Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.DP2 NS082126 - NINDS NIH HHS; R01 NS081716 - NINDS NIH HHS; R21 NS078660 - NINDS NIH HHShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896681/Published versio

Video gaming in a hyperconnected world : a cross-sectional study of heavy gaming, problematic gaming symptoms, and online socializing in adolescents

Aims: Examining online social interactions along with patterns of video gaming behaviors and game addiction symptoms has the potential to enrich our understanding of disorders related to excessive video game play. Methods: We performed latent class analysis in a sample of 9733 adolescents based on heavy use of games, social networking and instant messaging, and game addiction symptoms. We used latent class regression to determine associations between classes, psychosocial well-being and friendship quality. Results: We identified two types of heavy gaming classes that differed in probability of online social interaction. Classes with more online social interaction reported fewer problematic gaming symptoms than those with less online social interaction. Most adolescents estimated to be in heavy gaming classes had more depressive symptoms than normative classes. Male non-social gamers had more social anxiety. Female social gamers had less social anxiety and loneliness, but lower self-esteem. Friendship quality attenuated depression in some male social gamers, but strengthened associations with loneliness in some male non-social gamers. Conclusions: In adolescents, symptoms of video game addiction depend not only on video game play but also on concurrent levels of online communication, and those who are very socially active online report fewer symptoms of game addiction

Modulation of expression and cellular distribution of p21 by macrophage migration inhibitory factor

<p>Abstract</p> <p>Background</p> <p>The pleiotropic protein MIF, (macrophage migration inhibitory factor), has been demonstrated to modulate several key proteins governing cell cycle control and is considered to contribute to cell growth and differentiation. In this study we investigated the effect of MIF on the expression and cellular distribution of the CDK inhibitor p21.</p> <p>Methods</p> <p>The effect of endogenous MIF on p21 expression and distribution was examined by comparing murine dermal fibroblasts derived from <it>wt </it>and MIF -/- mice. The effect of MIF on cell growth and apoptotic rates was compared using ³H-Thymidine incorporation assays and annexin V/PI assays respectively. Total p21 protein levels were compared using flow cytometry and western blotting. p21 mRNA was assessed by RT-PCR. Intracellular p21 staining was performed to assess cellular distribution of total protein. To further confirm observations siRNA was used to knockdown MIF protein in <it>wt </it>cells. Cell cycle analysis was performed using PI incorporation assays.</p> <p>Results</p> <p>MIF-/- murine dermal fibroblasts exhibited reduced proliferative responses and were more susceptible to apoptosis. This was associated with reduced p21 expression and nuclear distribution. Treatment with recombinant MIF protein was demonstrated to reduce both basal and induced apoptosis and increase nuclear p21 expression. Reduced nuclear p21 expression was also observed in MIF siRNA treated <it>wt </it>cells.</p> <p>Conclusion</p> <p>The results demonstrate that in the absence of MIF p21 expression and nuclear distribution is reduced which is associated with a reduction in cell growth and increased apoptosis. MIF may therefore play a role in maintaining homeostatic control of p21.</p

INVESTIGATION OF RAS-DEPENDENT GENE EXPRESSION & CELL SURVIVAL SIGNALLING IN COLORECTAL CANCER

Ph.DDOCTOR OF PHILOSOPH

Solution structure of a bacterial microcompartment targeting peptide and its application in the construction of an ethanol bioreactor

Targeting of proteins to bacterial microcompartments (BMCs) is mediated by an 18-amino-acid peptide sequence. Herein, we report the solution structure of the N-terminal targeting peptide (P18) of PduP, the aldehyde dehydrogenase associated with the 1,2-propanediol utilization metabolosome from Citrobacter freundii. The solution structure reveals the peptide to have a well-defined helical conformation along its whole length. Saturation transfer difference and transferred NOE NMR has highlighted the observed interaction surface on the peptide with its main interacting shell protein, PduK. By tagging both a pyruvate decarboxylase and an alcohol dehydrogenase with targeting peptides, it has been possible to direct these enzymes to empty BMCs in vivo and to generate an ethanol bioreactor. Not only are the purified, redesigned BMCs able to transform pyruvate into ethanol efficiently, but the strains containing the modified BMCs produce elevated levels of alcohol

Development of DNA Based Active Macro–Materials for Biology and Medicine: A Review

DNA was first discovered as the carrier of genetic information for the majority of the known living organisms, encoding the secret of life. Its delicate design based upon double helical structure and base pairing offers a stable and reliable media for storing hereditary codes, laying the foundation for the central dogma (Watson et al. 2003). The impact of this molecule is far reaching into scientific community and our society, as manifested in many fields, for instance, forensics (Budowle et al. 2003), besides medicine. To date, a great deal of research effort has been directed towards understandin

Hybrid Decay: A Transgenerational Epigenetic Decline in Vigor and Viability Triggered in Backcross Populations of Teosinte with Maize.

In the course of generating populations of maize with teosinte chromosomal introgressions, an unusual sickly plant phenotype was noted in individuals from crosses with two teosinte accessions collected near Valle de Bravo, Mexico. The plants of these Bravo teosinte accessions appear phenotypically normal themselves and the F1 plants appear similar to typical maize × teosinte F1s. However, upon backcrossing to maize, the BC1 and subsequent generations display a number of detrimental characteristics including shorter stature, reduced seed set, and abnormal floral structures. This phenomenon is observed in all BC individuals and there is no chromosomal segment linked to the sickly plant phenotype in advanced backcross generations. Once the sickly phenotype appears in a lineage, normal plants are never again recovered by continued backcrossing to the normal maize parent. Whole-genome shotgun sequencing reveals a small number of genomic sequences, some with homology to transposable elements, that have increased in copy number in the backcross populations. Transcriptome analysis of seedlings, which do not have striking phenotypic abnormalities, identified segments of 18 maize genes that exhibit increased expression in sickly plants. A de novo assembly of transcripts present in plants exhibiting the sickly phenotype identified a set of 59 upregulated novel transcripts. These transcripts include some examples with sequence similarity to transposable elements and other sequences present in the recurrent maize parent (W22) genome as well as novel sequences not present in the W22 genome. Genome-wide profiles of gene expression, DNA methylation, and small RNAs are similar between sickly plants and normal controls, although a few upregulated transcripts and transposable elements are associated with altered small RNA or methylation profiles. This study documents hybrid incompatibility and genome instability triggered by the backcrossing of Bravo teosinte with maize. We name this phenomenon "hybrid decay" and present ideas on the mechanism that may underlie it

Video gaming in a hyperconnected world: A cross-sectional study of heavy gaming, problematic gaming symptoms, and online socializing in adolescents

Aims Examining online social interactions along with patterns of video gaming behaviors and game addiction symptoms has the potential to enrich our understanding of disorders related to excessive video game play. Methods We performed latent class analysis in a sample of 9733 adolescents based on heavy use of games, social networking and instant messaging, and game addiction symptoms. We used latent class regression to determine associations between classes, psychosocial well-being and friendship quality. Results We identified two types of heavy gaming classes that differed in probability of online social interaction. Classes with more online social interaction reported fewer problematic gaming symptoms than those with less online social interaction. Most adolescents estimated to be in heavy gaming classes had more depressive symptoms than normative classes. Male non-social gamers had more social anxiety. Female social gamers had less social anxiety and loneliness, but lower self-esteem. Friendship quality attenuated depression in some male social gamers, but strengthened associations with loneliness in some male non-social gamers. Conclusions In adolescents, symptoms of video game addiction depend not only on video game play but also on concurrent levels of online communication, and those who are very socially active online report fewer symptoms of game addiction