SUMMARY Brain abnormalities acquired early in life may cause schizophrenia, characterized by adulthood onset of psychosis, affective flattening, and cognitive impairments. Cognitive symptoms like impaired cognitive control are now recognized to be important treatment targets but cognition-promoting treatments are ineffective. We hypothesized that cognitive training during the adolescent period of neuroplastic development can tune compromised neural circuits to develop in the service of adult cognition and attenuate schizophrenia-related cognitive impairments that manifest in adulthood. We report, using neonatal ventral hippocampus lesion rats (NVHL), an established neurodevelopmental model of schizophrenia, that adolescent cognitive training prevented the adult cognitive control impairment in NVHL rats. The early intervention also normalized brain function, enhancing cognition-associated synchrony of neural oscillations between the hippocampi, a measure of brain function that indexed cognitive ability. Adolescence appears to be a critical window during which prophylactic cognitive therapy may benefit people at risk of schizophrenia.
Fifty-two patients with unstable fractures of distal clavicle treated by open reduction and internal fixation with hook plates or tension band wires were retrospectively reviewed. The 52 patients were divided into two groups based on the method of treatment. The hook plate (HP) group included 32 patients and the tension band wire (TBW) group included 20 patients. Both groups were similar in respect to injury mechanisms, compounding medical conditions, and shoulder score (p>0.1). However, hook plating had a significantly lower rate of complication (p=0.01) and symptomatic hardware (p=0.001). In addition, hook plating better facilitated the return to work and athletic activity (p=0.004 and p=0.003, respectively). In conclusion, if surgery of distal clavicular fractures is indicated, internal fixation with a hook plate has more advantages than with tension band wires.Résumé 52 patients présentant une fracture instable de la clavicule ont été traités par réduction sanglante et fixation interne par plaques crochet. Les 52 patients ont été revus et ont été divisés en deux groupes en fonction de la méthode de traitement. L'ostéosynthèse par plaques crochet HP groupe 1 incluait 32 patients et le haubannage TBW 20 patients. Les deux groupes sont identiques en ce qui concerne le mécanisme des traumatismes, les problèmes médicaux, les scores épaule (p>0,1). Cependant le traitement par crochetplaque permet une diminution significative des complications (p=0,01) notamment matérielles (p=0,001). Par ailleurs cette ostéosynthèse par crochet-plaque permet une reprise plus rapide du travail et des activités sportives (p=0,004, 0,003 respectivement). En conclusion, si il existe une indication chirurgicale dans les fractures distales de la clavicule, il est indiqué de réaliser l'ostéosynthèse par crochet-plaque. Cette ostéosynthèse présente beaucoup plus d'avantages que l'ostéosynthèse par hauban.
38We used the psychotomimetic phencyclidine (PCP) to investigate the relationships between 39 cognitive behavior, coordinated neural network function and information processing within the 40 hippocampus place cell system. We report in rats that PCP (5mg/kg i.p.) impairs a well-learned 41 hippocampus-dependent place avoidance behavior in rats that requires cognitive control, even 42 when PCP is injected directly into dorsal hippocampus. PCP increases 60-100 Hz medium 43 gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive 44 impairment caused by systemic PCP administration. PCP discoordinates theta-modulated 45 medium and slow gamma oscillations in CA1 local field potentials (LFP) such that medium 46 gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell 47 firing fields are preserved under PCP but the drug discoordinates the sub-second temporal 48 organization of discharge amongst place cells. This discoordination causes place cell ensemble 49 representations of a familiar space to cease resembling pre-PCP representations, despite 50 preserved place fields. These findings point to the cognitive impairments caused by PCP arising 51 from neural discoordination. PCP disrupts the timing of discharge with respect to the sub-second 52 timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from 53 local inhibitory synaptic activity, these findings point to excitation-inhibition discoordination as 54 the root of PCP-induced cognitive impairment. 55 56 Kao et al 4 SIGNIFICANCE STATEMENT 57 58Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma 59 oscillations in the local field potential, and the discharge of a subset of pyramidal neurons called 60 "place cells" is spatially organized such that discharge is restricted to locations called a cell's 61 "place field." Because this temporal coordination and spatial discharge organization is thought to 62 represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt 63 cognitive behavior and assess the importance of neural coordination and place fields for spatial 64 cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal 65 discharge, without disrupting firing fields. These findings dissociate place fields from spatial 66 cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial 67 cognition. 69 70 Place cells are hippocampus principal cells that discharge in 'place fields' that map discharge to 71 locations, making place cell studies de facto investigations of what information the hippocampus 72 represents and how that information is represented (Friston
DEPDC5, the key gene within the mechanistic target of rapamycin (mTOR) pathway, is one of the most common causative genes in patients with epilepsy and malformation of cortical development (MCD). Although somatic mutations in the dorsal cortical progenitors generate the malformed cortex, its pathogenesis of hyperexcitability is complex and remains unclear. We specifically deleted Depdc5 in the mouse forebrain dorsal progenitors to model DEPDC5-related epilepsy, and investigated whether and how parvalbumin interneurons were non-cell autonomously affected in the malformed cortex. We showed that long before seizures, coincident with microglia inflammation, proteolytic enzymes degraded perineuronal nets (PNN) in the malformed cortex, resulting in parvalbumin (PV+) interneuron loss and presynaptic inhibition impairment. Our studies therefore uncovered the hitherto unknown role of PNN in mTOR-related MCD, providing a new framework for mechanistic-based therapeutic development.
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The hippocampus plays a critical role in storing and retrieving spatial information. By targeting the dorsal hippocampus and manipulating specific "candidate" molecules using pharmacological and genetic manipulations, we have previously discovered that long-term active place avoidance memory requires transient activation of particular molecules in dorsal hippocampus. These molecules include amongst others, the persistent kinases Ca-calmodulin kinase II (CaMKII) and the atypical protein kinase C isoform PKC / for acquisition of the conditioned behavior, whereas persistent activation of the other atypical PKC, protein kinase M zeta (PKM ) is necessary for maintaining the memory for at least a month. It nonetheless remains unclear what other molecules and their interactions maintain active place avoidance long-term memory, and the candidate molecule approach is both impractical and inadequate to identify new candidates since there are so many to survey. Here we use a complementary approach to identify candidates by transcriptional profiling of hippocampus subregions after formation of the long-term active place avoidance memory. Interestingly, 24-h after conditioning and soon after expressing memory retention, immediate early genes were upregulated in the dentate gyrus but not Ammon's horn of the memory expressing group. In addition to determining what genes are differentially regulated during memory maintenance, we performed an integrative, unbiased survey of the genes with expression levels that covary with behavioral measures of active place avoidance memory persistence. Gene Ontology analysis of the most differentially expressed genes shows that active place avoidance memory is associated with activation of transcription and synaptic differentiation in dentate gyrus but not CA3 or CA1, whereas hypothesis-driven candidate molecule analyses identified insignificant changes in the expression of many LTP-associated molecules in the various hippocampal subfields, nor did they covary with active place avoidance memory expression, ruling out strong transcriptional regulation but not translational regulation, which was not investigated. These findings and the data set establish an unbiased resource to screen for molecules and evaluate hypotheses for the molecular components of a hippocampus-dependent, long-term active place avoidance memory.
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