Microscale inhomogeneity of brain tissue distorts electrical signal propagation.

Interpretations of local field potentials (LFPs) are typically shaped on an assumption that the brain is a homogenous conductive milieu. However, microscale inhomogeneities including cell bodies, dendritic structures, axonal fiber bundles and blood vessels are unequivocally present and have different conductivities and permittivities than brain extracellular fluid. To determine the extent to which these obstructions affect electrical signal propagation on a microscale, we delivered electrical stimuli intracellularly to individual cells while simultaneously recording the extracellular potentials at different locations in a rat brain slice. As compared with relatively unobstructed paths, signals were attenuated across frequencies when fiber bundles were in between the stimulated cell and the extracellular electrode. Across group of cell bodies, signals were attenuated at low frequencies, but facilitated at high frequencies. These results show that LFPs do not reflect a democratic representation of neuronal contributions, as certain neurons may contribute to the LFP more than others based on the local extracellular environment surrounding them.

Subthalamic nucleus high-frequency stimulation generates a concomitant synaptic excitation-inhibition in substantia nigra pars reticulata.

Deep brain stimulation is an efficient treatment for various neurological pathologies and a promising tool for neuropsychiatric disorders. This is particularly exemplified by high-frequency stimulation of the subthalamic nucleus (STN-HFS), which has emerged as an efficient symptomatic treatment for Parkinson's disease. How STN-HFS works is still not fully elucidated. With dual patch-clamp recordings in rat brain slices, we analysed the cellular responses of STN stimulation on SNr neurons by simultaneously recording synaptic currents and firing activity. We showed that STN-HFS caused an increase of the spontaneous spiking activity in half of SNr neurons while the remaining ones displayed a decrease. At the synaptic level, STN stimulation triggered inward current in 58% of whole-cell recorded neurons and outward current in the remaining ones. Using a pharmacological approach, we showed that STN-HFS-evoked responses were mediated in all neurons by a balance between AMPA/NMDA receptors and GABA(A) receptors, whose ratio promotes either a net excitation or a net inhibition. Interestingly, we observed a higher excitation occurrence in 6-hydroxydopamine (6-OHDA)-treated rats. In vivo injections of phaseolus revealed that GABAergic pallido-nigral fibres travel through the STN whereas striato-nigral fibres travel below it. Therefore, electrical stimulation of the STN does not only recruit glutamatergic axons from the STN, but also GABAergic passing fibres probably from the globus pallidus. For the first time, we showed that STN-HFS induces concomitant excitatory-inhibitory synaptic currents in SNr neurons by recruitment of efferences and passing fibres allowing a tight control on basal ganglia outflow.

Deep brain stimulation mechanisms: beyond the concept of local functional inhibition.

Deep brain electrical stimulation has become a recognized therapy in the treatment of a variety of motor disorders and has potentially promising applications in a wide range of neurological diseases including neuropsychiatry. Behavioural observation that electrical high-frequency stimulation of a given brain area induces an effect similar to a lesion suggested a mechanism of functional inhibition. In vitro and in vivo experiments as well as per operative recordings in patients have revealed a variety of effects involving local changes of neuronal excitability as well as widespread effects throughout the connected network resulting from activation of axons, including antidromic activation. Here we review current data regarding the local and network activity changes induced by high-frequency stimulation of the subthalamic nucleus and discuss this in the context of motor restoration in Parkinson's disease. Stressing the important functional consequences of axonal activation in deep brain stimulation mechanisms, we highlight the importance of developing anatomical knowledge concerning the fibre connections of the putative therapeutic targets.

Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol.

Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D(1) receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D(2) receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of drd1a-EGFP in striatonigral and drd2-EGFP in striatopallidal neurons. Drd2-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.