, we demonstrated that genetically defined fear-induced aggression is associated with significant changes in the genetic control of apoptosis in the brain. It is assumed that an increase in the Bcl-xl gene expression (accompanied by a decrease in the Bax gene expression) can indicate an increase in the threshold of neuronal apoptosis in highly aggressive rats.     

Functional Responses to the Chronic Activation of 5-HT<Subscript>1A</Subscript> Receptors in Mice with Genetic Predisposition to Catalepsy

The effects of chronic 5-HT_1A receptor activation on the behavior, functional activity of 5-HT_1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensitization of 5-HT_1A receptors in both strains. Pretreatment with the 5-HT⁷ receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT_1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT_1A receptor downregulated 5-HT_1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT_2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor–gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT_1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5- HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.     

The effects of chronic alcoholization on the expression of brain-derived neurotrophic factor and its receptors in the brains of mice genetically predisposed to depressive-like behavior

Brain-derived neurotropic factor (BDNF) plays an important role in mechanisms of depression. Precursor protein of this factor (proBDNF) can initiate apoptosis in the brain, while the mature form of BDNF is involved in neurogenesis. It is known that chronic alcoholization leads to the activation of apoptotic processes, neurodegeneration, brain injury, and cognitive dysfunction. In this work, we have studied the influence of long-term ethanol exposure on the proBDNF and BDNF protein levels, as well as on the expression of genes that encode these proteins in the brain structures of ASC mice with genetic predisposition to depressive-like behavior and in mice from parental nondepressive CBA strain. It was shown that chronic alcoholization results in a reduction of the BDNF level in the hippocampus and an increase in the amount of TrkB and p75 receptors in the frontal cortex of nondepressive CBA mice. At the same time, the long-term alcoholization of depressive ASC mice results in an increase of the proBDNF level in the frontal cortex and a reduction in the p75 protein level in the hippocampus. It has also been shown that, in depressive ASC mice, proBDNF and BDNF levels are significantly lower in the hippocampus and the frontal cortex compared with nondepressive CBA strain. However, no significant differences in the expression of genes encoding the studied proteins were observed. Thus, changes in the expression patterns of proBDNF, BDNF, and their receptors under the influence of alcoholization in the depressive ASC strain and nondepressive CBA strain mice are different.