SummaryDifferent striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behavior. The neural basis for the addictive nature of benzodiazepines however remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABAA receptors in nearby interneurons. Such disinhibition, which relies on α1-containing GABAARs expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell type-specific expression of α1-containing GABAARs in the ventral tegmental area. The data also suggest that subunitselective benzodiazepines sparing α1 may be devoid of addiction liability.

The ventral tegmental area (VTA) and nucleus accumbens (NAc) are essential for learning about environmental stimuli associated with motivationally relevant outcomes. The task of signalling such events, both rewarding and aversive, from the VTA to the NAc has largely been ascribed to dopamine neurons. The VTA also contains GABA (γ-aminobutyric acid)-releasing neurons, which provide local inhibition and also project to the NAc. However, the cellular targets and functional importance of this long-range inhibitory projection have not been ascertained. Here we show that GABA-releasing neurons of the VTA that project to the NAc (VTA GABA projection neurons) inhibit accumbal cholinergic interneurons (CINs) to enhance stimulus-outcome learning. Combining optogenetics with structural imaging and electrophysiology, we found that VTA GABA projection neurons selectively target NAc CINs, forming multiple symmetrical synaptic contacts that generated inhibitory postsynaptic currents. This is remarkable considering that CINs represent a very small population of all accumbal neurons, and provide the primary source of cholinergic tone in the NAc. Brief activation of this projection was sufficient to halt the spontaneous activity of NAc CINs, resembling the pause recorded in animals learning stimulus-outcome associations. Indeed, we found that forcing CINs to pause in behaving mice enhanced discrimination of a motivationally important stimulus that had been associated with an aversive outcome. Our results demonstrate that VTA GABA projection neurons, through their selective targeting of accumbal CINs, provide a novel route through which the VTA communicates saliency to the NAc. VTA GABA projection neurons thus emerge as orchestrators of dopaminergic and cholinergic modulation in the NAc.

The manner in which drug-evoked synaptic plasticity affects reward circuits remains largely elusive. We found that cocaine reduced NMDA receptor excitatory postsynaptic currents and inserted GluA2-lacking AMPA receptors in dopamine neurons of mice. Consequently, a stimulation protocol pairing glutamate release with hyperpolarizing current injections further strengthened synapses after cocaine treatment. Our data suggest that early cocaine-evoked plasticity in the ventral tegmental area inverts the rules for activity-dependent plasticity, eventually leading to addictive behavior.

Dopaminergic neurons of the substantia nigra pars compacta (SNc) exhibit functional heterogeneity that likely underpins their diverse roles in behavior. We examined how the functional diversity of identified dopaminergic neurons in vivo correlates with differences in somato-dendritic architecture and afferent synaptic organization. Stereological analysis of individually recorded and labeled dopaminergic neurons of rat SNc revealed that they received approximately 8,000 synaptic inputs, at least 30% of which were glutamatergic and 40-70% were GABAergic. The latter synapses were proportionally greater in number and denser on dendrites located in the substantia nigra pars reticulata (SNr) than on those located in SNc, revealing the existence of two synaptically distinct and region-specific subcellular domains. We also found that the relative extension of SNc neuron dendrites into the SNr dictated overall GABAergic innervation and predicted inhibition responses to aversive stimuli. We conclude that diverse wiring patterns determine the heterogeneous activities of midbrain dopaminergic neurons in vivo.© 2012 Nature America, Inc. All rights reserved.Correspondence should be addressed to P.H. (pablohenny@gmail.com). 5 Present addresses: Department of Basic Neurosciences, CMU, Geneva, Switzerland (M.T.C.B.), Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK (M.A.U.). AUTHOR CONTRIBUTIONS: P.H. performed the juxtacellular labeling of some neurons, carried out most of the immunohistochemical procedures, electron microscopic analysis, neuronal reconstructions and stereological analysis, analyzed most of the anatomical and some of the physiological data, prepared the figures, and wrote the manuscript. M.T.C.B. recorded and juxtacellularly labeled most of the neurons that we used, and performed most of the physiological analysis. A.N. carried out neuronal reconstructions in half of the neurons. M.F. performed the light microscopic stereological analysis of immunolabeled varicosities. M.A.U. provided important feedback during the development of the project and gave critical comments during the writing of the manuscript. P.J.M. supervised and contributed to the recording and juxtacellular labeling of neurons and the project in general, and provided insightful comments during the writing of the manuscript. J.P.B. supervised the entire project, provided expertise in immunohistochemistry and tissue processing, helped with ultrastructural analysis, and provided critical and insightful comments during the writing of the manuscript. COMPETING FINANCIAL INTERESTS:The authors declare no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Neurosci. Author manuscript; available in PMC 2014 November 25. Published in final edited form as:Nat Neurosci. ; 15(4): 613-619. doi:10.1038/nn.3048. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsMidbrain dopaminergic neurons, including those of the SNc, are important for a variety...

Trace element sampling and shipboard flow injection analysis during the June–August 2003 Climate Variability and Predictability (CLIVAR)‐CO2 Repeat Hydrography A16N transect has produced a high‐resolution section of dissolved Fe and Al in the upper 1000 m of the Atlantic Ocean between 62°N and 5°S. Using the surface water dissolved Al and the Model of Aluminum for Dust Calculation in Oceanic Waters (MADCOW) model we have calculated the deposition of mineral dust to the surface ocean along this transect and compare that to dissolved Fe concentrations. The lowest mean mineral dust depositions of ≤0.2 g m−2 a−1 are found to the north of 51°N; a region which also exhibits characteristics of biological Fe limitation through its low dissolved surface water Fe (∼0.1 nM) and residual macronutrients, e.g., nitrate >2 μM. To the south of this region, mean dust deposition increases by an order of magnitude reaching ∼3 g m−2 a−1 at 10°N, underneath the Saharan dust outflow. Surface water Fe values also increase along this section to >1 nM. Distinct minima in Fe concentrations at the depth of the chlorophyll maximum in the vertical profiles between 18 and 4°N illuminate the role that active biological uptake plays in Fe cycling. An extensive subsurface zone of enhanced dissolved Fe concentrations (>1.5 nM) underlying this region is a result of the biological vertical transport and remineralization of the surface water Fe and is coincident with the intermediate nutrient maximum and oxygen minimum of this region. Elevated concentrations of dissolved Al in subsurface waters seen between 30 and 20°N coincide with the domain of the subtropical mode waters (STMW) which result from the sinking of surface waters in late winter in regions imprinted by dust deposition. The magnitude of the Al enrichment observed in this water mass implies that the predominant source to the STMW is from the more dust‐impacted western Atlantic, with only limited contributions from the STMW formation region near Madeira. A deeper subsurface Al enrichment (30–45°N) is associated with the outflow from the Mediterranean, another heavily dust‐impacted basin. These two regions of Al enrichment show the widespread geochemical connection between atmospheric transport processes and the North Atlantic and underscore its susceptibility to imprinting by atmospherically borne materials, natural as well as anthropogenic.

[1] Dissolved Al was determined on $3500 surface water samples collected in the NW Pacific during the 2002 Intergovernmental Oceanographic Commission (IOC) Contaminant Baseline survey. In addition, dissolved Al was determined on samples collected at 9 vertical stations occupied along the cruise track. Surface water Al distributions, when converted to annual mineral dust deposition (Measures and Brown, 1996), imply extremely low depositions (mean values 0.3 g m À2 yr À1 ) to surface waters of the subarctic gyre despite the atmospheric transport of large amounts of mineral dust across this region from the desert regions of China. The calculated deposition values are also much lower than the 1-10 g m À2 yr À1 predicted for this region by the GESAMP model (Duce et al., 1991). The lowest mineral dust depositions correspond to the High Nutrient Low Chlorophyll (HNLC) region of the NW Pacific, which implies that the biogeochemical status of this region is the result of low atmospheric micronutrient input, similar to other HNLC regions. In the subtropical gyre the Al-derived dust deposition (mean values 0.1-0.6 g m À2 yr À1 ) agrees well with the (<1 g m À2 yr À1 ) predictions of the GESAMP model. Enriched concentrations of dissolved Al in the coastal waters near Kauai, from fluvial sources, indicate the potential role of remote high islands in adding reactive trace elements to the nearby surface waters. In the vertical profiles, elevated dissolved Al concentrations (4-8 nM) were found to correspond to the potential density of the western Pacific ''Subtropical Mode'' waters which form in the recirculation zone of the Kuroshio.

Dopaminergic neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are collectively implicated in motor-and rewardrelated behaviors. However, dopaminergic SN and VTA neurons differ on several functional levels, and dopaminergic SN neurons themselves vary in their intrinsic electrical properties, neurochemical characteristics and connections. This heterogeneity is not only important for normal function; calbindin (CB) expression by some dopaminergic SN neurons has been linked with their increased survival in Parkinson's disease. To test whether the activity of CB-negative and CB-positive dopaminergic SN neurons differs during distinct spontaneous and driven brain states, we recorded single units in anesthetized rats before, during and after aversive somatosensory stimuli. Recorded neurons were juxtacellularly labeled, confirmed to be dopaminergic, and tested for CB immunoreactivity. During cortical slow-wave activity, the firing of most dopaminergic neurons was slow and regular/irregular and unrelated to cortical slow oscillations. During spontaneous cortical activation, dopaminergic SN neurons fired in a more regular manner, with fewer bursts, but did not change their firing rate. Regardless of brain state, CB-negative dopaminergic neurons fired significantly faster than CB-positive dopaminergic neurons. This difference in firing rate was not mirrored by different firing patterns. Most CB-negative and CB-positive dopaminergic neurons did not respond to the aversive stimuli; of those that did respond, most were inhibited. We conclude that CB-negative and CB-positive dopaminergic neurons exhibit different activities in vivo. Furthermore, the firing of dopaminergic SN neurons is brain state-dependent, and, unlike dopaminergic VTA neurons, they are not commonly recruited or inhibited by aversive stimuli.