Neuronal implementation of the temporal difference learning algorithm in the midbrain dopaminergic system.

The temporal difference learning (TDL) algorithm has been essential to conceptualizing the role of dopamine in reinforcement learning (RL). Despite its theoretical importance, it remains unknown whether a neuronal implementation of this algorithm exists in the brain. Here, we provide an interpretation of the recently described signaling properties of ventral tegmental area (VTA) GABAergic neurons and show that a circuitry of these neurons implements the TDL algorithm. Specifically, we identified the neuronal mechanism of three key components of the TDL model: a sustained state value signal encoded by an afferent input to the VTA, a temporal differentiation circuit formed by two types of VTA GABAergic neurons the combined output of which computes momentary reward prediction (RP) as the derivative of the state value, and the computation of reward prediction errors (RPEs) in dopamine neurons utilizing the output of the differentiation circuit. Using computational methods, we also show that this mechanism is optimally adapted to the biophysics of RPE signaling in dopamine neurons, mechanistically links the emergence of conditioned reinforcement to RP, and can naturally account for the temporal discounting of reinforcement. Elucidating the implementation of the TDL algorithm may further the investigation of RL in biological and artificial systems.

A Selective Projection from the Subthalamic Nucleus to Parvalbumin-Expressing Interneurons of the Striatum.

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomic evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we conducted monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (∼4- to 8-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

Loss of striatal tyrosine-hydroxylase interneurons impairs instrumental goal-directed behavior.

The striatum mediates a broad range of cognitive and motor functions. Within the striatum, recently discovered tyrosine hydroxylase expressing interneurons (THINs) provide a source of intrastriatal synaptic connectivity that is critical for regulating striatal activity, yet the role of THIN's in behavior remains unknown. Given the important role of the striatum in reward-based behaviors, we investigated whether loss of striatal THINs would impact instrumental behavior in mice. We selectively ablated striatal THINs in TH-Cre mice using chemogenetic techniques, and then tested THIN-lesioned or control mice on three reward-based striatal-dependent instrumental tests: (a) progressive ratio test; (b) choice test following selective-satiety induced outcome devaluation; (c) outcome reinstatement test. Both striatal-THIN-lesioned and control mice acquired an instrumental response for flavored food pellets, and their behavior did not differ in the progressive ratio test, suggesting intact effort to obtain rewards. However, striatal THIN lesions markedly impaired choice performance following selective-satiety induced outcome devaluation. Unlike control mice, THIN-lesioned mice did not adjust their choice of actions following a change in outcome value. In the outcome reinstatement test THIN-lesioned and control mice showed response invigoration by outcome presentation, suggesting the incentive properties of outcomes were not disrupted by THIN lesions. Overall, we found that striatal THIN lesions selectively impaired goal-directed behavior, while preserving motoric and appetitive behaviors. These findings are the first to describe a function of striatal THINs in reward-based behavior, and further illustrate the important role for intrastriatal interneuronal connectivity in behavioral functions ascribed to the striatum more generally.

Heterogeneity and Diversity of Striatal GABAergic Interneurons: Update 2018.

Our original review, "Heterogeneity and Diversity of Striatal GABAergic Interneurons," to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades' worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre-driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons.

Differential processing of thalamic information via distinct striatal interneuron circuits.

Recent discoveries of striatal GABAergic interneurons require a new conceptualization of the organization of intrastriatal circuitry and their cortical and thalamic inputs. We investigated thalamic inputs to the two populations of striatal neuropeptide Y (NPY) interneurons, plateau low threshold spike (PLTS) and NPY-neurogliaform (NGF) cells. Optogenetic activation of parafascicular inputs evokes suprathreshold monosynaptic glutamatergic excitation in NGF interneurons and a disynaptic, nicotinic excitation through cholinergic interneurons. In contrast, the predominant response of PLTS interneurons is a disynaptic inhibition dependent on thalamic activation of striatal tyrosine hydroxylase interneurons (THINs). In contrast, THINs do not innervate NGF or fast spiking interneurons, showing significant specificity in THINs outputs. Chemospecific ablation of THINs impairs prepulse inhibition of the acoustic startle response suggesting an important behavioural role of this disynaptic pathway. Our findings demonstrate that the impact of the parafascicular nucleus on striatal activity and some related behaviour critically depend on synaptic interactions within interneuronal circuits.

Neostriatal GABAergic Interneurons Mediate Cholinergic Inhibition of Spiny Projection Neurons.

UNLABELLED: Synchronous optogenetic activation of striatal cholinergic interneurons ex vivo produces a disynaptic inhibition of spiny projection neurons composed of biophysically distinct GABAAfast and GABAAslow components. This has been shown to be due, at least in part, to activation of nicotinic receptors on GABAergic NPY-neurogliaform interneurons that monosynaptically inhibit striatal spiny projection neurons. Recently, it has been proposed that a significant proportion of this inhibition is actually mediated by activation of presynaptic nicotinic receptors on nigrostriatal terminals that evoke GABA release from the terminals of the dopaminergic nigrostriatal pathway. To disambiguate these the two mechanisms, we crossed mice in which channelrhodopsin is endogenously expressed in cholinergic neurons with Htr3a-Cre mice, in which Cre is selectively targeted to several populations of striatal GABAergic interneurons, including the striatal NPY-neurogliaform interneuron. Htr3a-Cre mice were then virally transduced to express halorhodopsin to allow activation of channelrhodopsin and halorhodopsin, individually or simultaneously. Thus we were able to optogenetically disconnect the interneuron-spiny projection neuron (SPN) cell circuit on a trial-by-trial basis. As expected, optogenetic activation of cholinergic interneurons produced inhibitory currents in SPNs. During simultaneous inhibition of GABAergic interneurons with halorhodopsin, we observed a large, sometimes near complete reduction in both fast and slow components of the cholinergic-evoked inhibition, and a delay in IPSC latency. This demonstrates that the majority of cholinergic-evoked striatal GABAergic inhibition is derived from GABAergic interneurons. These results also reinforce the notion that a semiautonomous circuit of striatal GABAergic interneurons is responsible for transmitting behaviorally relevant cholinergic signals to spiny projection neurons. SIGNIFICANCE STATEMENT: The circuitry between neurons of the striatum has been recently described to be far more complex than originally imagined. One example of this phenomenon is that striatal cholinergic interneurons have been shown to provide intrinsic nicotinic excitation of local GABAergic interneurons, which then inhibit the projection neurons of the striatum. As deficits of cholinergic interneurons are reported in patients with Tourette syndrome, the normal functions of these interneurons are of great interest. Whether this novel route of nicotinic input constitutes a major output of cholinergic interneurons remains unknown. The study addressed this question using excitatory and inhibitory optogenetic technology, so that cholinergic interneurons could be selectively activated and GABAergic interneurons selectively inhibited to determine the causal relationship in this circuit.

Are striatal tyrosine hydroxylase interneurons dopaminergic?

Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH-Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)-TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP-TH interneurons. Optogenetic activation of striatal EGFP-TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons.

Dopaminergic and cholinergic modulation of striatal tyrosine hydroxylase interneurons.

The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2015). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THIS responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia.

Novel fast adapting interneurons mediate cholinergic-induced fast GABAA inhibitory postsynaptic currents in striatal spiny neurons.

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor-mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism, only one such cell type, the neuropeptide-Y-expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre-expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor-mediated inhibitory postsynaptic current responses. The nicotinic receptor-mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli.

Diode probes for spatiotemporal optical control of multiple neurons in freely moving animals.

Neuronal control with high temporal precision is possible with optogenetics, yet currently available methods do not enable to control independently multiple locations in the brains of freely moving animals. Here, we describe a diode-probe system that allows real-time and location-specific control of neuronal activity at multiple sites. Manipulation of neuronal activity in arbitrary spatiotemporal patterns is achieved by means of an optoelectronic array, manufactured by attaching multiple diode-fiber assemblies to high-density silicon probes or wire tetrodes and implanted into the brains of animals that are expressing light-responsive opsins. Each diode can be controlled separately, allowing localized light stimulation of neuronal activators and silencers in any temporal configuration and concurrent recording of the stimulated neurons. Because the only connections to the animals are via a highly flexible wire cable, unimpeded behavior is allowed for circuit monitoring and multisite perturbations in the intact brain. The capacity of the system to generate unique neural activity patterns facilitates multisite manipulation of neural circuits in a closed-loop manner and opens the door to addressing novel questions.

GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons.

Neostriatal cholinergic interneurons are believed to be important for reinforcement-mediated learning and response selection by signaling the occurrence and motivational value of behaviorally relevant stimuli through precisely timed multiphasic population responses. An important problem is to understand how these signals regulate the functioning of the neostriatum. Here we describe the synaptic organization of a previously unknown circuit that involves direct nicotinic excitation of several classes of GABAergic interneurons, including neuroptide Y-expressing neurogilaform neurons, and enables cholinergic interneurons to exert rapid inhibitory control of the activity of projection neurons. We also found that, in vivo, the dominant effect of an optogenetically reproduced pause-excitation population response of cholinergic interneurons was powerful and rapid inhibition of the firing of projection neurons that is coincident with synchronous cholinergic activation. These results reveal a previously unknown circuit mechanism that transmits reinforcement-related information of ChAT interneurons in the mouse neostriatal network.

A novel functionally distinct subtype of striatal neuropeptide Y interneuron.

We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic GFP (green fluorescent protein)-NPY reporter mice. In vitro whole-cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical, and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, nonaccommodating spiking in response to depolarizing current injections, and an absence of plateau depolarizations or low-threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense, compact, and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Furthermore, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPNs) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABA(A) receptor-mediated IPSC that has not been previously described in striatum but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the neostriatum.

Glutamatergic signaling by midbrain dopaminergic neurons: recent insights from optogenetic, molecular and behavioral studies.

Although the notion that dopaminergic neurons utilize glutamate as a co-transmitter has long been supported by tantalizing molecular, immunocytochemical and electrophysiological evidence it has only been with the recent addition of optogenetic and other approaches that the existence and functional relevance of this mechanism could be unambiguously demonstrated. Here we discuss the possible mechanisms of action of glutamate released from mesoaccumbens dopaminergic neurons based on recently accumulated evidence. Surprisingly, rather then to confirm a role in conventional fast excitatory transmission, the latest evidence suggests that glutamate released from dopaminergic neurons may primarily act through different unconventional presynaptic and postsynaptic mechanisms.

Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum.

Whole-cell recordings were obtained from tyrosine hydroxylase-expressing (TH(+)) neurons in striatal slices from bacterial artificial chromosome transgenic mice that synthesize enhanced green fluorescent protein (EGFP) selectively in neurons expressing TH transcriptional regulatory sequences. Stereological cell counting indicated that there were approximately 2700 EGFP-TH(+) neurons/striatum. Whole-cell recordings in striatal slices demonstrated that EGFP-TH(+) neurons comprise four electrophysiologically distinct neuron types whose electrophysiological properties have not been reported previously in striatum. EGFP-TH(+) neurons were identified in retrograde tracing studies as interneurons. Recordings from synaptically connected pairs of EGFP-TH(+) interneurons and spiny neurons showed that the interneurons elicited GABAergic IPSPs/IPSCs in spiny neurons powerful enough to significantly delay evoked spiking. EGFP-TH(+) interneurons responded to local or cortical stimulation with glutamatergic EPSPs. Local stimulation also elicited GABA(A) IPSPs, at least some of which arose from identified spiny neurons. Single-cell reverse transcription-PCR showed expression of VMAT1 in EGFP-TH(+) interneurons, consistent with previous suggestions that these interneurons may be dopaminergic as well as GABAergic. All four classes of interneurons were medium sized with modestly branching, varicose dendrites, and dense, highly varicose axon collateral fields. These data show for the first time that there exists in the normal rodent striatum a substantial population of TH(+)/GABAergic interneurons comprising four electrophysiologically distinct subtypes whose electrophysiological properties differ significantly from those of previously described striatal GABAergic interneurons. These interneurons are likely to play an important role in striatal function through fast GABAergic synaptic transmission in addition to, and independent of, their potential role in compensation for dopamine loss in experimental or idiopathic Parkinson's disease.

Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens.

Recent evidence suggests the intriguing possibility that midbrain dopaminergic (DAergic) neurons may use fast glutamatergic transmission to communicate with their postsynaptic targets. Because of technical limitations, direct demonstration of the existence of this signaling mechanism has been limited to experiments using cell culture preparations that often alter neuronal function including neurotransmitter phenotype. Consequently, it remains uncertain whether glutamatergic signaling between DAergic neurons and their postsynaptic targets exists under physiological conditions. Here, using an optogenetic approach, we provide the first conclusive demonstration that mesolimbic DAergic neurons in mice release glutamate and elicit excitatory postsynaptic responses in projection neurons of the nucleus accumbens. In addition, we describe the properties of the postsynaptic glutamatergic responses of these neurons during experimentally evoked burst firing of DAergic axons that reproduce the reward-related phasic population activity of the mesolimbic projection. These observations indicate that, in addition to DAergic mechanisms, mesolimbic reward signaling may involve glutamatergic transmission.

Heterogeneity and diversity of striatal GABAergic interneurons.

The canonical view of striatal GABAergic interneurons has evolved over several decades of neuroanatomical/neurochemical and electrophysiological studies. From the anatomical studies, three distinct GABAergic interneuronal subtypes are generally recognized. The best-studied subtype expresses the calcium-binding protein, parvalbumin. The second best known interneuron type expresses a number of neuropeptides and enzymes, including neuropeptide Y, somatostatin, and nitric oxide synthase. The last GABAergic interneuron subtype expresses the calcium binding protein, calretinin. There is no overlap or co-localization of these three different sets of markers. The parvalbumin-immunoreactive GABAergic interneurons have been recorded in vitro and shown to exhibit a fast-spiking phenotype characterized by short duration action potentials with large and rapid spike AHPs. They often fire in a stuttering pattern of high frequency firing interrupted by periods of silence. They are capable of sustained firing rates of over 200 Hz. The NPY/SOM/NOS interneurons have been identified as PLTS cells, exhibiting very high input resistances, low threshold spike and prolonged plateau potentials in response to intracellular depolarization or excitatory synaptic stimulation. Thus far, no recordings from identified CR interneurons have been obtained. Recent advances in technological approaches, most notably the generation of several BAC transgenic mouse strains which express a fluorescent marker, enhanced green fluorescent protein, specifically and selectively only in neurons of a certain genetic makeup (e.g., parvalbumin-, neuropeptide Y-, or tyrosine hydroxylase-expressing neurons etc.) have led to the ability of electrophysiologists to visualize and patch specific neuron types in brain slices with epifluorescence illumination. This has led to a rapid expansion of the number of neurochemically and/or electrophysiologically identified interneuronal cell types in the striatum and elsewhere. This article will review the anatomy, neurochemistry, electrophysiology, synaptic connections, and function of the three "classic" striatal GABAergic interneurons as well as more recent data derived from in vitro recordings from BAC transgenic mice as well as recent in vivo data.

Differential dopaminergic modulation of neostriatal synaptic connections of striatopallidal axon collaterals.

Recent studies have demonstrated that GABAergic synaptic transmission among neostriatal spiny projection neurons (SPNs) is strongly modulated by dopamine with individual connections exhibiting either D(1) receptor (D(1)R)-mediated facilitation or D(2) receptor (D(2)R)-mediated inhibition and, at least in some preparations, a subset of connections exhibiting both of these effects. In light of the cell type-specific expression of D(1a)R in striatonigral and D(2)R in striatopallidal neurons and the differential expression of the other D(1) and D(2) family dopamine receptors, we hypothesize that the nature of the dopaminergic modulation is specific to the types of SPNs that participate in the connection. Here the biophysical properties and dopaminergic modulation of intrastriatal connections formed by striatopallidal neurons were examined. Contrary to previous expectation, synapses formed by striatopallidal neurons were biophysically and pharmacologically heterogeneous. Two distinct types of axon collateral connections could be distinguished among striatopallidal neurons. The more common, small-amplitude connections (80%) exhibited mean IPSC amplitudes several times smaller than their less frequent large-amplitude counterparts, principally because of a smaller number of release sites involved. The two types of connections were also differentially regulated by dopamine. Small-amplitude connections exhibited strong and exclusively D(2)R-mediated presynaptic inhibition, whereas large-amplitude connections were unresponsive to dopamine. Synaptic connections from striatopallidal to striatonigral neurons exhibited exclusively D(2)R-mediated presynaptic inhibition that was similar to the regulation of small-amplitude connections between pairs of striatopallidal cells. Together, these findings demonstrate a previously unrecognized complexity in the organization and dopaminergic control of synaptic communication among SPNs.

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.

[Treatment of children's and adolescent's knee injuries]. / Gyermek- és serdülókori térdsérülések ellátása.

INTRODUCTION: Authors made 162 knee arthroscopic operations due to hemarthrosis of the knee, acute knee blocking or acute developed instability on patients under 18 years after knee injury during a 12 years period. The retrospective analysis of patient reports shows, that in 61.7% of the cases they found chondral- or osteochondral fracture in the knee. MATERIAL AND METHODS: On three dimensional routine X-ray pictures they were performed after the injury, in 85% of the cases fractures were not seen. Fortunately the most part of the hyalin surface injuries was smaller than 0.5 cm or were situated on less weight-bearing area only hemarthrosis evacuation and removing of loose body were done. If the osteochondral fractures was bigger than 0.5 cm or was broken from the weight-bearing surface, they were fixed by KFI or Herbert-screws. When refixation of osteochondral fracture was not possible technically or in cases of chondral fractures, primary mosaic chondroplasty was used. The correct diagnosis and the early reconstruction of injured hyalin surface in childhood and teenagers is essential regarding to the function of the knee.

Endogenous hydrogen peroxide regulates the excitability of midbrain dopamine neurons via ATP-sensitive potassium channels.

ATP-sensitive K+ (K(ATP)) channels link metabolic state to cell excitability. Here, we examined regulation of K(ATP) channels in substantia nigra dopamine neurons by hydrogen peroxide (H2O2), which is produced in all cells during aerobic metabolism. Blockade of K(ATP) channels by glibenclamide (100 nM) or depletion of intracellular H2O2 by including catalase, a peroxidase enzyme, in the patch pipette increased the spontaneous firing rate of all dopamine neurons tested in guinea pig midbrain slices. Using fluorescence imaging with dichlorofluorescein to visualize intracellular H2O2, we found that moderate increases in H2O2 during partial inhibition of glutathione (GSH) peroxidase by mercaptosuccinate (0.1-0.3 mM) had no effect on dopamine neuron firing rate. However, with greater GSH inhibition (1 mM mercaptosuccinate) or application of exogenous H2O2, 50% of recorded cells showed K(ATP) channel-dependent hyperpolarization. Responsive cells also hyperpolarized with diazoxide, a selective opener for K(ATP) channels containing sulfonylurea receptor SUR1 subunits, but not with cromakalim, a selective opener for SUR2-based channels, indicating that SUR1-based K(ATP) channels conveyed enhanced sensitivity to elevated H2O2. In contrast, when endogenous H2O2 levels were increased after inhibition of catalase, the predominant peroxidase in the substantia nigra, with 3-amino-1,2,4-triazole (1 mM), all dopamine neurons responded with glibenclamide-reversible hyperpolarization. Fluorescence imaging of H2O2 indicated that catalase inhibition rapidly amplified intracellular H2O2, whereas inhibition of GSH peroxidase, a predominantly glial enzyme, caused a slower, smaller increase, especially in nonresponsive cells. Thus, endogenous H2O2 modulates neuronal activity via K(ATP) channel opening, thereby enhancing the reciprocal relationship between metabolism and excitability.