Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus

Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6‐hydroxydopamine‐induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I‐ and postsynaptic density 95‐immunoreactivities were reduced. The activated microglia engulfed pre‐ and post‐synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis‐related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.     

Dopamine depletion causes fragmented clustering of neurons in the sensorimotor striatum: evidence of lasting reorganization of corticostriatal input

Firing during sensorimotor exam was used to categorize single neurons in the lateral striatum of awake, unrestrained rats. Five rats received unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle to deplete striatal dopamine (DA; >98% depletion, postmortem assay). Three months after treatment, rats exhibited exaggerated rotational behavior induced by L-dihydroxyphenylalanine (L-DOPA) and contralateral sensory neglect. Electrode track "depth profiles" on the DA-depleted side showed fragmented clustering of neurons related to sensorimotor activity of single body parts (SBP neurons). Clusters were smaller than normal, and more SBP neurons were observed in isolation, outside of clusters. More body parts were represented per unit volume. No recovery in these measures was observed up to one year post lesion. Overall distributions of neurons related to different body parts were not altered. The fragmentation of SBP clusters after DA depletion indicates that a percentage of striatal SBP neurons switched responsiveness from one body part to one or more different body parts. Because the specific firing that characterizes striatal SBP neurons is mediated by corticostriatal inputs (Liles and Updyke [1985] Brain Res. 339:245-255), the data indicate that DA depletion resulted in a reorganization of corticostriatal connections, perhaps via unmasking or sprouting of connections to adjacent clusters of striatal neurons. After reorganization, sensory activity in a localized body part activates striatal neurons that have switched to that body part. In turn, switched signals sent from basal ganglia to premotor and motor neurons, which likely retain their original connections, would create mismatches in these normally precise topographic connections. Switched signals could partially explain parkinsonian deficits in motor functions involving somatosensory guidance and their intractability to L-DOPA therapy-particularly if the switching involves sprouting.     

Reaction time performance following unilateral striatal dopamine depletion and lesions of the subthalamic nucleus in the rat

The akinesia resulting from Parkinson's disease or striatal dopamine depletion in experimental animals can be ameliorated or reversed by inactivation of the subthalamic nucleus. This inactivation might be effective by restoring balance to the basal ganglia motor circuits. Alternatively, new movement-related deficits might be introduced which mask the original impairments (e.g. hyperkinesia might replace hypokinesia). In the present study, striatal dopamine depletion was effected unilaterally, in order to dissociate generalized effects, e.g. hyperkinesia, from response-specific initiation effects. Rats were trained in a lateralized visual reaction time task and then assigned to one of four groups: striatal dopamine depletion; cell body lesion of the subthalamic nucleus; combined striatal dopamine depletion and subthalamic nucleus lesion; or control. As expected, rats with striatal dopamine depletion exhibited slower reaction time and a bias to respond to the ipsilateral side. The subthalamic nucleus lesion resulted in no reaction time change (in particular, there was no evidence of faster reaction times), but there was an increase in anticipatory responding. The group with the combined striatal dopamine depletion and subthalamic nucleus lesion had no reaction time impairment. This group showed an increase in anticipatory errors and a contralateral response bias. These data demonstrate that lesions of the subthalamic nucleus do not merely cancel the akinesia which follows striatal dopamine depletion by the addition of a hyperkinetic impairment. Rather, there appears to be a change in the balance of the motor system.     

Two opposite effects of Δ9‐tetrahydrocannabinol on subthalamic nucleus neuron activity: Involvement of GABAergic and glutamatergic neurotransmission

Activation of CB1 cannabinoid receptors in the basal ganglia interferes with movement regulation. The aim of this study was to characterize the effect of Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC) on neurons in the subthalamic nucleus (STN) and to elucidate the mechanisms involved in this effect using single‐unit extracellular recordings in anesthetized rats. Administration of Δ⁹‐THC (0.25–2 mg/kg, i.v.) stimulated (by 107% ± 32%) neurons mainly recorded in the ventromedial portion of the caudal STN, whereas it inhibited (by 65% ± 4%) neurons recorded in the dorsolateral portion of the rostral STN. The CB1 receptor antagonist rimonabant (1 mg/kg, i.v.) completely reverted these effects. The excitatory effect of Δ⁹‐THC on STN neurons was not observed after antagonism of GABA_A receptors by bicuculline administration (10 ng, icv.) or after chemical lesion of the globus pallidus with ibotenic acid. The inhibitory effect was abolished when excitatory amino acid receptors were blocked by kynurenic acid (0.5 μmol, icv.). These results indicate that CB1 receptor activation modulates STN neuron activity by indirect mechanisms involving glutamatergic and GABAergic neurotransmission. Synapse 64:20–29, 2010. © 2009 Wiley‐Liss, Inc.     

Unilateral striatal dopamine depletion: time-dependent effects on cortical function and behavioural correlates

Previously, we showed that unilateral blockade of D1 dopamine receptors in the striatum inhibits immediate-early gene expression bilaterally throughout large parts of the cortex, including sensory-evoked expression in the barrel cortex. To further investigate this dopamine regulation of cortical function, we examined the effects of dopamine depletion on cortical gene regulation and behavioural correlates. Two days after unilateral infusion of 6-hydroxydopamine into the midbrain, rats displayed a (to some degree) bilateral reduction in cortical zif 268 expression that was more pronounced on the lesioned side. This decrease was found across motor, somatosensory, insular and piriform, but not cingulate, cortex, similar to the effects of blockade of striatal D1 receptors. Furthermore, whisker stimulation-evoked c-fos and zif 268 expression in the barrel cortex ipsilateral to the lesion was also attenuated by acute dopamine depletion. These cortical deficits were accompanied by a breakdown of spontaneous behaviours in an open-field test. In contrast, 21 days after dopamine depletion, both basal and sensory-evoked gene expression in the cortex were near-normal. This cortical recovery was paralleled by recovery in locomotion and in sensory-guided behaviour (scanning) related to the hemisphere contralateral to the lesion, but not in scanning by the dopamine-depleted hemisphere. Our results suggest that striatal dopamine exerts a widespread facilitatory influence on cortical function that is necessary, but not sufficient, for normal behaviour. Moreover, the mechanisms mediating this cortical facilitation appear to be subject to substantial neuroplasticity after dopamine perturbation.     

Premotor Ramping of Thalamic Neuronal Activity Is Modulated by Nigral Inputs and Contributes to Control the Timing of Action Release

The ventromedial (VM)/ventro-anterior-lateral (VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathologic motor control functions and decision-making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and, on the other hand, motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal-directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct (corr) and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action) and weaker for trials with no licks [omission (omi)] compared with correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led to a reduced probability of impulsive action and an increased amount of omissions trials. We propose a parsimonious model explaining our data and conclude that a thalamic ramping mechanism contributes to the control of proper timing of action release and that inhibitory nigral inputs are sufficient to interrupt this mechanism and modulate the amount of motor impulsivity in this task.SIGNIFICANCE STATEMENT Coordinated neural activity in motor circuits is essential for correct movement preparation and execution, and even slight imbalances in neural processing can lead to failure in behavioral tasks or motor disorders. Here we focused on how failure to regulate the control of activity balance in the motor thalamus can be implicated in impulsive action release or omissions to act, through an activity ramping mechanism that is required for proper action release. Using optogenetic activation of inhibitory basal ganglia terminals in motor thalamus we show that basal ganglia input is well positioned to control this ramping activity and determine the timing of action initiation.     

Homogeneous processing in the striatal direct and indirect pathways: single body part sensitive type IIb neurons may express either dopamine receptor D1 or D2

Striatal medium spiny projection neurons (MSNs) output through two diverging circuits, the ‘direct and indirect pathways’ which originate from minimally overlapping populations of MSNs expressing either the dopamine receptor D1 or the dopamine receptor D2. One modern theory of direct and indirect pathway function proposes that activation of direct pathway MSNs facilitates output of desired motor programs, while activation of indirect pathway MSNs inhibits competing motor programs. A separate theory suggests that coordinated timing or synchrony of the direct and indirect pathways is critical for the execution of refined movements. These hypotheses are made testable by a common type of striatal neuron known as type IIb MSNs. Clusters of these MSNs exhibit phasic increases in firing rate related to sensorimotor activity of single body parts. If these MSNs were to reside in only the direct pathway, evidence would be provided that D1 MSNs are ‘motor program’ specific, which would lend credence to the ‘competing motor programs’ hypothesis. However, if type IIb MSNs reside in both pathways, evidence would be provided for the ‘coordinated timing or synchrony’ hypothesis. Our results show that type IIb neurons may express either D1 or D2. This evidence supports the theory that the coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. We also propose a model in which the direct and indirect pathways act as a differentiator circuit, providing a possible mechanism by which coordinated activity of D1 and D2 neurons may output meaningful somatosensorimotor information to downstream structures.     

Characterisation of striatal NMDA receptors involved in the generation of parkinsonian symptoms: intrastriatal microinjection studies in the 6-OHDA-lesioned rat.

Treatments for Parkinson's disease based on replacement of lost dopamine have several problems. Following loss of dopamine, enhanced N-methyl-D-aspartate (NMDA) receptor-mediated transmission in the striatum is thought to be part of the cascade of events leading to the generation of parkinsonian symptoms. We determined the localisation and pharmacological characteristics of NMDA receptors that play a role in generating parkinsonian symptoms within the striatum. Rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and cannulae implanted bilaterally to allow injection of a range of NMDA receptor antagonists at different striatal sites. When injected rostrally into the dopamine-depleted striatum, the glycine site partial agonist, (+)-HA-966 (44-400 nmol) caused a dose-dependent contraversive rotational response consistent with an antiparkinsonian action. (+)-HA-966 (400 nmol) had no effect when infused into more caudal regions of the dopamine-depleted striatum, or following injection into any striatal region on the dopamine-intact side. To determine the pharmacological profile of NMDA receptors involved in inducing parkinsonism in 6-OHDA-lesioned rats, a range of NMDA receptor antagonists was infused directly into the rostral striatum. Ifenprodil (100 nmol) and 7-chlorokynurenate (37 nmol), but not MK-801 (15 nmol) or D-APV (25 nmol) elicited a dramatic rotational response when injected into the dopamine-depleted striatum. This pharmacological profile is not consistent with an effect mediated via blocking NR2B-containing NMDA receptors. The effect of intrastriatal injection of ifenprodil was increased in animals previously treated with levodopa (L-dopa) methyl ester. This was seen as an increase in on-time and in peak rotational response. We propose that stimulation of NR2B-containing NMDA receptors in the rostral striatum underlies the generation of parkinsonian symptoms. These studies are in line with previous findings suggesting that administration of NR2B-selective NMDA receptor antagonists may be therapeutically beneficial for parkinsonian patients, when given de novo and following L-dopa treatment.     

Effect of microiontophoretic application of dopamine on subthalamic nucleus neuronal activity in normal rats and in rats with unilateral lesion of the nigrostriatal pathway

The subthalamic nucleus (STN) receives dopamine inputs from the substantia nigra but their implication in the pathophysiology of parkinsonism is still debated. Extracellular microrecordings were used to study the effect of microiontophoretic injection of dopamine and the D1 receptor agonist SKF 38393 on the activity of STN neurons in normal and 6-hydroxydopamine-lesioned rats under urethane anaesthesia. Dopamine and SKF induced an increase in the firing rate of the majority of STN neurons in both normal and 6-OHDA rats. In rats with 6-OHDA lesions, the percentage of firing rate increase did not differ from that of controls. When GABA, glutamate and dopamine were all applied to the same individual STN neurons, GABA induced an inhibitory effect and glutamate and dopamine caused an excitatory effect in both groups. This excitatory response was suppressed by the application of GABA. Systemic administration of apomorphine provoked a decrease in the firing rate of STN neurons in rats with 6-OHDA lesions. These results show that dopamine exerts an excitatory influence on STN neurons, suggesting that the inhibitory effect induced by the systemic injection of apomorphine is due to the GABAergic inputs from the globus pallidus as predicted by the current model of basal ganglia organization. In addition, we show that dopamine, GABA and glutamate can act on the same STN neuron and that GABA can reverse the excitatory effect of dopamine and glutamate, suggesting the predominant influence of GABAergic inputs to the subthalamic nucleus.     

Discontinuation of citalopram medication and striatal dopamine activity

A 35-year-old caucasian woman who suffered from major depression with marked psychomotor symptoms was treated with a selective serotonin re-uptake inhibitor (SSRI), citalopram. After 16 months successful treatment, the medication was gradually discontinued. One week after stopping citalopram, she experienced lowered mood and unnatural slowness in her movements. These symptoms were associated with low striatal dopamine (DA) activity as measured with baseline and follow-up [¹⁸F]DOPA PET scans. We suggest that stimulation of serotonergic system in the brain increases dopaminergic activity in the striatum. After cessation of this stimulation, striatal dopaminergic activity may decrease considerably in vulnerable patients and cause transient emotional and psychomotor discontinuation symptoms that disappear spontaneously in a few weeks.     

Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer's disease

Parkinson's disease and Alzheimer's disease (AD) are recognized to coexist on a spectrum of neurodegeneration, and it has been proposed that molecular interactions among pathogenic proteins are a basis for the overlap between these two diseases. We instead hypothesized that degeneration of the nigrostriatal dopaminergic system enhances the clinical penetrance of early‐stage AD. To determine the effect of striatal dopamine (DA) on the pathological effects in an experimental model of AD, APP_SWE/PS1ΔE9 mice received striatal injections of the neurotoxin 6‐hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and in a water T‐maze protocol at different ages to determine the onset of cognitive impairment. APP_SWE/PS1ΔE9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age, APP_swe/PS1ΔE9 + 6OHDA mice demonstrated worse behavioral flexibility than other groups in a task‐switch phase of the water T‐maze. To determine the neuroprotective effects of dopaminergic neurotransmission against amyloid‐β₄₂ (Aβ₄₂) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D₁ and D₂ receptor agonists before being exposed to oligomerized Aβ₄₂. Although there were no differences in Aβ peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to Aβ_42. Depletion of DA in the striatum exacerbated the cognitive impairment seen in a mouse model of early‐stage AD; this may be due to a protective effect of dopaminergic innervation against Aβ striatal neurotoxicity. © 2015 Wiley Periodicals, Inc.     

MK-801 alters the effects of priming with L-DOPA on dopamine D1 receptor-induced changes in neuropeptide mRNA levels in the rat striatal output neurons.

In a previous study, we have shown in unilaterally dopamine-depleted rats that increased behavioral responsiveness to the dopamine D1-receptor agonist SKF-38393, which was induced by pretreatment with L-DOPA, is paralleled by specific alterations in striatal neuropeptide mRNA levels. The behavioral 'priming' effect of L-DOPA is prevented if L-DOPA is preceded by the NMDA-receptor antagonist MK-801. In the present study, the question is addressed whether blockade of the increased behavioral responsiveness with MK-801 also prevents the observed changes in striatal neuropeptide mRNA levels. After a challenge with SKF-38393 (3 mg/kg, s.c.), the striatal levels of preprodynorphin, preprotachykinin, and preproenkephalin mRNA were compared between unilaterally dopamine-depleted rats that were either primed with a single administration of L-DOPA (50 mg/kg, i.p.) or with L-DOPA preceded by MK-801 (0.1 mg/kg, i.p.). Priming with L-DOPA enhanced the increase in dynorphin mRNA levels in the dorsolateral part of the dopamine-depleted striatum that occurred after SKF-38393. On the other hand, it had no significant effect on substance P or enkephalin mRNA levels. MK-801 prior to L-DOPA prevented the increased responsiveness of dynorphin regulation. However, it induced a decreased response to dopamine D1-receptor stimulation in the substance P mRNA levels in dorsal regions of the dopamine-depleted striatum. The levels of enkephalin mRNA after challenge with SKF-38393 were not affected by the MK-801 administration. These results demonstrate that the increased behavioral responsiveness to the D1-receptor agonist SKF-38393 after priming with L-DOPA is primarily related to the upregulation of dynorphin mRNA levels in the dopamine-depleted striatum.     

Electrophysiological alterations in subthalamic neurons after unilateral dopamine depletion in the rat

The present study examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) on electrophysiological properties of subthalamic neurons (STN) in adult rats. Most neurons displayed regular spontaneous tonic firing patterns in both control and lesioned animals; however, the percentage of neurons with spontaneous burst firing at hyperpolarized membrane potentials was increased significantly in lesioned animals compared with controls (45% vs. 14% respectively). In the presence of bicuculline, a gamma-aminobutyric acid type A (GABAA) receptor antagonist, electrical stimulation of the internal capsule produced monosynaptic excitatory postsynaptic potentials (EPSPs) in almost all recorded neurons. DA (50 microM) increased the amplitude and/or duration of the EPSPs in neurons from both groups, whereas the DA D1 receptor agonist SKF 81297 (10 microM) produced a significant increase in amplitude and/or duration of EPSPs in neurons from the lesioned group only. This latter increase was blocked by pretreatment with the DA D1 antagonist SCH 23390 (10 microM). These data suggest that unilateral degeneration of DA neurons in the SNc changes firing properties and enhances electrophysiological responsiveness of STN neurons to activation of DA D1 receptors.     

Synchronized activation of striatal direct and indirect pathways underlies the behavior in unilateral dopamine‐depleted mice

For more than three decades it has been known, that striatal neurons become hyperactive after the loss of dopamine input, but the involvement of dopamine (DA) D1‐ or D2‐receptor‐expressing neurons has only been demonstrated indirectly. By recording neuronal activity using fluorescent calcium indicators in D1 or D2 eGFP‐expressing mice, we showed that following dopamine depletion, both types of striatal output neurons are involved in the large increase in neuronal activity generating a characteristic cell assembly of particular neurons that dominate the pattern. When we expressed channelrhodopsin in all the output neurons, light activation in freely moving animals, caused turning like that following dopamine loss. However, if the light stimulation was patterned in pulses the animals circled in the other direction. To explore the neuronal participation during this stimulation we infected normal mice with channelrhodopsin and calcium indicator in striatal output neurons. In slices made from these animals, continuous light stimulation for 15 s induced many cells to be active together and a particular dominant group of neurons, whereas light in patterned pulses activated fewer cells in more variable groups. These results suggest that the simultaneous activity of a large dominant group of striatal output neurons is intimately associated with parkinsonian symptoms.     

Changes in the firing pattern of globus pallidus neurons after the degeneration of nigrostriatal pathway are mediated by the subthalamic nucleus in the rat

Changes in the neuronal activity of globus pallidus (GP) have been shown in animal models of parkinsonism. In order to study the implication of the subthalamic nucleus (STN) in these changes, the effects of STN lesions alone or in combination with 6-hydroxydopamine (6-OHDA) -induced damage to the substantia nigra compacta (SNc) were examined in rats using electrophysiological recordings of GP cells. In normal rats, the firing rate was 22.1+/-1.4 spikes/s. The pattern was regular in 45%, irregular in 49% and bursty in 6% of the cases. In rats with STN lesions, the firing rate of GP units (20.15+/-1.25 spikes/s) did not differ from that of normal rats and only regular (46%) and irregular (54%) cells were found; a bursty pattern was not observed. 6-OHDA lesions of the SNc induced no change in the firing rate of GP neurons (21.5+/-1.4 spikes/s, P>0.05) but a significant decrease in the percentage of regular cells (27%, P<0.001), a significant increase in burst cells (21%, P<0.001) with no change in the percentage of irregular units (52%) were observed. In rats with combined SNc and STN lesions, the firing pattern did not change from that of normal rats. The present results show that STN lesions induced the disappearance of bursts in normal rats and normalization of firing pattern in the GP units of rats with 6-OHDA lesions suggesting that the STN plays an important role in the modulation of the pattern of activity of GP neurons which may account for the therapeutic effect of STN lesions in Parkinson's disease.     

Lesion of medial prefrontal dopamine terminals abolishes habituation of accumbens shell dopamine responsiveness to taste stimuli

Taste stimuli increase extracellular dopamine (DA) in the nucleus accumbens (NAc) and in the medial prefrontal cortex (mPFC). This effect shows single‐trial habituation in NAc shell but not in core or in mPFC. Morphine sensitization abolishes habituation of DA responsiveness in NAc shell but induces it in mPFC. These observations support the hypothesis of an inhibitory influence of mPFC DA on NAc DA. To test this hypothesis, we used in vivo microdialysis to investigate the effect of mPFC 6‐hydroxy‐dopamine (6‐OHDA) lesions on the NAc DA responsiveness to taste stimuli. 6‐OHDA was infused bilaterally in the mPFC of rats implanted with guide cannulae. After 1 week, rats were implanted with an intraoral catheter, microdialysis probes were inserted into the guide cannulae, and dialysate DA was monitored in NAc shell/core after intraoral chocolate. 6‐OHDA infusion reduced tissue DA in the mPFC by 75%. Tyrosine hydroxylase immunohistochemistry showed that lesions were confined to the mPFC. mPFC 6‐OHDA lesion did not affect the NAc shell DA responsiveness to chocolate in naive rats but abolished habituation in rats pre‐exposed to the taste. In the NAc core, mPFC lesion potentiated, delayed and prolonged the stimulatory DA response to taste but failed to affect DA in pre‐exposed rats. Behavioural taste reactions and motor activity were not affected. The results indicate a top‐down control of NAc DA by mPFC and a reciprocal relationship between DA transmission in these two areas. Moreover, habituation of DA responsiveness in the NAc shell is dependent upon an intact DA input to the mPFC.     

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.     

Early behavioral changes after nigro-striatal system damage can serve as predictors of striatal dopamine depletion

1. 1. Rats which had received a unilateral injection of 6-OHDA into the substantia nigra were assigned to four lesion groups according to the degree of DA depletion in the neostriatum. In these animals, behavioral changes in the open-field were investigated during the first post-operative week. Overall, this analysis showed that the animals could adequately be characterized by behavior on day 1 and day 7 after lesion.

2. 2. On the first day after lesion, the groups with the severest DA depletions ( > 80% and 55–80%) showed an ipsilateral asymmetry in turning. After one week, these groups showed a tendency to recover from this deficit; however, the group with the most strongest lesions ( > 80%) was still asymmetric.

3. 3. In scanning behavior, in contrast to turning, all the lesion groups displayed an initial ipsilateral asymmetry. On day 7 after lesion, only the group with DA depletions of > 80% still had an ipsilateral asymmetry. Locomotor activity and rearing were initially reduced after lesion, and showed a tendency to recover, especially in the group with the most severe DA depletions ( > 80%). There were no differences between groups neither on day 1 nor on day 7 by grooming, but this behavior increased in all the lesion groups with time.

4. 4. The correlational analyses yielded a positive relationship between the asymmetry in turning and neostriatal DA depletion. Locomotor activity and rearing on day 1 were both negatively correlated with DA depletion. The present results show that a number of behavioral parameters obtained in the open-field are affected by unilateral lesions of the nigro-striatal DA system. The degree of deficit, its time course and relation to lesion size differs among the various behavioral measures. Some of these early behavioral changes after unilateral nigrostriatal lesion are related to DA depletion and should therefore be useful to predict lesion size.

5. 5. Together, these data suggest that the study of such behavioral changes can provide an important tool, to investigate the compensatory mechanisms underlying striatal DA depletion and to understand preclinical states of the Parkinson's disease.

     

Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype

Dopamine is one of the principal neurotransmitters in the basal ganglia, where it plays a critical role in motor control and cognitive function through its interactions with the specific dopamine receptors D1 to D5. Although the activities mediated by most dopamine receptor subtypes have already been determined, the role of the D5 receptor subtype in the basal ganglia has still not been established. Furthermore, it is often difficult to distinguish between dopamine D5 and D1 receptors as they are stimulated by the same ligands, and they have a similar molecular structure and pharmacology. In an effort to understand the differences between these two receptor subtypes, we have studied the distribution of neurons containing D5 receptors in the striatum, and their molecular phenotype. As a result, we show that the D5 receptor subtype is present in two different populations of striatal neurons, projection neurons and interneurons. Overall, the abundance of this receptor subtype in the striatum is low, particularly in striatal projection neurons of both the direct and indirect projection pathways. In contrast, the expression of D5 receptors in striatal interneurons (cholinergic, somatostatin- or parvalbumin-positive neurons) is high, while low to moderate expression was observed in calretinin-positive neurons. Our results demonstrate the presence of D5 receptors in all the striatal cell populations so far described, although at different intensities in each. The fact that a large number of striatal neurons express the D5 receptor subtype suggests that this receptor fulfils an important function in the process of integrating information in the striatum.