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Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics. Optogenetic control of neural activity in the deep brain is achieved without intracranial surgery using ChRmine.

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking. Acute stress transiently disrupts reward-seeking behaviour and repeated stress exposure produces lasting anhedonia-like behaviour in rodents. Here, the authors show that stress triggers GABAergic activity in the ventral tegmental area which blunts reward-seeking behaviour in mice.

The authors developed an assay using optogenetic stimulation of dopaminergic neurons as a reference stimulus to measure the reward value of nutrients. They found that fasting increases and leptin decreases the reward value of sucrose. We developed an assay for quantifying the reward value of nutrient and used it to analyze the effects of metabolic state and leptin. In this assay, mice chose between two sippers, one of which dispensed water and was coupled to optogenetic activation of dopaminergic (DA) neurons and the other of which dispensed natural or artificial sweeteners. This assay measured the reward value of sweeteners relative to lick-induced optogenetic activation of DA neurons. Mice preferred optogenetic stimulation of DA neurons to sucralose, but not to sucrose. However, the mice preferred sucralose plus optogenetic stimulation versus sucrose. We found that food restriction increased the value of sucrose relative to sucralose plus optogenetic stimulation, and that leptin decreased it. Our data suggest that leptin suppresses the ability of sucrose to drive taste-independent DA neuronal activation and provide new insights into the mechanism of leptin's effects on food intake.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders. Acetylcholine is one of the most abundant chemicals in the brain, with key roles in learning, memory and attention. Neurons throughout the brain use acetylcholine to exchange messages. Acetylcholine binds to two different classes of receptors on neurons: nicotinic and muscarinic. As the name suggests, nicotinic receptors also respond to nicotine, the main addictive substance in tobacco, while muscarinic receptors respond to muscarine, present in certain poisonous mushrooms. Nicotinic and muscarinic receptors each consist of many different subtypes. But standard pharmacology techniques cannot discriminate between the effects of acetylcholine binding to these different subtypes. Likewise, they cannot distinguish between acetylcholine binding to the same receptor subtype on different neurons. Durand-de Cuttoli, Mondoloni et al. have now developed a new nanotechnology that uses light to target specific acetylcholine receptor subtypes in freely moving mice. The technology was tested in a brain region called the VTA, which is part of the brain’s reward system. Experiments showed that when acetylcholine binds to a specific subtype of nicotinic receptors on VTA neurons – called β2-containing receptors – it makes the neurons release the brain's reward signal, dopamine. Switching these receptors on and off changed how the mice responded to nicotine. With the receptors switched on, mice preferred locations associated with nicotine. Switching the receptors off removed this preference. Nicotine may thus be addictive in part because it triggers VTA neurons to release dopamine via its actions on β2-containing nicotinic receptors. This new technology will help reveal the mechanisms of action of acetylcholine and nicotine. Blocking the effects of nicotine at a specific time and place in the mouse brain may uncover the receptors and brain regions that drive nicotine consumption. Smoking remains a major cause of preventable death worldwide. This new approach could help us develop strategies to prevent or treat addiction.

Ultrasound is a promising new modality for non‐invasive neuromodulation. Applied transcranially, it can be focused down to the millimeter or centimeter range. The ability to improve the treatment's spatial resolution to a targeted brain region could help to improve its effectiveness, depending upon the application. The present paper details a neurostimulation scheme using gas‐filled nanostructures, gas vesicles (GVs), as actuators for improving the efficacy and precision of ultrasound stimuli. Sonicated primary neurons display dose‐dependent, repeatable Ca2+ responses, closely synced to stimuli, and increased nuclear expression of the activation marker c‐Fos in the presence of GVs. GV‐mediated ultrasound triggered rapid and reversible Ca2+ responses in vivo and could selectively evoke neuronal activation in a deep‐seated brain region. Further investigation indicate that mechanosensitive ion channels are important mediators of this effect. GVs themselves and the treatment scheme are also found not to induce significant cytotoxicity, apoptosis, or membrane poration in treated cells. Altogether, this study demonstrates a simple and effective method to achieve enhanced and better‐targeted neurostimulation with non‐invasive low‐intensity ultrasound. This study utilizes ultrasound‐responsive nanoscale gas vesicles (GVs) to mediate controllable transcranial ultrasound stimulation. Sonicated neurons and mouse brain display reversible and repeatable Ca2+ responses, and increased c‐Fos expression in the presence of GVs. Mechanosensitive ion channels are found to be involved in mediating the stimulation. This strategy enables targeted stimulation in a deep brain region with high spatiotemporal resolution.

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we report that cranial irradiation transiently altered VTA dopamine neuron firing patterns without affecting overall firing rates and led to sustained reductions in both “awake” and total dopamine neuron density. Additionally, radiation exposure impaired D2 receptor function and disrupted connectivity between the PFC and VTA. These multifaceted disruptions in the mesocortical dopamine signaling may underlie the development of radiation-induced cognitive dysfunction. These findings pave the way for novel research to prevent or reverse radiation-induced injury, ultimately improving the quality of life for brain tumor survivors.

Excitatory synapses on dopamine neurons in the VTA can undergo both long-term potentiation and depression. Additionally, drug-induced plasticity has been found at VTA synapses, and is proposed to play a role in reward-related learning and addiction by modifying dopamine cell firing. LTP at these synapses is difficult to generate experimentally in that it requires an undisturbed intracellular milieu and is often small in magnitude. Here, we demonstrate the induction of LTP as a property of evoked field potentials within the VTA. Excitatory field potentials were recorded extracellularly from VTA neurons in acute horizontal midbrain slices. Using extracellular and intracellular recording techniques, we found that evoked field potentials originate within the VTA itself and are largely composed of AMPA receptor-mediated EPSPs and action potentials triggered by activation of glutamatergic synapses on both dopamine and GABA neurons. High-frequency afferent stimulation (HFS) induced LTP of the field potential. The induction of this LTP was blocked by application of the NMDAR antagonist, d-APV, prior to HFS. As reported previously, glutamatergic synapses on GABA neurons did not express LTP while those on dopamine neurons did. We conclude that the potentiation of glutamatergic synapses on dopamine neurons is a major contributor to NMDA receptor-dependent LTP of the field potential. Field potential recordings may provide a convenient approach to explore the basic electrophysiological properties of VTA neurons and the development of addiction-related processes in this brain region.

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH + ) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH + neurons project more profusely than ventral tegmental area TH + neurons to the hippocampus, optogenetic activation of locus coeruleus TH + neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH + photoactivation are sensitive to hippocampal D 1 /D 5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo . Thus, locus coeruleus TH + neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus. Projections from the locus coeruleus, an area typically defined by noradrenergic signalling, to the hippocampus drive novelty-based memory enhancement through possible co-release of dopamine. Memory consolidation in the locus coeruleus Memory retention can be enhanced when something novel or categorically relevant occurs shortly before or after the time of memory encoding, as in 'flashbulb memory'. Dopamine-based mechanisms originating in the ventral tegmental area have been implicated in the phenomenon. These authors suggest that projections from the locus coeruleus—typically defined by noradrenergic signalling—to the hippocampus drive this novelty-based memory enhancement through the possible local release of dopamine.

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near −65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor–based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure–function relationships of the light-gated pore.

Agonists of GABA B receptors exert a bi-directional effect on the activity of dopamine (DA) neurons of the ventral tegmental area, which can be explained by the fact that coupling between GABA B receptors and G protein-gated inwardly rectifying potassium (GIRK) channels is significantly weaker in DA neurons than in GABA neurons. Thus, low concentrations of agonists preferentially inhibit GABA neurons and thereby disinhibit DA neurons. This disinhibition might confer reinforcing properties on addictive GABA B receptor agonists such as γ-hydroxybutyrate (GHB) and its derivatives. Here we show that, in DA neurons of mice, the low coupling efficiency reflects the selective expression of heteromeric GIRK2/3 channels and is dynamically modulated by a member of the regulator of G protein signaling (RGS) protein family. Moreover, repetitive exposure to GHB increases the GABA B receptor-GIRK channel coupling efficiency through downregulation of RGS2. Finally, oral self-administration of GHB at a concentration that is normally rewarding becomes aversive after chronic exposure. On the basis of these results, we propose a mechanism that might underlie tolerance to GHB.