Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

National Institute On Alcohol Abuse And Alcoholism

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Abstract

Differential Afferent Organization and Physiology in the Associative and Sensorimotor Basal Ganglia The basal ganglia (BG) control action selection, initiation and vigor. The parallel Associative and Sensorimotor BG circuits are thought to contribute to goal-directed and habitual/automatized behaviors, respectively. While extensive research has focused on elements of these circuits in the cortex and striatum, less is known about the circuit organization and physiology in other regions of the BG. To address this deficiency in knowledge, we have been examining pathways that connect different regions of the BG. These include the efferent output of the striatum and the projections from Globus pallidus external segment (GPe) to striatum via the "arkypallidal" pathway. Projections from the dorsal striatum to other BG regions include the striatonigral (StSN) and striatopallidal (StGPe) efferents. The StSN efferents are made by the direct pathway MSNs (dMSNs) that generally express D1-type DA receptors. These neurons mainly innervate GABAergic neurons in the substantia nigra pars reticulata (SNr), but can also synapse onto dopaminergic neurons in the substantia nigra pars compacta (SNc). Concerning these latter projections, we and others have recently characterized striatal direct pathway GABAergic projections that terminate on "dendron bouquets" of SNc neuron dendrites that extend ventrally into SNr. The D1-expressing MSNs can also innervate neurons in the GPe via the bridge collateral synapses. The indirect pathway MSNs (iMSNs) project to GPe neurons and generally express D2-type dopamine receptors. The GPe neurons send GABAergic afferents to both the subthalamic nucleus (STN) and the SNr. The STN neurons also project to SNr where they make glutamatergic synapses. The GABAergic synapses produce pauses in the tonic firing of target neurons, while the STN-SNr synapses are glutamatergic and increase firing rate. The dorsal striatum contains elements of the associative circuitry (dorsomedial striatum, DMS) and sensorimotor circuitry (dorsolateral striatum, DLS). While differences in the corticostriatal and thalamostriatal projections to these striatal subregions are well characterized, less is known about if and how the striatal efferents to GPe and SNr are segregated. We have used optogenetic efferent interrogation to determine the projection zones and synaptic properties of DLS, DMS, GPe and STN projections to SNr. To this end, we injected adeno-associated viral constructs encoding the Chronos light-activated channel into different BG subregions in C57Bl/6J mice. After at least 5 weeks we prepared brain slices containing the SNr and performed whole-cell patch clamp recordings combined with local optical afferent stimulation in these nuclei. Optical stimulation of DLS, DMS and GPe-SNr evoked inhibitory postsynaptic currents (IPSCs), consistent with the known GABAergic nature of these projections. We found that SNr neurons responsive to stimulation of DMS afferents were mainly located in the medial SNr, while DLS-responsive SNr neurons were located more laterally, consistent with previous studies. The amplitudes of synaptic responses induced by afferent activation were comparable for both DMS and DLS, indicating similar efficacies of direct pathway inputs within both associative and sensorimotor circuits. The indirect pathway projections from GPe to SNr show strong functional segregation across the SNr, with greater IPSC amplitudes in lateral than in medial SNr. These inputs also produce stronger inhibition of the tonic firing of SNr target neurons in lateral than in medial subregions. Likewise, when STN glutamatergic afferents were stimulated, the excitatory postsynaptic currents (EPSCs) were greater in lateral than in medial SNr. Consistent with this finding, optical STN afferent stimulation produced a stronger increase in firing rate of SNr lateral than in medial neurons. Thus, the indirect pathway may have a greater influence on the output of the sensorimotor circuit relative to the associative circuit. We are planning experiments to examine the in vivo consequences of altering the function of afferents to SNr and their target neurons to determine the effects on motor function and instrumental conditioning. We began by altering the activity of the parvalbumin (PV) expressing SNr neurons as these neurons are the predominant target for DLS StSNr projections and are less well innervated by DMS inputs. To this end, we expressed the hM4Di designer receptor activated exclusively by designed drug (DREADD) or an MCherry control flourescent protein in these neurons by viral injection into SNr in a PV-Cre mouse. We then examined effects of clozapine n-oxide (CNO) activation of this DREADD on instrumental lever pressing acquisition, outcome devaluation and extinction in mice that had undergone training culminating in a Random Ratio (RR) 10-20 schedule. Injection of CNO had no effect on acquisition or outcome devaluation in either mouse group. However, on the first day of extinction training, mice expressing hM4Di showed greater lever pressing compared to the MCherry-expressing controls. Responses were similar in the two groups on subsequent days of extinction training. This finding indicates that reducing activity of PV SNr GABAergic neurons interferes with extinction. This may mimic a situation in which DLS direct pathway GABAergic input to SNr PV neurons is enhanced. The hM4Di-mediated reduction in behavioral flexibility also resembles extinction impairment that we have observed in chronic ethanol exposed mice. Thus, chronic ethanol exposure may alter SNr neuronal excitability or synaptic inputs to reduce their contribution to operant extinction. Electrophysiological findings indicate that GABAergic synapses onto lateral SNr neurons are enhanced following chronic ethanol exposure. This enhanced inhibition likely has an effect on the SNr neurons similar to that of hM4Di activation, consistent with similar behavioral effects of DREADD-based inhibition and chronic ethanol exposure. Future studies will explore the role of lateral SNr neurons and their synaptic inputs in behavioral changes induced by ethanol drinking, as well as their role in alcohol drinking itself.