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Animal TMS models are especially useful for studying the cellular and molecular effects related to the lasting effects achieved with prolonged stimulation of a particular pattern (rTMS). In translational terms, it is exceptionally challenging to realize stimulation conditions resembling those supposed to occur in the human brain. Due to the very different ratio of coil-to-brain sizes, a focal stimulation of small animal brains as can be achieved in humans using figure-of-eight coils is hardly realistic today. Attempts to develop small (e.g. rodent coils) are confronted with reduced field power or limited number of high-frequency train pulses due to heating problems. Nevertheless, animal TMS models will be helpful in terms of studying relationships between stimulation-induced changes in neuronal activity and plasticity and changes in behavioral phenotypes. Differences in rTMS effects found in Parkinson patients compared to healthy controls which appear to be related to disturbed synaptic plasticity could be replicated in a rat Parkinson disease model ( Hsieh et al., 2015 ) and beneficial stimulation effects related to modulation of striatal dopamine content have been reported ( Ghiglieri et al., 2012 ). Principally, global brain stimulation using rTMS appears adequate if studying neuromodulatory effects not confined to a particular system as is found with changes in extracellular levels of dopamine or glutamate, brain-derived neurotrophic factor (BDNF), pro- or anti-inflammatory mediators and changes in the excitatory-inhibitory balance ( Suppa et al., 2016 ). Nonfocal cortical and/or subcortical stimulation should be suitable to also answer the question if distinct types of neurons (including their genesis and developmental state) or their compartments are more sensitive to a particular stimulation protocol than others if analyzing neuronal activity and plasticity markers. Even if those changes have been achieved with limited focal stimulation in vivo, matched in vitro studies on isolated neuronal systems allow estimating the relevance of focal stimulation as recently demonstrated for the entorhino-hippocampal pathway in mice ( Lenz et al., 2016 ). Focal electric stimulation applied in a way to either mimic the timing of spatially distant evoked activity – as in case of interhemispheric stimulation ( Barry et al., 2014 )-, or to mimic the electric field distribution likely achieved with an imaginary focal coil could further help to evaluate the differences between focal and global stimulation. However, it has to be kept in mind that magnetic fields induced a different electric field distribution within the tissue as can be achieved with contact electrodes, both with regard to spatial current density and also with regard to extra- and intracellular induction of electric field gradients. In this respect, animal studies demonstrating neuronal effects with patterned magnetic stimulation of rather low field strength (10–100 mT) are of further interest, indicating modulation of molecular processes like intracellular calcium release and gene expression even in the absence of detectable electric responses ( Grehl et al., 2015 ). Even if animal models cannot imitate TMS of human cortex in a one-to-one fashion, they definitely offer new ways to investigate how magnetically induced electric field can interact with neuronal processes and which factors determine a variable result of stimulation. [ABSTRACT FROM AUTHOR]

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA. [ABSTRACT FROM AUTHOR]

Introduction: Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS) but the factors that determine the direction of change remain still elusive. Classical forms of synaptic plasticity and metaplastic processes like homeostatic synaptic scaling and priming-dependent synaptic plasticity are possible mechanistic scenarios. Although the activity of excitatory neurons finally represents the degree of cortical activation, a multitude of inhibitory cortical systems governs about magnitude and pattern of cortical activity and the degree of plasticity allowed without loosing essential excitation-inhibition balance. It is thus likely that rTMS-induced changes in cortical excitability are associated with changes in cortical inhibition and that classes of interneurons differently contribute. Objectives: We established a rat model of rTMS enabling to study cellular effects of rTMS in more detail and with possible relation to behavioural changes. To focus on changes in inhibitory cortical activity, we studied the expression of certain activity markers which are specific to inhibitory neurons in general, like the two isoforms of the glutamic acid decarboxylase GAD65 and GAD67, or relate to a certain class of interneurons, like the expression of the calcium-binding proteins parvalbumin (PV), calbindin (CB) and calretinin (CR). Our recent studies focus on the temporal dynamics of these activity markers which is of particular interest in case of combining rTMS with other artificial or natural interventions or repeated rTMS. Materials and methods: Adult male Sprague–Dawley rats (n =42.15weeks old) were trained to tolerate the procedure of manual restrain and rTMS without signs of stress before receiving a single block (600 pulses) of either verum or sham intermittent theta-burst stimulation protocol (iTBS) at an intensity just subthreshold for evoking motor responses (MagStim rapid, 70mm figure-of-eight coil). Then, rat were deeply anesthetized and perfused at different intervals post-rTMS (10, 20, 40, 80, 160min) for immunohistochemical analysis of neuronal activity marker expression (GAD65/67, PV, CB for inhibitory neurons; c-Fos and zif268 mainly for excitatory neurons). Results: Three phases of changes in neuronal activity marker expression could be distinguished: an early phase (10–20min) of strongly increased c-Fos and GAD65 expression, a following phase (40–80min) of reduced GAD67, PV and CB expression and a late phase (>160min) of reduced c-Fos and GAD65 expression. Conclusion: Early increased levels of c-Fos and GAD65 indicate a strong co-activation of excitatory and inhibitory neurons due to iTBS. The delayed decrease in GAD67, PV and CB expression indicates a secondary depression of activity of inhibitory neurons without signs of increased excitatory activity (c-Fos, zif268). The late decrease in c-Fos and GAD65 finally indicates a matched reduction in the activity of both excitatory and inhibitory activities. Obviously, excitation-inhibition balance is never violated but the phases of changed synaptic (GAD65) and somatic (GAD67, PV, CB) inhibitory neuron activity to not co-vary in time. This study has been supported by the Deutsche Forschungsgemeinschaft, DFG (FU 256/3-2, SFB 874, TP A4). [Copyright &y& Elsevier]