Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat.

Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional-motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, "enhancing" the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH-immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional-motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons.

Organization of the Anterior Limb of the Internal Capsule in the Rat.

Dysfunction of the orbitofrontal (OFC) and anterior cingulate (ACC) cortices has been linked with several psychiatric disorders, including obsessive-compulsive disorder, major depressive disorder, posttraumatic stress disorder, and addiction. These conditions are also associated with abnormalities in the anterior limb of the internal capsule, the white matter (WM) bundle carrying ascending and descending fibers from the OFC and ACC. Furthermore, deep-brain stimulation (DBS) for psychiatric disorders targets these fibers. Experiments in rats provide essential information on the mechanisms of normal and abnormal brain anatomy, including WM composition and perturbations. However, whereas descending prefrontal cortex (PFC) fibers in primates form a well defined and topographic anterior limb of the internal capsule, the specific locations and organization of these fibers in rats is unknown. We address this gap by analyzing descending fibers from injections of an anterograde tracer in the rat ACC and OFC. Our results show that the descending PFC fibers in the rat form WM fascicles embedded within the striatum. These bundles are arranged topographically and contain projections, not only to the striatum, but also to the thalamus and brainstem. They can therefore be viewed as the rat homolog of the primate anterior limb of the internal capsule. Furthermore, mapping these projections allows us to identify the fibers likely to be affected by experimental manipulations of the striatum and the anterior limb of the internal capsule. These results are therefore essential for translating abnormalities of human WM and effects of DBS to rodent models.SIGNIFICANCE STATEMENT Psychiatric diseases are linked to abnormalities in specific white matter (WM) pathways, and the efficacy of deep-brain stimulation relies upon activation of WM. Experiments in rodents are necessary for studying the mechanisms of brain function. However, the translation of results between primates and rodents is hindered by the fact that the organization of descending WM in rodents is poorly understood. This is especially relevant for the prefrontal cortex, abnormal connectivity of which is central to psychiatric disorders. We address this gap by studying the organization of descending rodent prefrontal pathways. These fibers course through a subcortical structure, the striatum, and share important organization principles with primate WM. These results allow us to model primate WM effectively in the rodent.

The rat prefrontostriatal system analyzed in 3D: evidence for multiple interacting functional units.

Previous studies in monkeys disclosed a specific arrangement of corticostriatal projections. Prefrontal and premotor areas form dense projection fields surrounded by diffuse terminal areas extending outside the densely innervated region and overlapping with projections from other areas. In this study, the mode of prefrontostriatal innervation was analyzed in rats using a 3D approach. Following injections of tracers in defined cortical areas, 3D maps from individual cases were elaborated and combined into a global 3D map allowing us to define putative overlaps between projection territories. In addition to providing a detailed 3D mapping of the topographic representation of prefrontal cortical areas in the rat striatum, the results stress important similarities between the rodent and primate prefrontostriatal projections. They share the dual pattern of focal and diffuse corticostriatal projections. Moreover, besides segregated projections consistent with parallel processing, the interweaving of projection territories establishes specific patterns of overlaps spatially organized along the dorsoventral, mediolateral, and anteroposterior striatal axis. In particular, the extensive striatal projection fields from the prelimbic and anterior cingulate areas, which partly overlap the terminal fields from medial, orbital, and lateral prefrontal cortical areas, provide putative domains of convergence for integration between reward, cognitive, and motor processes.

Subthalamic nucleus high-frequency stimulation restores altered electrophysiological properties of cortical neurons in parkinsonian rat.

Electrophysiological recordings performed in parkinsonian patients and animal models have confirmed the occurrence of alterations in firing rate and pattern of basal ganglia neurons, but the outcome of these changes in thalamo-cortical networks remains unclear. Using rats rendered parkinsonian, we investigated, at a cellular level in vivo, the electrophysiological changes induced in the pyramidal cells of the motor cortex by the dopaminergic transmission interruption and further characterized the impact of high-frequency electrical stimulation of the subthalamic nucleus, a procedure alleviating parkinsonian symptoms. We provided evidence that a lesion restricted to the substantia nigra pars compacta resulted in a marked increase in the mean firing rate and bursting pattern of pyramidal neurons of the motor cortex. These alterations were underlain by changes of the electrical membranes properties of pyramidal cells including depolarized resting membrane potential and increased input resistance. The modifications induced by the dopaminergic loss were more pronounced in cortico-striatal than in cortico-subthalamic neurons. Furthermore, subthalamic nucleus high-frequency stimulation applied at parameters alleviating parkinsonian signs regularized the firing pattern of pyramidal cells and restored their electrical membrane properties.

Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine-induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits.

Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits.

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.

Integration and propagation of somatosensory responses in the corticostriatal pathway: an intracellular study in vivo.

The dorsolateral striatum is critically involved in the execution and learning of sensorimotor tasks. It is proposed that this striatal function is achieved by the integration of convergent somatosensory and motor corticostriatal (CS) inputs in striatal medium-spiny neurons (MSNs). However, the cellular mechanisms of integration and propagation of somatosensory information in the CS pathway remain unknown. Here, by means of in vivo intracellular recordings in the rat, we analysed how sensory events generated by multi-whisker deflection, which provide essential somaesthetic information in rodents, are processed in contralateral barrel cortex layer 5 neurons and in the related somatosensory striatal MSNs. Pyramidal layer 5 barrel cortex neurons, including neurons antidromically identified as CS, responded to whisker deflection by depolarizing post-synaptic potentials that could reliably generate action potential discharge. In contrast, only half of recorded somatosensory striatal MSNs displayed whisker-evoked synaptic depolarizations that were effective in eliciting action potentials in one-third of responding neurons. The remaining population of MSNs did not exhibit any detectable electrical events in response to whisker stimulation. The relative inconstancy of sensory-evoked responses in MSNs was due, at least in part, to a Cl(-)-dependent membrane conductance concomitant with the cortical inputs,which was probably caused by whisker-induced activation of striatal GABAergic interneurons. Our results suggest that the propagation of whisker-mediated sensory flow through the CS pathway results in a refinement of sensory information in the striatum, which might allow the selection of specific sets of MSNs that are functionally significant during a given somaesthetic-guided behaviour.

Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies.

Motor stereotypy is a key symptom of various disorders such as Tourette's syndrome and punding. Administration of nicotine or cholinesterase inhibitors is effective in treating some of these symptoms. However, the role of cholinergic transmission in motor stereotypy remains unknown. During strong cocaine-induced motor stereotypy, we showed earlier that increased dopamine release results in decreased acetylcholine release in the territory of the dorsal striatum related to the prefrontal cortex. Here, we investigated the role of striatal cholinergic transmission in the arrest of motor stereotypy. Analysis of N-methyl-d-aspartic acid-evoked release of dopamine and acetylcholine during declining intensity of motor stereotypy revealed a dissociation between dopamine and acetylcholine release. Whereas dopamine release remained increased, the inhibition of acetylcholine release decreased, mirroring the time course of motor stereotypy. Furthermore, pharmacological treatments restoring striatal acetylcholine release (raclopride, dopamine D2 antagonist; intraperitoneal or local injection in prefrontal territory of the dorsal striatum) rapidly stopped motor stereotypy. In contrast, pharmacological treatments that blocked the post-synaptic effects of acetylcholine (scopolamine, muscarinic antagonist; intraperitoneal or striatal local injection) or induced degeneration of cholinergic interneurons (AF64A, cholinergic toxin) in the prefrontal territory of the dorsal striatum robustly prolonged the duration of strong motor stereotypy. Thus, we propose that restoration of cholinergic transmission in the prefrontal territory of the dorsal striatum plays a key role in the arrest of motor stereotypy.

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.

Distinct coincidence detectors govern the corticostriatal spike timing-dependent plasticity.

Corticostriatal projections constitute the main input to the basal ganglia, an ensemble of interconnected subcortical nuclei involved in procedural learning. Thus, long-term plasticity at corticostriatal synapses would provide a basic mechanism for the function of basal ganglia in learning and memory. We had previously reported the existence of a corticostriatal anti-Hebbian spike timing-dependent plasticity (STDP) at synapses onto striatal output neurons, the medium-sized spiny neurons. Here, we show that the blockade of GABAergic transmission reversed the time dependence of corticostriatal STDP. We explored the receptors and signalling mechanisms involved in the corticostriatal STDP. Although classical models for STDP propose NMDA receptors as the unique coincidence detector, the involvement of multiple coincidence detectors has also been demonstrated. Here, we show that corticostriatal STDP depends on distinct coincidence detectors. Specifically, long-term potentiation is dependent on NMDA receptor activation, while long-term depression requires distinct coincidence detectors: the phospholipase Cbeta (PLCbeta) and the inositol-trisphosphate receptor (IP3R)-gated calcium stores. Furthermore, we found that PLCbeta activation is controlled by group-I metabotropic glutamate receptors, type-1 muscarinic receptors and voltage-sensitive calcium channel activities. Activation of PLCbeta and IP3Rs leads to robust retrograde endocannabinoid signalling mediated by 2-arachidonoyl-glycerol and cannabinoid CB1 receptors. Interestingly, the same coincidence detectors govern the corticostriatal anti-Hebbian STDP and the Hebbian STDP reported at cortical synapses. Therefore, LTP and LTD induced by STDP at corticostriatal synapses are mediated by independent signalling mechanisms, each one being controlled by distinct coincidence detectors.

A 3D multi-modal and multi-dimensional digital brain model as a framework for data sharing.

Computer based three-dimensional reconstruction and co-registration of experimental data provide powerful tools for integration of observation derived from various technical approaches leading to better understanding of brain functions. Here we describe a method to build a 3D multi-modal and multi-dimensional model of brain structures providing framework for data sharing. All image processing, registration and 3D reconstruction were performed using open source software IMOD package software and ImageJ. The reconstruction procedure is based on series of AChE and Nissl stained sections aligned to blockface pictures. Integration of experimental data into the reference model is achieved by co-registration of Nissl sections of experimental brain cases by positioning landmarks on corresponding anatomical structures. To overcome the challenge of comparing for experimental sections with those of the reference model, adjustment of experimental model to the brain model was done section by section and limited to the structures of interest. For this adjustment we stress the use of cytoarchitectural criteria for accurate registration of anatomical structures and co-registration procedures.

Cocaine-induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia.

The dysfunction of basal ganglia circuits related to stereotyped motor activity was analysed using the well-established model of cocaine-induced stereotypy in the rat. We examined and compared the neurochemical and electrophysiological effects occurring in medial prefrontal and sensorimotor basal ganglia circuits of the dorsal striatum after cocaine injection in sensitized and non-sensitized rats. Acute injections of cocaine (25 mg/kg), not inducing stereotyped behaviour, affected both medial prefrontal and sensorimotor circuits in a similar way: (i) a mild and delayed increase and decrease of N-methyl-D-aspartate-evoked dopamine and acetylcholine release, respectively and (ii) a marked decrease of cortically evoked inhibition of substantia nigra pars reticulata neurons revealing an imbalance of information transmission between the direct and indirect trans-striatal pathways. In contrast, following sensitization to cocaine, a challenge injection of the same dose of cocaine, generating strong stereotyped behaviour, provoked neurochemical and electrophysiological effects only in the medial prefrontal but not in the sensorimotor circuits: (i) a strong increase of dopamine and decrease of acetylcholine release in the medial prefrontal territory of the dorsal striatum and (ii) a reduction of all inhibitory and excitatory components of the responses evoked in substantia nigra pars reticulata by medial prefrontal stimulation. Therefore, these data disclose distinct reactivity of the medial prefrontal and sensorimotor circuits of the basal ganglia to repeated cocaine administration leading to stereotyped behaviour induced by subsequent cocaine challenge. Thus, we suggest that stereotyped behaviour is correlated to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia resulting in a loss of control of motor behaviour.

Brief subthreshold events can act as Hebbian signals for long-term plasticity.

BACKGROUND: Action potentials are thought to be determinant for the induction of long-term synaptic plasticity, the cellular basis of learning and memory. However, neuronal activity does not lead systematically to an action potential but also, in many cases, to synaptic depolarizing subthreshold events. This is particularly exemplified in corticostriatal information processing. Indeed, the striatum integrates information from the whole cerebral cortex and, due to the membrane properties of striatal medium spiny neurons, cortical inputs do not systematically trigger an action potential but a wide range of subthreshold postsynaptic depolarizations. Accordingly, we have addressed the following question: does a brief subthreshold event act as a Hebbian signal and induce long-term synaptic efficacy changes? METHODOLOGY/PRINCIPAL FINDINGS: Here, using perforated patch-clamp recordings on rat brain corticostriatal slices, we demonstrate, that brief (30 ms) subthreshold depolarizing events in quasi-coincidence with presynaptic activity can act as Hebbian signals and are sufficient to induce long-term synaptic plasticity at corticostriatal synapses. This "subthreshold-depolarization dependent plasticity" (SDDP) induces strong, significant and bidirectional long-term synaptic efficacy changes at a very high occurrence (81%) for time intervals between pre- and postsynaptic stimulations (Deltat) of -110

Assessment of bursting activity and interspike intervals variability: a case study for methodological comparison.

The detection and characterization of bursting activity remains a topic where no consensual definition has been reached so far. We compare here three different approaches of spike trains variability: statistical characterization (average frequency, coefficient of variation), burst detection (Poisson and rank surprise) and multi-scale analysis (detrended fluctuations analysis). Using both real and simulated data, we show that Poisson surprise provides information closely related to the coefficient of variation and that rank surprise detects significant bursts which are associated with long-range correlations. Since these long-range correlations are only adequately characterized with multi-scale analysis, this study emphasizes the complementarity of these approaches for the complete characterization of spike trains.

Striatal medium-sized spiny neurons: identification by nuclear staining and study of neuronal subpopulations in BAC transgenic mice.

Precise identification of neuronal populations is a major challenge in neuroscience. In the striatum, more than 95% of neurons are GABAergic medium-sized spiny neurons (MSNs), which form two intermingled populations distinguished by their projections and protein content. Those expressing dopamine D(1)-receptors (D1Rs) project preferentially to the substantia nigra pars reticulata (SNr), whereas those expressing dopamine D(2)- receptors (D2Rs) project preferentially to the lateral part of the globus pallidus (LGP). The degree of segregation of these populations has been a continuous subject of debate, and the recent introduction of bacterial artificial chromosome (BAC) transgenic mice expressing fluorescent proteins driven by specific promoters was a major progress to facilitate striatal neuron identification. However, the fraction of MSNs labeled in these mice has been recently called into question, casting doubt on the generality of results obtained with such approaches. Here, we performed an in-depth quantitative analysis of striatal neurons in drd1a-EGFP and drd2-EGFP mice. We first quantified neuronal and non-neuronal populations in the striatum, based on nuclear staining with TO-PRO-3, and immunolabeling for NeuN, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein Mr approximately 32,000), and various markers for interneurons. TO-PRO-3 staining was sufficient to identify MSNs by their typical nuclear morphology and, with a good probability, interneuron populations. In drd1a-EGFP/drd2-EGFP double transgenic mice all MSNs expressed EGFP, which was driven in about half of them by drd1a promoter. Retrograde labeling showed that all MSNs projecting to the SNr expressed D1R and very few D2R (<1%). In contrast, our results were compatible with the existence of some D1R-EGFP-expressing fibers giving off terminals in the LGP. Thus, our study shows that nuclear staining is a simple method for identifying MSNs and other striatal neurons. It also unambiguously confirms the degree of segregation of MSNs in the mouse striatum and allows the full exploitation of results obtained with BAC-transgenic mice.

Chronic but not acute dopaminergic transmission interruption promotes a progressive increase in cortical beta frequency synchronization: relationships to vigilance state and akinesia.

Dopaminergic (DA) denervation results in the appearance of an excessive cortical beta frequency synchronization in parkinsonian patients and animal models of the disease. The present study analyzed electrocorticogram signals in awake rats to further characterize this excessive synchronization in terms of time course, relation to motor activity and state of vigilance. Using substantia nigra pars compacta lesions and both acute and chronic pharmacological interruptions of DA transmission, the present data demonstrated that the appearance of excessive beta synchronization requires a prolonged interruption in DA transmission and builds up progressively. This synchronization was vigilance-state dependent and observed solely during awake-like activity. Furthermore, these data demonstrated for the first time that the appearance of akinesia preceded the excessive cortical beta synchronization. In addition, this synchronization was stronger in the motor than in the somato-sensory cortex and in unilaterally compared with bilaterally lesioned animals. Finally, excessive beta synchronization was accompanied by an increased coherence between motor and somato-sensory cortical activities. These data suggest that excessive beta synchronization is associated with plastic processes whose time course is delayed with respect to the akinesia. Moreover, the expression of this phenomenon, which likely reflects functional changes in the cortico-basal ganglia circuits, requires a specific brain state.

Evidence for a direct subthalamo-cortical loop circuit in the rat.

The subthalamic nucleus (STN), a major component of the basal ganglia (BG), plays a crucial role in motor activity and cognitive functions. In current models of the BG, the STN is considered to act by activating the gamma-aminobutyric acid (GABA)ergic neurons of the BG output nuclei, thus inhibiting their thalamic and brain stem targets. However, in addition to the BG output nuclei, the STN has also been reported to innervate the cerebral cortex and the striatum. Here, the anatomo-functional organization of STN projections to the cerebral cortex was investigated using anatomical and electrophysiological approaches. First, wheatgerm agglutinin-conjugated horseradish peroxidase was injected into defined areas of the cerebral cortex to analyse the spatial distribution of retrogradely labelled STN neurons. The mode of cortical innervation by the STN was then determined using extracellular deposits of Phaseolus vulgaris-leucoagglutinin into the STN. Finally, the functional organization of the cortico-STN relationships was investigated by extracellularly recording single STN units antidromically driven from the cerebral cortex. Our results indicate that STN innervates the sensory-motor and prefrontal cortices, the densest projections terminating in cortical layers I-III of the orofacial motor area. The matching between the topographic distribution of subthalamo-cortical neurons and cortico-subthalamic projections forms the basis of a functional cortico-STN loop circuit that is partially opened. In pathological situations such as Parkinson's disease and epilepsy, the STN-cortex loop circuit might contribute to propagate pathological oscillations favouring the emergence of abnormal synchronized activities and a loss of functional selectivity in the cortico-BG network.

Chemical transmission between dopaminergic neuron pairs.

Midbrain dopaminergic (DAergic) neurons play a major regulatory role in in goal-directed behavior and reinforcement learning. DAergic neuron activity, and therefore spatiotemporal properties of dopamine release, precisely encodes reward signals. Neuronal activity is shaped both by external afferences and local interactions (chemical and electrical transmissions). Numerous hints suggest the existence of chemical interactions between DAergic neurons, but direct evidence and characterization are still lacking. Here, we show, using dual patch-clamp recordings in rat brain slices, a widespread bidirectional chemical transmission between DAergic neuron pairs. Hyperpolarizing postsynaptic potentials were partially mediated by D2-like receptors, and entirely resulted from the inhibition of the hyperpolarization-activated depolarizing current (Ih). These results constitute the first evidence in paired recordings of a chemical transmission relying on conductance decrease in mammals. In addition, we show that chemical transmission and electrical synapses frequently coexist within the same neuron pair and dynamically interact to shape DAergic neuron activity.

Three-dimensional organization of dendrites and local axon collaterals of shell and core medium-sized spiny projection neurons of the rat nucleus accumbens.

Medium-sized spiny projection neurons (MSN) in the head of the primate caudate nucleus are thought to have preferred dendritic orientations that tend to parallel the orientations of the striosomes. Moreover, recurrent axon collaterals of MSN in the rat dorsal striatum have been categorized into two types, i.e., restricted and widespread. The nucleus accumbens (Acb) has a highly complex compartmental organization, and the spatial organization of dendritic and axonal arbors of MSN has not yet been systematically studied. In this study, using single-cell juxtacellular labeling with neurobiotin as well as anterograde neuroanatomical tracing with biotinylated dextran amine, we investigated the three-dimensional (3D) organization of dendrites and axons of MSN of the rat Acb in relation to subregional (shell-core) and compartmental (patch-matrix) boundaries. Our results show that dendritic arbors of MSN in both the Acb shell and core subregions are preferentially oriented, i.e., they are flattened in at least one of the 3D-planes. The preferred orientations are influenced by shell-core and patch-matrix boundaries, suggesting parallel and independent processing of information. Dendritic orientations of MSN of the Acb core are more heterogeneous than those of the shell and the dorsal striatum, suggesting a more complex distribution of striatal inputs within the core. Although dendrites respect the shell-core and patch-matrix boundaries, recurrent axon collaterals may cross these boundaries. Finally, different degrees of overlap between dendritic and axonal arborizations of individual MSN were identified, suggesting various possibilities of lateral inhibitory interactions within and between, functionally distinct territories of the Acb.

Cell-specific spike-timing-dependent plasticity in GABAergic and cholinergic interneurons in corticostriatal rat brain slices.

Striatum, the main input nucleus of basal ganglia, is involved in the learning of cognitive and motor sequences in response to environmental stimuli. Striatal output neurons (medium spiny neurons, MSNs) integrate cortical activity and the two main classes of interneurons (GABAergic and cholinergic interneurons) tightly regulate the corticostriatal information transfer. We have explored the transmission between cortex and striatal interneurons and their capability to develop activity-dependent long-term plasticity based on the quasi-coincident cortical and striatal activities (spike-timing-dependent plasticity, STDP). We have observed glutamatergic monosynaptic connections between cortical cells and both striatal interneurons. Excitatory postsynaptic current latencies and rise times revealed that a cortical stimulation activates GABAergic interneurons before cholinergic, and both interneurons before MSNs. In addition, we have observed that striatal interneurons are able to develop bidirectional long-term plasticity and that there is a cell-specificity of STDP among striatal interneurons. Indeed, in GABAergic interneurons, long-term depression (LTD) and long-term potentiation (LTP) are induced by post-pre and pre-post STDP protocols, respectively. Cholinergic interneurons displayed a partially reversed STDP when compared to GABAergic interneurons: post-pre protocols induced LTP as well as LTD (the induction of either LTP or LTD is correlated with rheobase) and pre-post protocols induced LTD. The cell-specificity of STDP also concerned the receptors activated for the induction of LTP and LTD in GABAergic and cholinergic interneurons: in GABAergic interneurons LTP and LTD required NMDA receptor-activation whereas, in cholinergic interneurons, LTP was underlain by NMDA receptor-activation and LTD by metabotropic glutamate receptors.