Bi-directional regulation of cognitive control by distinct prefrontal cortical output neurons to thalamus and striatum.

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control.

Intrinsic electrophysiological properties predict variability in morphology and connectivity among striatal Parvalbumin-expressing Pthlh-cells.

Determining the cellular content of the nervous system in terms of cell types and the rules of their connectivity represents a fundamental challenge to the neurosciences. The recent advent of high-throughput techniques, such as single-cell RNA-sequencing has allowed for greater resolution in the identification of cell types and/or states. Although most of the current neuronal classification schemes comprise discrete clusters, several recent studies have suggested that, perhaps especially, within the striatum, neuronal populations exist in continua, with regards to both their molecular and electrophysiological properties. Whether these continua are stable properties, established during development, or if they reflect acute differences in activity-dependent regulation of critical genes is currently unknown. We set out to determine whether gradient-like molecular differences in the recently described Pthlh-expressing inhibitory interneuron population, which contains the Pvalb-expressing cells, correlate with differences in morphological and connectivity properties. We show that morphology and long-range inputs correlate with a spatially organized molecular and electrophysiological gradient of Pthlh-interneurons, suggesting that the processing of different types of information (by distinct anatomical striatal regions) has different computational requirements.

Regulatory effects of Ningdong granule on microglia-mediated neuroinflammation in a rat model of Tourette's syndrome.

Tourette's syndrome (TS) is an inherited neurologic disorder characterized by involuntary stereotyped motor and vocal tics. Its pathogenesis is still unclear and its treatment remains limited. Recent research has suggested the involvement of immune mechanisms in the pathophysiology of TS. Microglia are the brain's resident innate immune cells. They can mediate neuroinflammation and regulate brain development and homeostasis. A traditional Chinese medicine (TCM), Ningdong granule (NDG), has been found to be efficacious in the treatment of TS while causing few adverse reactions. In the current study, a rat model of 3,3'-iminodipropionitrile (IDPN)-induced TS was used to explore the regulating effects and mechanisms of NDG on microglia-mediated neuroinflammation. IDNP led to robust pathological changes and neurobehavioral complications, with activation of microglia in the striatum of rats with TS. After activation by IDNP, microglia strongly responded to this specific injury, and TNF-α, IL-6, and MCP-1 were released in the striatum and/or serum of rats with TS. Interestingly, NDG inhibited the activation of microglia and decreased the abnormal expression of TNF-α, IL-6, and MCP-1 in the striatum and/or serum of rats with TS, thus controlling tics. However, there were no significant changes in the striatum and/or serum of rats with TS after treatment with haloperidol. The anti-TS action of haloperidol might occur not through microglial activation and neuroinflammation but through the DAT system, thus controlling tics. In conclusion, microglia might play key roles in mediating neuroinflammatory responses in TS, triggering the release of TNF-α, IL-6, and MCP-1.NDG inhibited tics in rats with TS, and this mechanism may be associated with a reduction in the increased number of activated microglia and a decrease in the expression of pro-inflammatory cytokines and chemokines in the striatum and/or serum.

The microcircuits of striatum in silico.

The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma-dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.

The Functional Organization of Cortical and Thalamic Inputs onto Five Types of Striatal Neurons Is Determined by Source and Target Cell Identities.

To understand striatal function, it is essential to know the functional organization of the numerous inputs targeting the diverse population of striatal neurons. Using optogenetics, we activated terminals from ipsi- or contralateral primary somatosensory cortex (S1) or primary motor cortex (M1), or thalamus while obtaining simultaneous whole-cell recordings from pairs or triplets of striatal medium spiny neurons (MSNs) and adjacent interneurons. Ipsilateral corticostriatal projections provided stronger excitation to fast-spiking interneurons (FSIs) than to MSNs and only sparse and weak excitation to low threshold-spiking interneurons (LTSIs) and cholinergic interneurons (ChINs). Projections from contralateral M1 evoked the strongest responses in LTSIs but none in ChINs, whereas thalamus provided the strongest excitation to ChINs but none to LTSIs. In addition, inputs varied in their glutamate receptor composition and their short-term plasticity. Our data revealed a highly selective organization of excitatory striatal afferents, which is determined by both pre- and postsynaptic neuronal identity.

Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.

Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.

Three divisions of the mouse caudal striatum differ in the proportions of dopamine D1 and D2 receptor-expressing cells, distribution of dopaminergic axons, and composition of cholinergic and GABAergic interneurons.

The greater part of the striatum is composed of striosomes and matrix compartments, but we recently demonstrated the presence of a region that has a distinct structural organization in the ventral half of the mouse caudal striatum (Miyamoto et al. in Brain Struct Funct 223:4275-4291, 2018). This region, termed the tri-laminar part based upon its differential immunoreactivities for substance P and enkephalin, consists of medial, intermediate, and lateral divisions. In this study, we quantitatively analyzed the distributions of both projection neurons and interneurons in each division using immunohistochemistry. Two types of projection neurons expressing either the dopamine D1 receptor (D1R) or D2 receptor (D2R) showed complementary distributions throughout the tri-laminar part, but the proportions significantly differed among the three divisions. The proportion of D1R-expressing neurons in the medial, intermediate, and lateral divisions was 88.6 ± 8.2% (651 cells from 3 mice), 14.7 ± 3.8% (1025 cells), and 49.3 ± 4.5% (873 cells), respectively. The intermediate division was further characterized by poor innervation of tyrosine hydroxylase immunoreactive axons. The numerical density of choline acetyltransferase immunoreactive neurons differed among the three divisions following the order from the medial to lateral divisions. In contrast, PV-positive somata were distributed throughout all three divisions at a constant density. Two types of GABAergic interneurons labeled for nitric oxide synthase and calretinin showed the highest cell density in the medial division. The present results characterize the three divisions of the mouse caudal striatum as distinct structures, which will facilitate studies of novel functional loops in the basal ganglia.

Neuroprotective Effect of Schisandra Chinensis on Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonian Syndrome in C57BL/6 Mice.

Schisandra chinensis (Turcz.) Baill. (S. chinensis) is a well-known botanical medicine and nutritional supplement that has been shown to have potential effects on neurodegeneration. To investigate the potential neuroprotective effect of S. chinensis fruit extract, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce behavioral disorders and dopaminergic neuronal damage in mice, and biochemical indicators were examined. Male C57BL/6 mice were used to establish the MPTP-induced parkinsonian syndrome model. Open field and rotarod tests were performed to evaluate the overall manifestation of motor deficits and rodent motor coordination. The mice were divided into 8 groups as follows: normal control; MPTP alone (25 mg/kg, i.p.); S. chinensis extract pretreatment (0.5, 1.5, 5 g/kg, p.o.); and S. chinensis extract treatment (0.5, 1.5, 5 g/kg, p.o.). Liquid chromatography coupled to electrochemical detection was used to monitor neurochemicals in the striatum. Tyrosine hydroxylase content was measured by immunohistochemistry, and biochemical antioxidative indicators were used to evaluate the potential neuroprotective effects of S. chinensis fruit extract. The results demonstrated that treatment with S. chinensis fruit extract ameliorated MPTP-induced deficits in behavior, exercise balance, dopamine level, dopaminergic neurons, and tyrosine hydroxylase-positive cells in the striatum of mice. Among the pretreated and treatment groups, a high dose of S. chinensis fruit extract was the most effective treatment. In conclusion, S. chinensis fruit extract is a potential herbal drug candidate for the amelioration and prevention of Parkinson's disease.

Distinct Cortical-Thalamic-Striatal Circuits through the Parafascicular Nucleus.

The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF has the highest density of striatum-projecting neurons among all sub-cortical structures. This projection arises from transcriptionally and physiologically distinct classes of PF neurons that are also reciprocally connected with functionally distinct cortical regions, differentially innervate striatal neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and somatosensory circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.

Thalamostriatal projections and striosome-matrix compartments.

The neostriatum has a mosaic organization consisting of striosome and matrix compartments. It receives glutamatergic excitatory afferents from the cerebral cortex and thalamus. Recent behavioral studies in rats revealed a selectively active medial prefronto-striosomal circuit during cost-benefit decision-making. However, clarifying the input/output organization of striatal compartments has been difficult because of its complex structure. We recently demonstrated that the source of thalamostriatal projections are highly organized in striatal compartments. This finding indicated that the functional properties of striatal compartments are influenced by their cortical and thalamic afferents, presumably with different time latencies. In addition, these afferents likely support the unique dynamics of striosome and matrix compartments. In this manuscript, we review the anatomy of basal ganglia networks with regard to striosome/matrix structure. We place specific focus on thalamostriatal projections at the population and single neuron level.

Cholinergic Interneurons Amplify Thalamostriatal Excitation of Striatal Indirect Pathway Neurons in Parkinson's Disease Models.

The motor symptoms of Parkinson's disease (PD) are thought to stem from an imbalance in the activity of striatal direct- and indirect-pathway spiny projection neurons (SPNs). Disease-induced alterations in the activity of networks controlling SPNs could contribute to this imbalance. One of these networks is anchored by the parafascicular nucleus (PFn) of the thalamus. To determine the role of the PFn in striatal PD pathophysiology, optogenetic, chemogenetic, and electrophysiological tools were used in ex vivo slices from transgenic mice with region-specific Cre recombinase expression. These studies revealed that in parkinsonian mice, the functional connectivity of PFn neurons with indirect pathway SPNs (iSPNs) was selectively enhanced by cholinergic interneurons acting through presynaptic nicotinic acetylcholine receptors (nAChRs) on PFn terminals. Attenuating this network adaptation by chemogenetic or genetic strategies alleviated motor-learning deficits in parkinsonian mice, pointing to a potential new therapeutic strategy for PD patients.

Arsenic-Induced Neurotoxicity by Dysfunctioning Cholinergic and Dopaminergic System in Brain of Developing Rats.

Chronic exposure to arsenic via drinking water throughout the globe is assumed to cause a developmental neurotoxicity. Here, we investigated the effect of perinatal arsenic exposure on the neurobehavioral and neurochemical changes in the corpus striatum, frontal cortex, and hippocampus that is critically involved in motor and cognition functions. In continuation of previous studies, this study demonstrates that perinatal exposures (GD6-PD21) to arsenic (2 or 4 mg/kg body weight, p.o.) cause hypo-activity in arsenic-exposed rats on PD22. The hypo-activity was found to be linked with a decrease in the mRNA and protein expression of the DA-D2 receptor. Further, a protein expression of tyrosine hydroxylase (TH), levels of dopamine, and its metabolites were also significantly impaired in corpus striatum. The arsenic-exposed groups showed spatial learning and memory significantly below the average in a dose-dependent manner for the controls. Here, we evaluated the declined expression of CHRM2 receptor gene and protein expression of ChAT, PKCß-1 in the frontal cortex and hippocampus, which are critically involved in cognition functions including learning and memory. A trend of recovery was found in the cholinergic and dopaminergic system of the brain, but changes remained persisted even after the withdrawal of arsenic exposure on PD45. Taken together, our results indicate that perinatal arsenic exposure appears to be critical and vulnerable as the development of cholinergic and dopaminergic system continues during this period.

Aspects of excitatory/inhibitory synapses in multiple brain regions are correlated with levels of brain-derived neurotrophic factor/neurotrophin-3.

Appropriate synapse formation during development is necessary for normal brain function, and synapse impairment is often associated with brain dysfunction. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are key factors in regulating synaptic development. We previously reported that BDNF/NT-3 secretion was enhanced by calcium-dependent activator protein for secretion 2 (CADPS2). Although BDNF/NT-3 and CADPS2 are co-expressed in various brain regions, the effect of Cadps2-deficiency on brain region-specific BDNF/NT-3 levels and synaptic development remains elusive. Here, we show developmental changes of BDNF/NT-3 levels and we assess disruption of excitatory/inhibitory synapses in multiple brain regions (cerebellum, hypothalamus, striatum, hippocampus, parietal cortex and prefrontal cortex) of Cadps2 knockout (KO) mice compared with wild-type (WT) mice. Compared with WT, BDNF levels in KO mice were reduced in young/adult hippocampus, but increased in young hypothalamus, while NT-3 levels were reduced in adult cerebellum and young hippocampus, but increased in adult parietal cortex. Immunofluorescence of vGluT1, an excitatory synapse marker, and vGAT, an inhibitory synapse marker, in adult KO showed that vGluT1 was higher in the cerebellum and parietal cortex but lower in the hippocampus, whereas vGAT was lower in the hippocampus and parietal cortex compared with WT. Immunolabeling for both vGluT1 and vGAT was increased in the parietal cortex but vGAT was decreased in the cerebellum in adult KO compared with WT. These data suggest that CADPS2-mediated secretion of BDNF/NT-3 may be involved in development and maturation of synapses and in the balance between inhibitory and excitatory synapses.

Sensory overamplification in layer 5 auditory corticofugal projection neurons following cochlear nerve synaptic damage.

Layer 5 (L5) cortical projection neurons innervate far-ranging brain areas to coordinate integrative sensory processing and adaptive behaviors. Here, we characterize a plasticity in L5 auditory cortex (ACtx) neurons that innervate the inferior colliculus (IC), thalamus, lateral amygdala and striatum. We track daily changes in sound processing using chronic widefield calcium imaging of L5 axon terminals on the dorsal cap of the IC in awake, adult mice. Sound level growth functions at the level of the auditory nerve and corticocollicular axon terminals are both strongly depressed hours after noise-induced damage of cochlear afferent synapses. Corticocollicular response gain rebounded above baseline levels by the following day and remained elevated for several weeks despite a persistent reduction in auditory nerve input. Sustained potentiation of excitatory ACtx projection neurons that innervate multiple limbic and subcortical auditory centers may underlie hyperexcitability and aberrant functional coupling of distributed brain networks in tinnitus and hyperacusis.

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions.

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior.

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits.

Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca2+ signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.

Cell-Type-Specific Contributions of Medial Prefrontal Neurons to Flexible Behaviors.

Behavioral flexibility and impulse control are necessary for successful execution of adaptive behavior. They are impaired in patients with damage to the prefrontal cortex (PFC) and in some clinically important conditions, such as obsessive-compulsive disorder. Although the medial prefrontal cortex (mPFC) has been investigated as a critical structure for behavioral flexibility and impulse control, the contribution of the underlying pyramidal neuron cell types in the mPFC remained to be understood. Here we show that interneuron-mediated local inactivation of pyramidal neurons in the mPFC of male and female mice induces both premature responses and choice bias, and establish that these impulsive and compulsive responses are modulated independently. Cell-type-specific photoinhibition of pyramidal deep layer corticostriatal or corticothalamic neurons reduces behavioral flexibility without inducing premature responses. Together, our data confirm the role of corticostriatal neurons in behavioral flexibility and demonstrate that flexible behaviors are also modulated by direct projections from deep layer corticothalamic neurons in the mPFC to midline thalamic nuclei.SIGNIFICANCE STATEMENT Behavioral flexibility and impulse control are indispensable for animals to adapt to changes in the environment and often affected in patients with PFC damage and obsessive-compulsive disorder. We used a probabilistic reversal task to dissect the underlying neural circuitry in the mPFC. Through characterization of the three major pyramidal cell types in the mPFC with optogenetic silencing, we demonstrated that corticostriatal and corticothalamic but not corticocortical pyramidal neurons are temporally recruited for behavioral flexibility. Together, our findings confirm the role of corticostriatal projections in cognitive flexibility and identify corticothalamic neurons as equally important for behavioral flexibility.

Subcortical neurodegeneration in chorea: Similarities and differences between chorea-acanthocytosis and Huntington's disease.

INTRODUCTION: Chorea-acanthocytosis (ChAc) and Huntington's disease (HD) are neurodegenerative conditions that share clinical and neuropathological features, despite their distinct genetic etiologies. METHODS: In order to compare these neuropathologies, serial gallocyanin-stained brain sections from three subjects with ChAc were analyzed and compared with our previous studies of eight HD cases, in addition to three hemispheres from two male controls. RESULTS: Astrogliosis was much greater in the ChAc striatum, as compared to that found in HD, with dramatic increase in total striatal glia numbers and the number of glia per striatal neuron. Striatal astrocytes are most likely derived from the striatal subependymal layer in ChAc, which showed massive proliferation. The thalamic centromedian-parafascicular complex is reciprocally connected to the striatum and is more heavily affected in HD than in ChAc. CONCLUSION: The distinct patterns of selective vulnerability and gliosis observed in HD and ChAc challenge simplistic views on the pathogenesis of these two diseases with rather similar clinical signs. The particular roles played by astroglia in ChAc and in HD clearly need to be elucidated in more detail.

Parvalbumin-producing striatal interneurons receive excitatory inputs onto proximal dendrites from the motor thalamus in male mice.

In rodents, the dorsolateral striatum regulates voluntary movement by integrating excitatory inputs from the motor-related cerebral cortex and thalamus to produce contingent inhibitory output to other basal ganglia nuclei. Striatal parvalbumin (PV)-producing interneurons receiving this excitatory input then inhibit medium spiny neurons (MSNs) and modify their outputs. To understand basal ganglia function in motor control, it is important to reveal the precise synaptic organization of motor-related cortical and thalamic inputs to striatal PV interneurons. To examine which domains of the PV neurons receive these excitatory inputs, we used male bacterial artificial chromosome transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein in PV neurons. An anterograde tracing study with the adeno-associated virus vector combined with immunodetection of pre- and postsynaptic markers visualized the distribution of the excitatory appositions on PV dendrites. Statistical analysis revealed that the density of thalamostriatal appositions along the dendrites was significantly higher on the proximal than distal dendrites. In contrast, there was no positional preference in the density of appositions from axons of the dorsofrontal cortex. Population observations of thalamostriatal and corticostriatal appositions by immunohistochemistry for pathway-specific vesicular glutamate transporters confirmed that thalamic inputs preferentially, and cortical ones less preferentially, made apposition on proximal dendrites of PV neurons. This axodendritic organization suggests that PV neurons produce fast and reliable inhibition of MSNs in response to thalamic inputs and process excitatory inputs from motor cortices locally and plastically, possibly together with other GABAergic and dopaminergic dendritic inputs, to modulate MSN inhibition.

Functional comparison of corticostriatal and thalamostriatal postsynaptic responses in striatal neurons of the mouse.

Synaptic inputs from cortex and thalamus were compared in electrophysiologically defined striatal cell classes: direct and indirect pathways' striatal projection neurons (dSPNs and iSPNs), fast-spiking interneurons (FS), cholinergic interneurons (ChINs), and low-threshold spiking-like (LTS-like) interneurons. Our purpose was to observe whether stimulus from cortex or thalamus had equivalent synaptic strength to evoke prolonged suprathreshold synaptic responses in these neuron classes. Subthreshold responses showed that inputs from either source functionally mix up in their dendrites at similar electrotonic distances from their somata. Passive and active properties of striatal neuron classes were consistent with the previous studies. Cre-dependent adeno-associated viruses containing Td-Tomato or eYFP fluorescent proteins were used to identify target cells. Transfections with ChR2-eYFP driven by the promoters CamKII or EF1.DIO in intralaminar thalamic nuclei using Vglut-2-Cre mice, or CAMKII in the motor cortex were used to stimulate cortical or thalamic afferents optogenetically. Both field stimuli in the cortex or photostimulation of ChR2-YFP cortical fibers evoked similar prolonged suprathreshold responses in SPNs. Photostimulation of ChR2-YFP thalamic afferents also evoked suprathreshold responses. Differences previously described between responses of dSPNs and iSPNs were observed in both cases. Prolonged suprathreshold responses could also be evoked from both sources onto all other neuron classes studied. However, to evoke thalamostriatal suprathreshold responses, afferents from more than one thalamic nucleus had to be stimulated. In conclusion, both thalamus and cortex are capable to generate suprathreshold responses converging on diverse striatal cell classes. Postsynaptic properties appear to shape these responses.