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Identifier 000393684
Title The role of inhibition in behavior and physiology of mouse cerebral cortex
Alternative Title Ο ρόλος της αναστολής στη συμπεριφορά και φυσιολογία του εγκεφαλικού φλοιού μυών
Author Κωνσταντουδάκη, Ξανθίππη
Thesis advisor Σιδηροπούλου, Κυριακή
Reviewer Χαλεπάκης, Γεώργιος
Καραγωγέως, Δόμνα
Abstract The prefrontal cortex (PFC) is involved in higher-­‐order cognitive functions (short-­‐term and long-­‐term mnemonic functions) as well as in emotional processes. Although age seems to play a significant role in both the normal function of PFC and the emergence of disease states, very little is known with regards to the age-­‐dependent changes of behaviors involving the PFC and the underlying cellular mechanisms. Previous studies, primarily based on dendritic morphology, have suggested that this higher-­‐order brain region exhibits delayed cortical development compared to primary sensory cortical areas that lasts until young adulthood. Investigating the PFC postnatal development is critical to radically improve our understanding of brain function and behavior as well as of the emergence substrate of devastating neuropsychiatric disorders involving the PFC. The PFC, similar to other cortical areas, is composed of glutamatergic excitatory neurons and GABAergic inhibitory interneurons. A balance between these two systems is required for proper functioning of the PFC. Recently, the role of the GABAergic system has strongly been implicated in contributing to possible imbalances between the two main systems, ultimately leading to pathological states. Our goal in this dissertation was two-­‐fold. Firstly, we aimed to better understand the postnatal development of the PFC and secondly, to study changes in PFC behavior and underlying cellular mechanisms in cases with reduced GABAergic inhibition. Our results are presented in three different chapters. In Chapter I, we used a multidisciplinary approach including cellular, electrophysiological and behavioral techniques in different age groups of mice in order to better understand the PFC development. In many cases, a comparison to other cortical areas was made. We find a differential expression of distinct types of dendritic spines in pyramidal neurons of PFC between different age groups of mice. In particular, ‘adolescent’ pyramidal neurons (40 days old) exhibit the lowest spine density measured, with an increased percentage of stubby spines, while the ‘juvenile’ (35 days old) and ‘young adult’ pyramidal neurons (60 days old) have increased number of spines, and particularly of the mushroom type. This developmental pattern was also observed in our electrophysiological studies, in which the ‘juvenile’ and ‘young adult’ age groups exhibit increased long-­‐term potentiation (LTP) of synaptic transmission in response to tetanic stimulation, while the ‘adolescent’ age group exhibits decreased LTP. Finally, ‘adolescent’ mice perform poorer in PFC-­‐dependent tasks, such as the delayed alternation in the T-­‐maze and the temporal order object recognition task, without exhibiting differences in non-­‐PFC-­‐dependent tasks, such as the novel object and objet-­‐to-­‐place recognition tasks, compared to young adult mice. In Chapter II, we studied the role of decreased inhibition in PFC physiology and in mouse behavior, using the Rac1 conditional transgenic mouse (Rac1 cKO) that displays ~50% less cortical interneurons due to the loss of the Rac1 protein from Nkx2.1-­‐expressing cells. We find that the adult Rac1 cKO exhibit increased susceptibility to pharmacological-­‐induced epileptic seizures as well as increased anxiety. At the cellular level, Rac1 cKO mice exhibit impaired short-­‐term plasticity and LTP in response to tetanic stimulation within the PFC. Changes in dendritic morphology, such as reduced mushroom-­‐type spines and reduced dendritic length, could underlie the decrease in LTP of the Rac1 cKO mice. In Rac1 cKO brain slices, up-­‐regulation of GABA-­‐receptor-­‐mediated neurotransmission using a mild dose of diazepam was sufficient to rescue the impaired LTP. The above findings led us to further hypothesize that the PFC network of Rac1 cKO mice exhibit an imbalance of excitation and inhibition, caused by deregulation of the glutamatergic system in response to functional reductions of the GABAergic system, which ultimately result in increased anxiety and vulnerability to epileptic seizures. We also studied the juvenile Rac1 cKO mice, which exhibit decreased anxiety and increased LTP induction after tetanic stimulation with an underling increase in the number of dendritic spines compared to juvenile Rac1 Het (heterozygous) mice, used as control. Finally, acute or chronic inhibition of the GABAergic system in Rac1 Het mice with picrotoxin also impaired the LTP in the PFC. Our results suggest that proper inhibition during the juvenile period is critical for the normal development of synaptic properties and plasticity within layer II of PFC, as well as for the development of the normal behavior and cognitive functions. In Chapter III, we undertook a computational approach to study how reductions in GABAergic inhibition in a PFC microcircuit model affect the properties of persistent activity, considered the cellular correlate of working memory function in PFC. To this end, we constructed a PFC microcircuit, consisting of pyramidal neuron models and all three different types of interneurons: fast-­‐spiking (FS), regular-­‐spiking (RS), and irregular-­‐spiking (IS) interneurons. Persistent activity was induced in the microcircuit model and its properties were analyzed. Removing or decreasing the FS model input to the pyramidal neuron models greatly limited the biophysical modulation of persistent activity induction, decreased the ISIs (inter-­‐spike intervals), neuronal synchronicity and gamma-­‐power oscillations during persistent activity. The effect on synchronicity and oscillations could be reversed by the addition of other inhibitory inputs to the soma, but beyond the levels of the control network. Thus, generic somatic inhibition acts as a pacemaker of persistent activity and FS specific inhibition modulates the output of the pacemaker. Overall, our results contributed to the growing knowledge on PFC functions during development and their underlying mechanisms that render the PFC “the region that humans prize for its ability to regulate our thoughts and behaviors”.
Language English
Subject Adolescence
Anxiety
Epilepsy
Interneurons
Memory
Prefrontal cortex
Άγχος
Ενδιάμεσοι νευρώνες
Επιληψία
Εφηβεία
Μνήμη
Προμετωπιαίος φλοιός
Issue date 2015-05-27
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
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