Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment.

Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice. The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.

Somatostatin and Somatostatin-Containing Interneurons-From Plasticity to Pathology.

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.

Conditioning­induced changes in sensory cortical maps detected in mice by intrinsic signal optical imaging.

Intrinsic signal optical imaging (ISOI) has been used previously for the detection of changes in sensory processing in the somatosensory cortex in response to environment alteration or after deprivation of sensory information. To date, there have been no reports of ISOI being used in learning­induced changes in the somatosensory cortex. In the present study, ISOI was performed twice in the same mouse: before and after conditional fear learning. The conditioning paradigm consisted of pairing sensory stimulation of vibrissae with electric tail shock. In order to map the cortical representation of the vibrissa B1 with ISOI, we deflected the vibrissa with an intensive stimulation (frequency of 10 Hz for 6 s). After conditioning, we found that the cortical representation of vibrissa B1 had expanded by an average of 44%, compared with pre­learning, by using images obtained with ISOI. Previously, we demonstrated an enlargement of the cortical representation of the vibrissae stimulated by the same behavioral training paradigm but using [14C]2­deoxyglucose. This current investigation provides the first ISOI­based evidence of learning­induced changes in plasticity in the barrel cortex. The results indicate that irrespective of physiological mechanisms used for visualization of the vibrissae representation or subject's testing state (aware or anesthetized animal), the conditioning induced changes in each case in the cortical processing of intensive stimuli. This suggests specific functional reorganization of the neuronal circuits. Moreover, ISOI as a noninvasive method of mapping cortical activation in the same animal before and after behavioral training could serve as a very useful tool for precise manipulation within the cortex and for assessing the resulting effects on experience­dependent cortical plasticity.

Lenticular nucleus volume predicts performance in real-time strategy game: cross-sectional and training approach using voxel-based morphometry.

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 game 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 (LNV) 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 naive to RTS games (a second (training) study). Our findings provide new insights into how the LNV, 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, such as contributing to optimizing cognitive training interventions.

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex.

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.

Glutamate, GABA, and Presynaptic Markers Involved in Neurotransmission Are Differently Affected by Age in Distinct Mouse Brain Regions.

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 months old), middle-aged (1 year old), and old (2 years old) mice. We found age-related changes mainly in protein levels while, apart from the 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. Principal component analysis (PCA) of protein data revealed that each brain region possessed a type of "biochemical distinctiveness" (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 γ-aminobutyric acid (GABA) levels in aging suggested that mechanisms keeping an overall balance between the two amino acids in the brain are weakened in the hippocampus. Our results unravel the differences in mRNA/protein interactions in the aging brain.

No Risk, No Differences. Neural Correlates of Temperamental Traits Revealed Using Naturalistic fMRI Method.

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.

Real-time strategy video game experience and structural connectivity - A diffusion tensor imaging study.

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.

Somatostatin receptors in the brain.

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.

BDNF expression in cat striate cortex is regulated by binocular pattern deprivation.

Deprivation of patterned visual information, as in early onset congenital cataract patients, results in a severe impairment in global motion perception. Previously we reported a delayed maturation of the peripheral visual field representation in primary visual area 17, based on a 2-D DIGE screen for protein expression changes and in situ hybridization for the activity reporter gene ZIF268. To corroborate these findings we here explore the binocular pattern deprivation (BD)-regulated expression of brain-derived neurotrophic factor (BDNF), a well-described neurotrophin precipitously regulated by early visual experience. To assess the timing of maturation-related BDNF expression we compared the central and the peripheral visual field representations of area 17 of 1, 2, 4 and 6-month-old and adult cats reared under normal visual conditions. To scrutinize the outcome of BD, four different deprivation strategies were compared, including early onset BD from birth and lasting for 2, 4 or 6 months (2BD, 4BD, 6BD), and late onset BD for 2 months upon 2 months of normal vision (2N2BD), as animal models of congenital and delayed onset cataract. During normal cortical development the BDNF transcript levels, measured by quantitative RT-PCR, remained stable. Higher BDNF mRNA levels were found in central area 17 of 2BD and 6BD animals compared to age-matched controls. In central area 17, the high BDNF mRNA levels at the end of the BD period may activate a mechanism by which plastic processes, halted by deprivation, may begin. We here confirm that the peripheral visual field representation of area 17 matures slower than its central counterpart. Only in central area 17 normal visual input upon BD could upregulate BDNF mRNA which may lead to a fast activation of local plastic adaptations.

A causal role for right frontopolar cortex in directed, but not random, exploration.

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.

Plasticity Beyond V1: Reinforcement of Motion Perception upon Binocular Central Retinal Lesions in Adulthood.

Induction of a central retinal lesion in both eyes of adult mammals is a model for macular degeneration and leads to retinotopic map reorganization in the primary visual cortex (V1). Here we characterized the spatiotemporal dynamics of molecular activity levels in the central and peripheral representation of five higher-order visual areas, V2/18, V3/19, V4/21a,V5/PMLS, area 7, and V1/17, in adult cats with central 10° retinal lesions (both sexes), by means of real-time PCR for the neuronal activity reporter gene zif268. The lesions elicited a similar, permanent reduction in activity in the center of the lesion projection zone of area V1/17, V2/18, V3/19, and V4/21a, but not in the motion-driven V5/PMLS, which instead displayed an increase in molecular activity at 3 months postlesion, independent of visual field coordinates. Also area 7 only displayed decreased activity in its LPZ in the first weeks postlesion and increased activities in its periphery from 1 month onward. Therefore we examined the impact of central vision loss on motion perception using random dot kinematograms to test the capacity for form from motion detection based on direction and velocity cues. We revealed that the central retinal lesions either do not impair motion detection or even result in better performance, specifically when motion discrimination was based on velocity discrimination. In conclusion, we propose that central retinal damage leads to enhanced peripheral vision by sensitizing the visual system for motion processing relying on feedback from V5/PMLS and area 7.SIGNIFICANCE STATEMENT Central retinal lesions, a model for macular degeneration, result in functional reorganization of the primary visual cortex. Examining the level of cortical reactivation with the molecular activity marker zif268 revealed reorganization in visual areas outside V1. Retinotopic lesion projection zones typically display an initial depression in zif268 expression, followed by partial recovery with postlesion time. Only the motion-sensitive area V5/PMLS shows no decrease, and even a significant activity increase at 3 months post-retinal lesion. Behavioral tests of motion perception found no impairment and even better sensitivity to higher random dot stimulus velocities. We demonstrate that the loss of central vision induces functional mobilization of motion-sensitive visual cortex, resulting in enhanced perception of moving stimuli.

Age-Related Changes in Resting-State EEG Activity in Attention Deficit/Hyperactivity Disorder: A Cross-Sectional Study.

Numerous studies indicate that attention deficit/hyperactivity disorder (ADHD) is related to some developmental trends, as its symptoms change widely over time. Nevertheless, the etiology of this phenomenon remains ambiguous. There is a disagreement whether ADHD is related to deviations in brain development or to a delay in brain maturation. The model of deviated brain development suggests that the ADHD brain matures in a fundamentally different way, and does not reach normal maturity at any developmental stage. On the contrary, the delayed brain maturation model assumes that the ADHD brain indeed matures in a different, delayed way in comparison to healthy age-matched controls, yet eventually reaches proper maturation. We investigated age-related changes in resting-state EEG activity to find evidence to support one of the alternative models. A total of 141 children and teenagers participated in the study; 67 diagnosed with ADHD and 74 healthy controls. The absolute power of delta, theta, alpha, and beta frequency bands was analyzed. We observed a significant developmental pattern of decreasing absolute EEG power in both groups. Nonetheless, ADHD was characterized by consistently lower absolute EGG power, mostly in the theta frequency band, in comparison to healthy controls. Our results are in line with the deviant brain maturation theory of ADHD, as the observed effects of age-related changes in EEG power are parallel but different in the two groups.

Application of the DREADD technique in biomedical brain research.

The DREADD (Designer Receptors Exclusively Activated by Designer Drugs) technique is a new chemogenetic approach allowing for selective and remote control of neural activity with a high degree of spatial resolution. Since its discovery in 2007 the DREADD technique was successfully employed into basic research, and together with the optogenetic method provided so far the best tool to influence the activity of the brain circuits and cell populations. The first aim of this review was to concisely describe the technique with regard to such issues like the history of its development, biochemistry as well as modes of the designer receptors delivery and expression. The other aim was to summarize approaches employed for probing of the brain circuits using the DREADD technique and to characterize the current knowledge of the method's application in medical research focusing on two diseases - Parkinson's disease and drug addiction - in which designer receptors were found notably valuable.

Functional and Structural Neuroplasticity Induced by Short-Term Tactile Training Based on Braille Reading.

Neuroplastic changes induced by sensory learning have been recognized within the cortices of specific modalities as well as within higher ordered multimodal areas. The interplay between these areas is not fully understood, particularly in the case of somatosensory learning. Here we examined functional and structural changes induced by short-term tactile training based of Braille reading, a task that requires both significant tactile expertise and mapping of tactile input onto multimodal representations. Subjects with normal vision were trained for 3 weeks to read Braille exclusively by touch and scanned before and after training, while performing a same-different discrimination task on Braille characters and meaningless characters. Functional and diffusion-weighted magnetic resonance imaging sequences were used to assess resulting changes. The strongest training-induced effect was found in the primary somatosensory cortex (SI), where we observed bilateral augmentation in activity accompanied by an increase in fractional anisotropy (FA) within the contralateral SI. Increases of white matter fractional anisotropy were also observed in the secondary somatosensory area (SII) and the thalamus. Outside of somatosensory system, changes in both structure and function were found in i.e., the fusiform gyrus, the medial frontal gyri and the inferior parietal lobule. Our results provide evidence for functional remodeling of the somatosensory pathway and higher ordered multimodal brain areas occurring as a result of short-lasting tactile learning, and add to them a novel picture of extensive white matter plasticity.

Somatostatin and Somatostatin-Containing Neurons in Shaping Neuronal Activity and Plasticity.

Since its discovery over four decades ago, somatostatin (SOM) receives growing scientific and clinical interest. Being localized in the nervous system in a subset of interneurons somatostatin acts as a neurotransmitter or neuromodulator and its role in the fine-tuning of neuronal activity and involvement in synaptic plasticity and memory formation are widely recognized in the recent literature. Combining transgenic animals with electrophysiological, anatomical and molecular methods allowed to characterize several subpopulations of somatostatin-containing interneurons possessing specific anatomical and physiological features engaged in controlling the output of cortical excitatory neurons. Special characteristic and connectivity of somatostatin-containing neurons set them up as significant players in shaping activity and plasticity of the nervous system. However, somatostatin is not just a marker of particular interneuronal subpopulation. Somatostatin itself acts pre- and postsynaptically, modulating excitability and neuronal responses. In the present review, we combine the knowledge regarding somatostatin and somatostatin-containing interneurons, trying to incorporate it into the current view concerning the role of the somatostatinergic system in cortical plasticity.

Effect of Associative Learning on Memory Spine Formation in Mouse Barrel Cortex.

Associative fear learning, in which stimulation of whiskers is paired with mild electric shock to the tail, modifies the barrel cortex, the functional representation of sensory receptors involved in the conditioning, by inducing formation of new inhibitory synapses on single-synapse spines of the cognate barrel hollows and thus producing double-synapse spines. In the barrel cortex of conditioned, pseudoconditioned, and untreated mice, we analyzed the number and morphological features of dendritic spines at various maturation and stability levels: sER-free spines, spines containing smooth endoplasmic reticulum (sER), and spines containing spine apparatus. Using stereological analysis of serial sections examined by transmission electron microscopy, we found that the density of double-synapse spines containing spine apparatus was significantly increased in the conditioned mice. Learning also induced enhancement of the postsynaptic density area of inhibitory synapses as well as increase in the number of polyribosomes in such spines. In single-synapse spines, the effects of conditioning were less pronounced and included increase in the number of polyribosomes in sER-free spines. The results suggest that fear learning differentially affects single- and double-synapse spines in the barrel cortex: it promotes maturation and stabilization of double-synapse spines, which might possibly contribute to permanent memory formation, and upregulates protein synthesis in single-synapse spines.

Learning-Dependent Plasticity of the Barrel Cortex Is Impaired by Restricting GABA-Ergic Transmission.

Experience-induced plastic changes in the cerebral cortex are accompanied by alterations in excitatory and inhibitory transmission. Increased excitatory drive, necessary for plasticity, precedes the occurrence of plastic change, while decreased inhibitory signaling often facilitates plasticity. However, an increase of inhibitory interactions was noted in some instances of experience-dependent changes. We previously reported an increase in the number of inhibitory markers in the barrel cortex of mice after fear conditioning engaging vibrissae, observed concurrently with enlargement of the cortical representational area of the row of vibrissae receiving conditioned stimulus (CS). We also observed that an increase of GABA level accompanied the conditioning. Here, to find whether unaltered GABAergic signaling is necessary for learning-dependent rewiring in the murine barrel cortex, we locally decreased GABA production in the barrel cortex or reduced transmission through GABAA receptors (GABAARs) at the time of the conditioning. Injections of 3-mercaptopropionic acid (3-MPA), an inhibitor of glutamic acid decarboxylase (GAD), into the barrel cortex prevented learning-induced enlargement of the conditioned vibrissae representation. A similar effect was observed after injection of gabazine, an antagonist of GABAARs. At the behavioral level, consistent conditioned response (cessation of head movements in response to CS) was impaired. These results show that appropriate functioning of the GABAergic system is required for both manifestation of functional cortical representation plasticity and for the development of a conditioned response.

Circadian rhythmicity of synapses in mouse somatosensory cortex.

The circadian rhythmicity displayed by motor behavior of mice: activity at night and rest during the day; and the associated changes in the sensory input are reflected by cyclic synaptic plasticity in the whisker representations located in the somatosensory (barrel) cortex. It was not clear whether diurnal rhythmic changes in synapse density previously observed in the barrel cortex resulted from changes in the activity of the animals, from daily light/dark (LD) rhythm or are driven by an endogenous clock. These changes were investigated in the barrel cortex of C57BL/6 mouse strain kept under LD 12 : 12 h conditions and in constant darkness (DD). Stereological analysis of serial electron microscopic sections was used to assess numerical density of synapses. In mice kept under LD conditions, the total density of synapses and the density of excitatory synapses located on dendritic spines was higher during the light period (rest phase). In contrast, the density of inhibitory synapses located on dendritic spines increased during the dark period (activity phase). Under DD conditions, the upregulation of the inhibitory synapses during the activity phase was retained, but the cyclic changes in the density of excitatory synapses were not observed. The results show that the circadian plasticity concerns only synapses located on spines (and not those on dendritic shafts), and that excitatory and inhibitory synapses are differently regulated during the 24 h cycle: the excitatory synapses are influenced by light, whilst the inhibitory synapses are driven by the endogenous circadian clock.

Binocular pattern deprivation interferes with the expression of proteins involved in primary visual cortex maturation in the cat.

BACKGROUND: Binocular pattern deprivation from eye opening (early BD) delays the maturation of the primary visual cortex. This delay is more pronounced for the peripheral than the central visual field representation within area 17, particularly between the age of 2 and 4 months [Laskowska-Macios, Cereb Cortex, 2014]. RESULTS: In this study, we probed for related dynamic changes in the cortical proteome. We introduced age, cortical region and BD as principal variables in a 2-D DIGE screen of area 17. In this way we explored the potential of BD-related protein expression changes between central and peripheral area 17 of 2- and 4-month-old BD (2BD, 4BD) kittens as a valid parameter towards the identification of brain maturation-related molecular processes. Consistent with the maturation delay, distinct developmental protein expression changes observed for normal kittens were postponed by BD, especially in the peripheral region. These BD-induced proteomic changes suggest a negative regulation of neurite outgrowth, synaptic transmission and clathrin-mediated endocytosis, thereby implicating these processes in normal experience-induced visual cortex maturation. Verification of the expression of proteins from each of the biological processes via Western analysis disclosed that some of the transient proteomic changes correlate to the distinct behavioral outcome in adult life, depending on timing and duration of the BD period [Neuroscience 2013;255:99-109]. CONCLUSIONS: Taken together, the plasticity potential to recover from BD, in relation to ensuing restoration of normal visual input, appears to rely on specific protein expression changes and cellular processes induced by the loss of pattern vision in early life.