Interactions of glutamate and dopamine in a computational model of the striatum

A network model of simplified striatal principal neurons with mutual inhibition was used to investigate possible interactions between cortical glutamatergic and nigral dopaminergic afferents in the neostriatum. Glutamatergic and dopaminergic inputs were represented by an excitatory synaptic conductance and a slow membrane potassium conductance, respectively. Neuronal activity in the model was characterized by episodes of increased action potential firing rates of variable duration and frequency. Autocorrelation histograms constructed from the action potential activity of striatal model neurons showed that reducing peak excitatory conductance had the effect of increasing interspike intervals. On the other hand, the maximum value of the dopamine-sensitive potassium conductance was inversely related to the duration of firing episodes and the maximal firing rates. A smaller potassium conductance restored normal firing rates in the most active neurons at the expense of a larger proportion of neurons showing reduced activity. Thus, a homogeneous network with mutual inhibition can produce equally complex dynamics as have been proposed to occur in a striatal network with two neuron populations that are oppositely regulated by dopamine. Even without mutual inhibition it appears that increased dopamine concentrations could partially compensate for the effects of reduced glutamatergic input in individual neurons.     

Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity.     

Severely impaired learning and altered neuronal morphology in mice lacking NMDA receptors in medium spiny neurons

The striatum is composed predominantly of medium spiny neurons (MSNs) that integrate excitatory, glutamatergic inputs from the cortex and thalamus, and modulatory dopaminergic inputs from the ventral midbrain to influence behavior. Glutamatergic activation of AMPA, NMDA, and metabotropic receptors on MSNs is important for striatal development and function, but the roles of each of these receptor classes remain incompletely understood. Signaling through NMDA-type glutamate receptors (NMDARs) in the striatum has been implicated in various motor and appetitive learning paradigms. In addition, signaling through NMDARs influences neuronal morphology, which could underlie their role in mediating learned behaviors. To study the role of NMDARs on MSNs in learning and in morphological development, we generated mice lacking the essential NR1 subunit, encoded by the Grin1 gene, selectively in MSNs. Although these knockout mice appear normal and display normal 24-hour locomotion, they have severe deficits in motor learning, operant conditioning and active avoidance. In addition, the MSNs from these knockout mice have smaller cell bodies and decreased dendritic length compared to littermate controls. We conclude that NMDAR signaling in MSNs is critical for normal MSN morphology and many forms of learning.     

Long-term potentiation of excitatory inputs to brain reward areas by nicotine

Nicotine reinforces smoking behavior by activating nicotinic acetylcholine receptors (nAChRs) in the midbrain dopaminergic (DA) reward centers, including the ventral tegmental area (VTA). Although nicotine induces prolonged excitation of the VTA in vivo, the nAChRs on the DA neurons desensitize in seconds. Here, we show that activation of nAChRs on presynaptic terminals in the VTA enhances glutamatergic inputs to DA neurons. Under conditions where the released glutamate can activate NMDA receptors, long-term potentiation (LTP) of the excitatory inputs is induced. Both the short- and the long-term effects of nicotine required activation of presynaptic alpha7 subunit-containing nAChRs. These results can explain the long-term excitation of brain reward areas induced by a brief nicotine exposure. They also show that nicotine alters synaptic function through mechanisms that are linked to learning and memory.     

Conditional Knockout of NMDA Receptors in Dopamine Neurons Prevents Nicotine-Conditioned Place Preference

Nicotine from smoking tobacco produces one of the most common forms of addictive behavior and has major societal and health consequences. It is known that nicotine triggers tobacco addiction by activating nicotine acetylcholine receptors (nAChRs) in the midbrain dopaminergic reward system, primarily via the ventral tegmental area. Heterogeneity of cell populations in the region has made it difficult for pharmacology-based analyses to precisely assess the functional significance of glutamatergic inputs to dopamine neurons in nicotine addiction. By generating dopamine neuron-specific NR1 knockout mice using cre/loxP-mediated method, we demonstrate that genetic inactivation of the NMDA receptors in ventral tegmental area dopamine neurons selectively prevents nicotine-conditioned place preference. Interestingly, the mutant mice exhibit normal performances in the conditioned place aversion induced by aversive air puffs. Therefore, this selective effect on addictive drug-induced reinforcement behavior suggests that NMDA receptors in the dopamine neurons are critical for the development of nicotine addiction.     

Dissociable reward and timing signals in human midbrain and ventral striatum

Reward prediction error (RPE) signals are central to current models of reward-learning. Temporal difference (TD) learning models posit that these signals should be modulated by predictions, not only of magnitude but also timing of reward. Here we show that BOLD activity in the VTA conforms to such TD predictions: responses to unexpected rewards are modulated by a temporal hazard function and activity between a predictive stimulus and reward is depressed in proportion to predicted reward. By contrast, BOLD activity in ventral striatum (VS) does not reflect a TD RPE, but instead encodes a signal on the variable relevant for behavior, here timing but not magnitude of reward. The results have important implications for dopaminergic models of cortico-striatal learning and suggest a modification of the conventional view that VS BOLD necessarily reflects inputs from dopaminergic VTA neurons signaling an RPE.     

The short-latency dopamine signal: a role in discovering novel actions?

An influential concept in contemporary computational neuroscience is the reward prediction error hypothesis of phasic dopaminergic function. It maintains that midbrain dopaminergic neurons signal the occurrence of unpredicted reward, which is used in appetitive learning to reinforce existing actions that most often lead to reward. However, the availability of limited afferent sensory processing and the precise timing of dopaminergic signals suggest that they might instead have a central role in identifying which aspects of context and behavioural output are crucial in causing unpredicted events.     

Spatio-temporal convergence (STC) in otolith neurons

It has been recently demonstrated that some primary otolith afferents and most otolith-related vestibular nuclei neurons encode two spatial dimensions that can be described by two vectors in temporal and spatial quadrature. These cells are called broadly-tuned neurons. They are characterized by a non-zero tuning ratio which is defined as the ratio of the minimum over the maximum sensitivity of the neuron. Broadly-tuned neurons exhibit response gains that do not vary according to the cosine of the angle between the stimulus direction and the cell's maximum sensitivity vector and response phase values that depend on stimulus orientation. These responses were observed during stimulation with pure linear acceleration and can be explained by spatio-temporal convergence (STC) of primary otolith afferents and/or otolith hair cells. Simulations of STC of the inputs to primary otolith afferents and vestibular nuclei neurons have revealed interesting characteristics: First, in the case of two narrowly-tuned input signals, the largest tuning ratio is achieved when the input signals are of equal gain. The smaller the phase difference between the input vectors, the larger the orientation differences that are required to produce a certain tuning ratio. Orientation and temporal phase differences of 30–40° create tuning ratios of approximately 0.10–0.15 in target neurons. Second, in the case of multiple input signals, the larger the number of converging inputs, the smaller the tuning ratio of the target neuron. The tuning ratio depends on the number of input units, as long as there are not more than about 10. For more than 10–20 input vectors, the tuning ratio becomes almost independent of the number of inputs. Further, if the inputs comprise two populations (with different gain and phase values at a given stimulus frequency), the largest tuning ratio is obtained when the larger population has a smaller gain. These findings are discussed in the context of known anatomical and physiological characteristics of innervation patterns of primary otolith afferents and their possible convergence onto vestibular nuclei neurons.     

Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice

Degeneration of medium spiny GABA neurons in the basal ganglia underlies motor dysfunction in Huntington's disease (HD), which presently lacks effective therapy. In this study, we have successfully directed human embryonic stem cells (hESCs) to enriched populations of DARPP32-expressing forebrain GABA neurons. Transplantation of these human forebrain GABA neurons and their progenitors, but not spinal GABA cells, into the striatum of quinolinic acid-lesioned mice results in generation of large populations of DARPP32(+) GABA neurons, which project to the substantia nigra as well as receiving glutamatergic and dopaminergic inputs, corresponding to correction of motor deficits. This finding raises hopes for cell therapy for HD.     

A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells.     

Regulation of motor behaviour

The review is devoted to analysis of the basic links of motor behavior control systems: sensorimotor cortex, cerebellum, a red nucleus and striatum. The organization and communications of these structures and their participation in learning and memory processes are described. The synaptic neurotransmitter and nonsynaptic neuromodulatory systems innervating these structures are also described. Hierarchical synaptic networks are formed by GABA and glutamatergic systems. The nonsynaptic dopaminergic system innervates both of these structures, but carries out a modulatory function. The mesocorticolimbic dopaminergic system induces an emotional and motivational state - processes of reinforcement, and participates in realization of purposeful behavior. The nigrostriatal dopaminergic system, through triggering an endocellular signal and the processes ofphosphorylation and dephosphorylation modulates activity ofGABA and glutamatergic receptors ofdorsal striatum spiny neurons and adapted thalamocortical networks.     

Further contribution to the study of corticostriatal glutamatergic and nigrostriatal dopaminergic interactions within the striatal network: an in vivo voltammetric investigation

Summary In vivo voltammetry was used in freely moving rats to study the processes whereby striatal dopamine (DA) release is regulated by corticostriatal glutamatergic neurons. Electrical stimulation of the cerebral cortex was found to markedly increase the striatal DA-related voltammetric signal amplitude. Similar enhancements have been observed after intracerebroventricular administration of 10nmoles glutamate, quisqualate and AMPA, whereas NMDA was found to decrease the amplitude of the striatal signals. The NMDA receptor antagonist APV did not significantly affect the voltammetric signal but prevented the NMDA-induced depression of the DA-related signals. These data are in agreement with those obtained in numerous previous studies suggesting that the glutamatergic corticostriatal neurons exert activatory effects on the striatal DA release via non-NMDA receptors. The mechanism involved might be of a presynaptic nature. The role of the NMDA receptors may however consist of modulating the dopaminergic transmission phasically and in a depressive way, which would be consistent with behavioural data suggesting the existence of a functional antagonism between the activity of the corticostriatal glutamatergic and nigrostriatal dopaminergic systems.Abbreviations Glu glutamate - DA dopamine - NMDA N-methyl-D-aspartate - CPP 3-(2-carboxypiperazin-4µl)propyl-1-phosphonic acid - AMPA -amino-3-hydroxy-5-metylisoxazole-4-propionic acid - APV aminophosphonovaleric acid - DOPAC dihydroxyphenylacetic acid - HVA homovanillic acid - DARPP 32 dopamine-cAMP-regulated phosphoprotein 32 - CSF cerebrospinal fluid Laboratory associated with the University of Aix-Marseille II     

Gamma neurons mediate dopaminergic input during aversive olfactory memory formation in Drosophila

Mushroom body (MB)-dependent olfactory learning in Drosophila provides a powerful model to investigate memory mechanisms. MBs integrate olfactory conditioned stimulus (CS) inputs with neuromodulatory reinforcement (unconditioned stimuli, US), which for aversive learning is thought to rely on dopaminergic (DA) signaling to DopR, a D1-like dopamine receptor expressed in MBs. A wealth of evidence suggests the conclusion that parallel and independent signaling occurs downstream of DopR within two MB neuron cell types, with each supporting half of memory performance. For instance, expression of the Rutabaga (Rut) adenylyl cyclase in γ neurons is sufficient to restore normal learning to rut mutants, whereas expression of Neurofibromatosis 1 (NF1) in α/β neurons is sufficient to rescue NF1 mutants. DopR mutations are the only case where memory performance is fully eliminated, consistent with the hypothesis that DopR receives the US inputs for both γ and α/β lobe traces. We demonstrate, however, that DopR expression in γ neurons is sufficient to fully support short- and long-term memory. We argue that DA-mediated CS-US association is formed in γ neurons followed by communication between γ and α/β neurons to drive consolidation.     

Neural network models of velocity storage in the horizontal vestibulo-ocular reflex

The vestibulo-ocular reflex (VOR) produces compensatory eye movements by utilizing head rotational velocity signals from the semicircular canals to control contractions of the extraocular muscles. In mammals, the time course of horizontal VOR is longer than that of the canal signals driving it, revealing the presence of a central integrator known as velocity storage. Although the neurons mediating VOR have been described neurophysiologically, their properties, and the mechanism of velocity storage itself, remain unexplained. Recent models of integration in VOR are based on systems of linear elements, interconnected in arbitrary ways. The present study extends this work by modeling horizontal VOR as a learning network composed of nonlinear model neurons. Network architectures are based on the VOR arc (canal afferents, vestibular nucleus (VN) neurons and extraocular motoneurons) and have both forward and lateral connections. The networks learn to produce velocity storage integration by forming lateral (commissural) inhibitory feedback loops between VN neurons. These loops overlap and interact in a complex way, forming both fast and slow VN pathways. The networks exhibit some of the nonlinear properties of the actual VOR, such as dependency of decay rate and phase lag upon input magnitude, and skewing of the response to higher magnitude sinusoidal inputs. Model VN neurons resemble their real counterparts. Both have increased time constant and gain, and decreased spontaneous rate as compared to canal afferents. Also, both model and real VN neurons exhibit rectification and skew. The results suggest that lateral inhibitory interactions produce velocity storage and also determine the properties of neurons mediating VOR. The neural network models demonstrate how commissural inhibition may be organized along the VOR pathway.     

Integration of Sensory Quanta in Cuneate Nucleus Neurons In Vivo

Discriminative touch relies on afferent information carried to the central nervous system by action potentials (spikes) in ensembles of primary afferents bundled in peripheral nerves. These sensory quanta are first processed by the cuneate nucleus before the afferent information is transmitted to brain networks serving specific perceptual and sensorimotor functions. Here we report data on the integration of primary afferent synaptic inputs obtained with in vivo whole cell patch clamp recordings from the neurons of this nucleus. We find that the synaptic integration in individual cuneate neurons is dominated by 4–8 primary afferent inputs with large synaptic weights. In a simulation we show that the arrangement with a low number of primary afferent inputs can maximize transfer over the cuneate nucleus of information encoded in the spatiotemporal patterns of spikes generated when a human fingertip contact objects. Hence, the observed distributions of synaptic weights support high fidelity transfer of signals from ensembles of tactile afferents. Various anatomical estimates suggest that a cuneate neuron may receive hundreds of primary afferents rather than 4–8. Therefore, we discuss the possibility that adaptation of synaptic weight distribution, possibly involving silent synapses, may function to maximize information transfer in somatosensory pathways.     

TRPV1 marks synaptic segregation of multiple convergent afferents at the rat medial solitary tract nucleus

TRPV1 receptors are expressed on most but not all central terminals of cranial visceral afferents in the caudal solitary tract nucleus (NTS). TRPV1 is associated with unmyelinated C-fiber afferents. Both TRPV1+ and TRPV1- afferents enter NTS but their precise organization remains poorly understood. In horizontal brainstem slices, we activated solitary tract (ST) afferents and recorded ST-evoked glutamatergic excitatory synaptic currents (ST-EPSCs) under whole cell voltage clamp conditions from neurons of the medial subnucleus. Electrical shocks to the ST produced fixed latency EPSCs (jitter<200 μs) that identified direct ST afferent innervation. Graded increases in shock intensity often recruited more than one ST afferent and ST-EPSCs had consistent threshold intensity, latency to onset, and unique EPSC waveforms that characterized each unitary ST afferent contact. The TRPV1 agonist capsaicin (100 nM) blocked the evoked TRPV1+ ST-EPSCs and defined them as either TRPV1+ or TRPV1- inputs. No partial responses to capsaicin were observed so that in NTS neurons that received one or multiple (2-5) direct ST afferent inputs--all were either blocked by capsaicin or were unaltered. Since TRPV1 mediates asynchronous release following TRPV1+ ST-evoked EPSCs, we likewise found that recruiting more than one ST afferent further augmented the asynchronous response and was eliminated by capsaicin. Thus, TRPV1+ and TRPV1- afferents are completely segregated to separate NTS neurons. As a result, the TRPV1 receptor augments glutamate release only within unmyelinated afferent pathways in caudal medial NTS and our work indicates a complete separation of C-type from A-type afferent information at these first central neurons.     

Ventral migration of early-born neurons requires Dcc and is essential for the projections of primary afferents in the spinal cord

Neuronal migration and lamina-specific primary afferent projections are crucial for establishing spinal cord circuits, but the underlying mechanisms are poorly understood. Here, we report that in mice lacking Dcc (deleted in colorectal cancer), some early-born neurons could not migrate ventrally in the spinal cord. Conversely, forced expression of Dcc caused ventral migration and prevented dorsolateral migration of late-born spinal neurons. In the superficial layer of the spinal cord of Dcc-/- mutants, mislocalized neurons are followed by proprioceptive afferents, while their presence repels nociceptive afferents through Sema3a. Thus, our study has shown that Dcc is a key molecule required for ventral migration of early-born neurons, and that appropriate neuronal migration is a prerequisite for, and coupled to, normal projections of primary afferents in the developing spinal cord.     

mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions.     

Intranuclear coupling of hypothalamic magnocellular nuclei by glutamate synaptic circuits

Magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) display bursting activity that is synchronized under certain conditions. They receive excitatory synaptic inputs from intrahypothalamic glutamate circuits, some of which are activated by norepinephrine. Ascending noradrenergic afferents and intrahypothalamic glutamate circuits may be responsible for the generation of synchronous bursting among oxytocin neurons and/or asynchronous bursting among vasopressin neurons located in the bilateral supraoptic and paraventricular nuclei. Here, we tested whether magnocellular neurons of the PVN receive excitatory synaptic input from the contralateral PVN and the region of the retrochiasmatic SON (SONrx) via norepinephrine-sensitive internuclear glutamate circuits. Whole cell patch-clamp recordings were performed in PVN magnocellular neurons in coronal hypothalamic slices from male rats, and the ipsilateral SONrx region and contralateral PVN were stimulated using electrical and chemical stimulation. Electrical and glutamate microdrop stimulation of the ipsilateral SONrx region or contralateral PVN elicited excitatory postsynaptic potentials/currents (EPSP/Cs) in PVN magnocellular neurons mediated by glutamate release, revealing internuclear glutamatergic circuits. Microdrop application of norepinephrine also elicited EPSP/Cs, suggesting that these circuits could be activated by activation of noradrenergic receptors. Repetitive electrical stimulation and drop application of norepinephrine, in some cases, elicited bursts of action potentials. Our data reveal glutamatergic synaptic circuits that interconnect the magnocellular nuclei and that can be activated by norepinephrine. These internuclear glutamatergic circuits may provide the functional architecture to support burst generation and/or burst synchronization in hypothalamic magnocellular neurons under conditions of activation.     

Excitatory glutamate is essential for development and maintenance of the piloneural mechanoreceptor

The piloneural collar in mammalian hairy skin comprises an intricate pattern of circumferential and longitudinal sensory afferents that innervate primary and secondary pelage hairs. The longitudinal afferents tightly associate with terminal Schwann cell processes to form encapsulated lanceolate nerve endings of rapidly adapting mechanoreceptors. The molecular basis for piloneural development, maintenance and function is poorly understood. Here, we show that Nefh-expressing glutamatergic neurons represent a major population of longitudinal and circumferential sensory afferents innervating the piloneural collar. Our findings using a VGLUT2 conditional-null mouse model indicate that glutamate is essential for innervation, patterning and differentiation of NMDAR(+) terminal Schwann cells during piloneural collar development. Similarly, treatment of adult mice with a selective NMDAR antagonist severely perturbed piloneural collar structure and reduced excitability of these mechanosensory neurons. Collectively, these results show that DRG-derived glutamate is essential for the proper development, maintenance and sensory function of the piloneural mechanoreceptor.