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The ability to control and modulate the action potential firing in neurons represents a powerful tool for neuroscience research and clinical applications. While neuronal excitation has been achieved with many tools, including electrical and optical stimulation, hyperpolarization and neuronal inhibition are typically obtained through patch-clamp or optogenetic manipulations. Here we report the use of conjugated polymer films interfaced with neurons for inducing a light-mediated inhibition of their electrical activity. We show that prolonged illumination of the interface triggers a sustained hyperpolarization of the neuronal membrane that significantly reduces both spontaneous and evoked action potential firing. We demonstrate that the polymeric interface can be activated by either visible or infrared light and is capable of modulating neuronal activity in brain slices and explanted retinas. These findings prove the ability of conjugated polymers to tune neuronal firing and suggest their potential application for the in-vivo modulation of neuronal activity.

Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a G q -protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP. Stress is a major cause of relapse to cocaine seeking behaviour. Tung et al . show that orexin mediates stress-induced reinstatement of cocaine seeking behaviour in mice by endocannabinoid-dependent disinhibition in the ventral tegmental area.

The balance between excitation and inhibition in the cortex is crucial in determining sensory processing. Because the amount of excitation varies, maintaining this balance is a dynamic process; yet the underlying mechanisms are poorly understood. We show here that the activity of even a single layer 2/3 pyramidal cell in the somatosensory cortex of the rat generates widespread inhibition that increases disproportionately with the number of active pyramidal neurons. This supralinear increase of inhibition results from the incremental recruitment of somatostatin-expressing inhibitory interneurons located in layers 2/3 and 5. The recruitment of these interneurons increases tenfold when they are excited by two pyramidal cells. A simple model demonstrates that the distribution of excitatory input amplitudes onto inhibitory neurons influences the sensitivity and dynamic range of the recurrent circuit. These data show that through a highly sensitive recurrent inhibitory circuit, cortical excitability can be modulated by one pyramidal cell.

Although the technique of somatic voltage clamp is widely used, computational models have predicted that this controls voltage in the dendritic tree poorly. Williams and Mitchell directly quantify this error using simultaneous recordings from the soma and apical dendrites of rat neocortical pyramidal neurons. Spruston and Johnston also highlight this in an associated news and views. The somatic voltage clamp technique has revolutionized understanding of synaptic physiology and the excitability of neurons. Although computer simulations have indicated that the somatic voltage clamp poorly controls voltage in the dendritic tree of neurons, where the majority of synaptic contacts are made, there has not been an experimental description of the performance of the somatic voltage clamp. Here, we directly quantify errors in the measurement of dendritic synaptic input by the somatic voltage clamp using simultaneous whole-cell recordings from the soma and apical dendrite of rat neocortical pyramidal neurons. The somatic voltage clamp did not control voltage at sites other than the soma and distorted measurement of the amplitude, kinetics, slope conductance and reversal potential of synaptic inputs in a dendritic distance–dependent manner. These errors question the use of the somatic voltage clamp as a quantitative tool in dendritic neurons.

Schizophrenia is a complex brain disease involving several neurotransmitter systems, including aberrant noradrenergic activity, which might underlie cognitive deficits. Clonidine is an α2A-agonist and previous research has demonstrated that single dosages of clonidine normalize sensori(motor) gating in schizophrenia. Currently, we investigated whether clonidine is able to normalize mismatch negativity (MMN) and P3a amplitude deficits in this same group of patients. This is important, since reports have shown that MMN amplitude is associated with cognitive functioning and daily life functions in schizophrenia. Twenty chronically ill, male schizophrenia patients were tested with the MMN paradigm from the Copenhagen Psychophysiological Test Battery (CPTB) on 5 occasions, separated by a week. Patients received randomized, yet balanced, either a placebo or a single dose (25, 50, 75 or 150 μg) of clonidine (each dose only once) on top of their usual medication on each occasion. Patients were matched on age and gender with 20 healthy controls (HC) who did not receive any treatment. We found decreased MMN and P3a amplitudes in our patients compared to HC. Although clonidine did neither significantly increase MMN nor P3a amplitude in our patients, it did increase certain levels of MMN and P3a amplitude such that these were not significantly different anymore from the healthy controls. Together with our previous reports indicating normalized sensori(motor) gating in the same patients following administration of clonidine, our results could be of potential high clinical relevance in treating schizophrenia. Future studies should focus on longer trial periods to investigate if clonidine also improves cognitive functioning in schizophrenia.

Spillover of glutamate under physiological conditions has only been established as an adjunct to conventional synaptic transmission. Here we describe a pure spillover connection between the climbing fiber and molecular layer interneurons in the rat cerebellar cortex. We show that, instead of acting via conventional synapses, multiple climbing fibers activate AMPA- and NMDA-type glutamate receptors on interneurons exclusively via spillover. Spillover from the climbing fiber represents a form of glutamatergic volume transmission that could be triggered in a regionalized manner by experimentally observed synchronous climbing fiber activity. Climbing fibers are known to direct parallel fiber synaptic plasticity in interneurons, so one function of this spillover is likely to involve controlling synaptic plasticity.

Neurons in the recipient layers of sensory cortices receive excitatory input from two major sources: the feedforward thalamocortical and recurrent intracortical inputs. To address their respective functional roles, we developed a new method for silencing cortex by competitively activating GABA A while blocking GABA B receptors. In the rat primary auditory cortex, in vivo whole-cell recording from the same neuron before and after local cortical silencing revealed that thalamic input occupied the same area of frequency-intensity tonal receptive field as the total excitatory input, but showed a flattened tuning curve. In contrast, excitatory intracortical input was sharply tuned with a tuning curve that closely matched that of suprathreshold responses. This can be attributed to a selective amplification of cortical cells' responses at preferred frequencies by intracortical inputs from similarly tuned neurons. Thus, weakly tuned thalamocortical inputs determine the subthreshold responding range, whereas intracortical inputs largely define the tuning. Such circuits may ensure a faithful conveyance of sensory information.

The effects of caffeine are mediated through its non-selective antagonistic effects on adenosine A1 and A2A adenosine receptors resulting in increased neuronal activity but also vasoconstriction in the brain. Caffeine, therefore, can modify BOLD FMRI signal responses through both its neural and its vascular effects depending on receptor distributions in different brain regions. In this study we aim to distinguish neural and vascular influences of a single dose of caffeine in measurements of task-related brain activity using simultaneous EEG–FMRI. We chose to compare low-level visual and motor (paced finger tapping) tasks with a cognitive (auditory oddball) task, with the expectation that caffeine would differentially affect brain responses in relation to these tasks. To avoid the influence of chronic caffeine intake, we examined the effect of 250mg of oral caffeine on 14 non and infrequent caffeine consumers in a double-blind placebo-controlled cross-over study. Our results show that the task-related BOLD signal change in visual and primary motor cortex was significantly reduced by caffeine, while the amplitude and latency of visual evoked potentials over occipital cortex remained unaltered. However, during the auditory oddball task (target versus non-target stimuli) caffeine significantly increased the BOLD signal in frontal cortex. Correspondingly, there was also a significant effect of caffeine in reducing the target evoked response potential (P300) latency in the oddball task and this was associated with a positive potential over frontal cortex. Behavioural data showed that caffeine also improved performance in the oddball task with a significantly reduced number of missed responses. Our results are consistent with earlier studies demonstrating altered flow-metabolism coupling after caffeine administration in the context of our observation of a generalised caffeine-induced reduction in cerebral blood flow demonstrated by arterial spin labelling (19% reduction over grey matter). We were able to identify vascular effects and hence altered neurovascular coupling through the alteration of low-level task FMRI responses in the face of a preserved visual evoked potential. However, our data also suggest a cognitive effect of caffeine through its positive effect on the frontal BOLD signal consistent with the shortening of oddball EEG response latency. The combined use of EEG–FMRI is a promising methodology for investigating alterations in brain function in drug and disease studies where neurovascular coupling may be altered on a regional basis. ► Caffeine reduced task related BOLD responses in visual and motor cortex. ► However, amplitude and latency of visual evoked potentials remained unaltered. ► Performance and frontal BOLD response in an auditory oddball task were enhanced. ► Correspondingly, caffeine reduced the latency of target-evoked potentials. ► EEG–FMRI can separate vascular and neural influences of caffeine in low consumers.

Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

Endogenous polyamines profoundly affect the activity of various ion channels, including that of calcium-permeable AMPA-type glutamate receptors (CP-AMPARs). Here we show that stargazin, a transmembrane AMPAR regulatory protein (TARP) known to influence transport, gating and desensitization of AMPARs, greatly reduces block of CP-AMPARs by intracellular polyamines. By decreasing CP-AMPAR affinity for cytoplasmic polyamines, stargazin enhances the charge transfer following single glutamate applications and eliminates the frequency-dependent facilitation seen with repeated applications. In cerebellar stellate cells, which express both synaptic CP-AMPARs and stargazin, we found that the rectification and unitary conductance of channels underlying excitatory postsynaptic currents were matched by those of recombinant AMPARs only when the latter were associated with stargazin. Taken together, our observations establish modulatory actions of stargazin that are specific to CP-AMPARs, and suggest that during synaptic transmission the activity of such receptors, and thus calcium influx, is fundamentally changed by TARPs.