Malgorzata Kossut

Despite the obvious differences in the pathophysiology of distinct neuropsychiatric diseases or neurodegenerative disorders, some of them share some general but pivotal mechanisms, one of which is the disruption of excitation/inhibition balance. Such an imbalance can be generated by changes in the inhibitory system, very often mediated by somatostatin-containing interneurons (SOM-INs). In physiology, this group of inhibitory interneurons, as well as somatostatin itself, profoundly shapes the brain activity, thus influencing the behavior and plasticity; however, the changes in the number, density and activity of SOM-INs or levels of somatostatin are found throughout many neuropsychiatric and neurological conditions, both in patients and animal models. Here, we (1) briefly describe the brain somatostatinergic system, characterizing the neuropeptide somatostatin itself, its receptors and functions, as well the physiology and circuitry of SOM-INs; and (2) summarize the effects of the activity of somatostatin and SOM-INs in both physiological brain processes and pathological brain conditions, focusing primarily on learning-induced plasticity and encompassing selected neuropsychological and neurodegenerative disorders, respectively. The presented data indicate the somatostatinergic-system-mediated inhibition as a substantial factor in the mechanisms of neuroplasticity, often disrupted in a plethora of brain pathologies.

It is unclear why some people learn faster than others. We performed two independent studies in which we investigated the neural basis of real-time strategy (RTS) gaming and neural predictors of RTS games skill-acquisition. In the first (cross-sectional) study we found that experts in the RTS game StarCraft II (SC2) had a larger lenticular nucleus volume than non-RTS players. We followed a cross validation procedure where we used the volume of regions identified in the first study to predict the quality of learning a new, complex skill (SC2) in a sample of individuals who were naïve to RTS games (second training study). Our findings provide new insights into how the volume of lenticular nucleus, which is associated with motor as well as cognitive functions, can be utilized to predict successful skill-learning, and be applied to a much broader context than just video games, e.g. contributing to optimizing cognitive training interventions.

Learning-related plasticity in the cerebral cortex is linked to the action of disinhibitory circuits of interneurons. Pavlovian conditioning, in which stimulation of the vibrissae is used as conditioned stimulus, induces plastic enlargement of the cortical functional representation of vibrissae activated during conditioning, visualized with [ ¹⁴ C]-2-deoxyglucose (2DG). Using layer-specific, cell-selective DREADD transductions, we examined the involvement of somatostatin- (SOM-INs) and vasoactive intestinal peptide (VIP-INs)-containing interneurons in the development of learning-related plastic changes. We injected DREADD-expressing vectors into layer IV (L4) barrels or layer II/III (L2/3) areas corresponding to activated vibrissae. The activity of interneurons was modulated during training, and 2DG maps were obtained 24 h later. In mice with L4 but not L2/3 SOM-INs suppressed during conditioning, the plastic change of whisker representation and the conditioned reaction were absent. No effect of inhibiting VIP-INs was found. We report that the activity of L4 SOM-INs is indispensable for learning-induced plastic change.

Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80–90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.

Molecular synaptic aging perturbs neurotransmission and decreases the potential for neuroplasticity. The direction and degree of changes observed in aging are often region or cell specific, hampering the generalization of age-related effects. Using real-time PCR and western blot analyses, we investigated age-related changes in several presynaptic markers (VGLUT1, VGLUT2, GAD65, GAD67, VGAT, synaptophysin) involved in the initial steps of glutamatergic and GABAergic neurotransmission, in several cortical regions, in young (3-4-month old), middle aged (1-year-old) and old (2-year-old) mice. We found age-related changes mainly in protein levels while, apart from occipital cortex, virtually no significant changes in mRNA levels were detected which suggests that aging acts on the investigated markers mainly through post-transcriptional mechanisms depending on the brain region. PCA for protein levels revealed that each brain region possessed a type of “biochemical distinciveness” (each analyzed brain region was best characterized by higher variability level of a particular synaptic marker) that was lost with age. Analysis of Glutamate and GABA levels in aging suggested, that mechanisms keeping an overall balance between the two amino acids in the brain are weakened in hippocampus. Our results unravel the differences in mRNA/protein interactions in the aging brain.

The main goal of this study was to identify the moderating role of temperamental traits, as defined by Strelau’s Regulative Theory of Temperament (RTT), in explaining brain activity evoked by video stimuli of varying stimulatory value. fMRI scans were performed in a group of 61 young females in the luteal phase of the menstrual cycle. The validity of stimulus selection had been verified prior to the main study by collecting declarative measures of affective reactions, including valence, arousal, and basic emotions ratings. The choice of dynamic and complex video-stimuli allowed us to induce high levels of arousal effectively. Three categories of movies used in the experiment included neutral, low arousing, and highly arousing scenes. Movies classified into the last category depicted extreme-sport activities allowing us to confront the subjects with recordings potentially life-threatening situations. Results of the study revealed that activation of orbitofrontal cortex in highly arousing conditions is linked to the levels of activity, while traits of perseverance and emotional reactivity were negatively correlated with the BOLD signal in this structure. Low arousing movies evoked higher activation of the amygdala and left hippocampus in emotionally reactive subjects. Obtained results might be coherently interpreted in the light of RTT theory, therefore providing its first validation using functional brain imaging.

Somatostatin is a peptide that participates in numerous biochemical and signaling pathways. It functions via receptors (SSTRs1-5), which belong to the family of receptors coupled with protein G. All somatostatin receptors are characterized by a certain degree of homology in molecular structure. The cell effects of their agonists in peripheral tissues rely mainly on the inhibition of the hormones release. Somatostatin is also an important neuromodulator and neurotransmitter. SSTRs may affect other receptors, forming structural and functional homodimers and heterodimers. SSTRs play also role in the regulation of physiological processes, such as itching and pain, reproductive functions, regulation of feeding or mood. Besides physiological functions, SSTRs contribute also to the pathogenesis of glial tumors, neurodegenerative diseases, or post hemorrhagic stroke changes. Recent years of research have provided new data regarding the role of somatostatin receptor signaling pathways in the brain and the knowledge in this field is developing rapidly.

Experienced video game players exhibit superior performance in visuospatial cognition when compared to non‐players. However, very little is known about the relation between video game experience and structural brain plasticity. To address this issue, a direct comparison of the white matter brain structure in RTS (real time strategy) video game players (VGPs) and non‐players (NVGPs) was performed. We hypothesized that RTS experience can enhance connectivity within and between occipital and parietal regions, as these regions are likely to be involved in the spatial and visual abilities that are trained while playing RTS games. The possible influence of long‐term RTS game play experience on brain structural connections was investigated using diffusion tensor imaging (DTI) and a region of interest (ROI) approach in order to describe the experience‐related plasticity of white matter. Our results revealed significantly more total white matter connections between occipital and parietal areas and within occipital areas in RTS players compared to NVGPs. Additionally, the RTS group had an altered topological organization of their structural network, expressed in local efficiency within the occipito‐parietal subnetwork. Furthermore, the positive association between network metrics and time spent playing RTS games suggests a close relationship between extensive, long‐term RTS game play and neuroplastic changes. These results indicate that long‐term and extensive RTS game experience induces alterations along axons that link structures of the occipito‐parietal loop involved in spatial and visual processing.

The explore-exploit dilemma occurs anytime we must choose between exploring unknown options for information and exploiting known resources for reward. Previous work suggests that people use two different strategies to solve the explore-exploit dilemma: directed exploration, driven by information seeking, and random exploration, driven by decision noise. Here, we show that these two strategies rely on different neural systems. Using transcranial magnetic stimulation to inhibit the right frontopolar cortex, we were able to selectively inhibit directed exploration while leaving random exploration intact. This suggests a causal role for right frontopolar cortex in directed, but not random, exploration and that directed and random exploration rely on (at least partially) dissociable neural systems.