Background: Accumulated evidence suggests that insulin resistance and impairments in cerebral insulin receptor signaling may contribute to age-related cognitive deficits and Alzheimer's disease. The enhancement of insulin receptor signaling is, therefore, a promising strategy for the treatment of age-related cognitive disorders. The mitochondrial respiratory chain, being involved in insulin-stimulated H₂O₂ production, has been identified recently as a potential target for the enhancement of insulin signaling. The aim of the present study is to examine: (1) whether a specific respiratory substrate, dicholine salt of succinic acid (CS), can enhance insulin-stimulated insulin receptor autophosphorylation in neurons, and (2) whether CS can ameliorate cognitive deficits of various origins in animal models. Results: In a primary culture of cerebellar granule neurons, CS significantly enhanced insulin-stimulated insulin receptor autophosphorylation. In animal models, CS significantly ameliorated cognitive deficits, when administered intraperitoneally for 7 days. In 16-month-old middle-aged C57Bl/6 mice (a model of normal aging), CS enhanced spatial learning in the Morris water maze, spontaneous locomotor activity, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to the age-matched control (saline). In rats with chronic cerebral hypoperfusion, CS enhanced spatial learning, passive avoidance performance, and increased brain N-acetylaspartate/creatine levels, as compared to control rats (saline). In rats with beta-amyloid peptide-(25–35)-induced amnesia, CS enhanced passive avoidance performance and increased activity of brain choline acetyltransferase, as compared to control rats (saline). In all used models, CS effects lasted beyond the seven-day treatment period and were found to be significant about two weeks following the treatment. Conclusion: The results of the present study suggest that dicholine salt of succinic acid, a novel neuronal insulin sensitizer, ameliorates cognitive deficits and neuronal dysfunctions in animal models relevant to age-related cognitive impairments, vascular dementia, and Alzheimer's disease.

Objectives. Abnormal attentional and cognitive processes are thought to increase the risk for depression and anxiety. To improve understanding of brain mechanisms of anxiety and depressive disorders, and condition of their comorbidity the study of early attentional processes was provided. Methods. Participants were patients with depressive (80 s.), anxiety (69 s.), and comorbid (41 s.) disorders, and healthy volunteers (50 s.). Acoustic startle response (ASR) and P50 component of the auditory event-related potential were recorded. Results. In the ASR model decreased startle response amplitude at the left eye in patients with comorbid disorder was found, and ASR latency was lengthened in all clinical groups. Deficit of prepulse inhibition was unique for comorbid disorder, and might be considered as risk of evolution to more serious condition. Reduced prepulse facilitation was revealed in patients with comorbid and anxiety disorders. In P50 suppression paradigm decreased S1 response amplitude was revealed in all clinical groups, P50 latency was prolonged in depressive and comorbid patients, and P50 suppression deficit was observed in depression and anxiety groups. Conclusions. The obtained results might be useful for development of integrative neural models of comorbidity of anxiety and depression, and elaboration of diagnostic and therapeutic approaches.

Prepulse modification of the acoustic startle response (ASR) and P50 gating are potential neurophysiological endophenotypes of schizophrenia and may be used in the construction of valid clinical biomarkers. Such approach requires a large amount of data obtained in the representative samples from different gender, socio-typological and ethnic groups, replicating studies using the similar protocols and meta-analyses. This is a replication study of ASR and the first study of P50 suppression in Russian patients with schizophrenia (n = 28) and healthy controls (n = 25). ASR and P50 were estimated according to standard protocols. Patients exhibited increased baseline ASR latency (d = 0.35, p = .026) and reduced prepulse inhibition (PPI) at 60 ms interval (d = 0.39, p = .003) and 120 ms interval (d = 0.37, p = .005) relative to controls. In the P50 test patients displayed greater S2 response amplitude (d = 0.24, p = .036) and deficit of P50 suppression (d = 0.43, p = .001). No correlations of PPI and P50 suppression were found in both groups. Only in controls prepulse ASR facilitation (at 2500 ms interval) positively correlated with P50 suppression (r = –.514, p = .013). In patients PPI displayed significant correlations with Difficulty in abstract thinking (N5: r = –.49, p = .005) and Hallucination (P3: r = .40, p = .036) PANSS scales. Logistic regression showed that the combination of PPI and P50 suppression could serve as a diagnostic predictor. Obtained results demonstrated that both PPI and P50 could be regarded as potential schizophrenia biomarkers in Russian population.

We investigated the association between hypnotizability, COMT polymorphism, P50 suppression ratio, and prepulse inhibition of acoustic startle response (ASR) in 21 high (HH) and 19 low (LH) hypnotizable subjects. The frequency of Met/Met carriers of COMT polymorphysm was higher in HH than in LH group (33.3% versus 10.6%, p = .049). Increased ASR amplitude and latency and decreased prepulse inhibition at 120 ms lead interval were found in the HH compared to the LH group. The effect of COMT genotype on prepulse inhibition was observed in LH group only. No between-group differences in P50 measures were found. The obtained results suppose the participation of dopamine system in mechanisms of hypnotizability and different allocation of attentional resources in HH and LH subjects.

Accumulated data have evidenced that brain cholinergic circuits play a crucial role in learning and memory; however, our knowledge about the participation of neocortical and hippocampal cholinergic systems in spatial learning needs to be refined. The aim of this study was to evaluate the association of the activity of membrane-bound and soluble choline acetyltransferase (ChAT) in the synaptosomal sub-fractions of the neocortex and hippocampus with performance of the spatial navigation task in the Morris water maze at different temporal stages of memory trace formation. To identify distinct stages of memory formation, rats were trained using a 5-day protocol with four trials per day. The mean escape latency for each trial was collected, and the entire dataset was subjected to principal component analysis. Based on the Morris water maze protocol, there were three relatively distinct stages of memory formation: days 1–2, day 3, and days 4–5. The remotely stored memory trace tested in repeated and reversal learning beginning on day 19 (14 days after the end of initial learning) was associated at the individual level mainly with performance during the second trial on day 21 (the third day or repeated or reversal learning). The ChAT activity data suggest the participation of cortical cholinergic projections mainly in the first stage of spatial learning (automatic sensory processing) and the involvement of hippocampal interneurons in the second stage (error-corrected learning). Cholinergic cortical interneurons participated mainly in the stage of asymptotic performance (days 4–5). It is advisable to evaluate other signalling pathways at the identified stages of memory formation.