Camila L. Zold

Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats.

There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinsons disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor‐mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6‐hydroxydopamine‐induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane‐anaesthetized rats most GP neurons were excited during the active part of cortical slow waves (‘direct‐phase’ neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6‐hydroxydopamine‐lesioned rats. ‘Inverse‐phase’ GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse‐phase activity. Therefore, spreading of inverse‐phase oscillations through pallidonigral axons might contribute to the abnormal direct‐phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6‐hydroxydopamine‐lesioned rats reduced GP inverse‐phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist‐resistant clinical signs of parkinsonism.

D2 receptor stimulation, but not D1, restores striatal equilibrium in a rat model of Parkinsonism.

In Parkinsons disease dopamine depletion imbalances the two major output pathways of the striatum. L-DOPA replacement therapy is believed to correct this imbalance by providing effective D1 and D2 receptor stimulation to striatonigral and striatopallidal neurons, respectively. Here we tested this assumption in the rat model of Parkinsonism by monitoring the spike response of identified striatal neurons to cortical stimulation. As predicted, in 6-hydroxydopamine lesioned rats we observed that L-DOPA (6 mg/kg+benserazide), apomorphine and the D2 agonist quinpirole (0.5 mg/kg i.p.) counteract the enhanced responsiveness of striatopallidal neurons. Unexpectedly, the depressed responsiveness of striatonigral neurons was corrected by quinpirole whereas D1 stimulation exerted no (apomorphine, cPB) or worsening effects (L-DOPA, SKF38393 10 mg/kg). Therefore, quinpirole, but not D1 stimulation, restores functional equilibrium between the two striatal output pathways. Our results might explain the therapeutic effect of D2-based medications in Parkinsons disease.

Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models

The main clinical manifestations of Parkinsons disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had ∼45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over‐responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over‐responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye‐movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinsons disease.

Striatal NMDA receptors gate cortico-pallidal synchronization in a rat model of Parkinson's disease

Anomalous patterns of synchronization between basal ganglia and cortex underlie the symptoms of Parkinsons disease. Computational modeling studies suggest that changes in cortical feedback loops involving trans-striatal and trans-subthalamic circuits bring up this anomalous synchronization. We asked whether striatal outflow synchronizes globus pallidus neurons with cortical activity in a rat model of Parkinsons disease. We found that striatal firing is highly increased in rats with chronic nigrostriatal lesion and that this hyperactivity can be reduced by locally infusing a competitive NMDA receptor antagonist. Moreover, NMDA receptor-dependent striatal output had frequency dependent effects on distinct pathological patterns of cortico-pallidal coupling. Blockade of striatal NMDA receptors almost completely abolished an anomalous ~1Hz cortico-pallidal anti-phase synchronization induced by nigrostriatal degeneration. Moreover, under striatal NMDA receptor blockade, synchronization with 2.5-5Hz cortical oscillations falls to negligible levels and oscillations at 10-20Hz are markedly attenuated, whereas beta synchronization (with a peak at ~26Hz) is marginally reduced. Thus, tonic activation of striatal NMDA receptors allows different forms of anomalous oscillations along the cortico-striato-pallidal axis. Moreover, the frequency dependent effects of NMDA receptors suggest that low and high frequency parkinsonian oscillations stem from partially different mechanisms. Finally, our results may help to reconcile views about the contributions of changes in firing rate and oscillatory synchronization to Parkinsons disease symptoms by showing that they are related to each other.

Loss of homeostasis in the direct pathway in a mouse model of asymptomatic Parkinson’s disease

The characteristic slowness of movement in Parkinsons disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 ± 7% dopaminergic neuron loss) and symptomatic (85 ± 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism. SIGNIFICANCE STATEMENT Prevailing models of Parkinsons disease state that motor symptoms arise from an imbalance in the activity of medium spiny neurons (MSNs) from the direct (dMSNs) and indirect (iMSNs) pathways. Therefore, it is hypothesized that symptom severity and the magnitude of this imbalanced activity are correlated. Using a mouse model of Parkinsons disease, we found that behaviorally undetectable nigrostriatal lesions induced a significant disconnection of dMSNs from the motor cortex. In contrast, iMSNs show an increased connectivity with the motor cortex, but only after a severe dopaminergic lesion associated with an evident parkinsonian syndrome. Overall, our data suggest that the lack of symptoms after a partial dopaminergic lesion is not due to compensatory mechanisms maintaining the activity of both striatal pathways balanced.

Striatal gating through up states and oscillations in the basal ganglia: Implications for Parkinson's disease.

Up states are a hallmark of striatal physiology. Spontaneous activity in the thalamo-cortical network drives robust plateau depolarizations in the medium spiny projection neurons of the striatum. Medium spiny neuron firing is only possible during up states and is very tightly regulated by dopamine and NMDA receptors. In a rat model of Parkinsons disease the medium spiny neurons projecting to the globus pallidus (indirect pathway) show more depolarized up states and increased firing. This is translated into abnormal patterns of synchronization between the globus pallidus and frontal cortex, which are believed to underlie the symptoms of Parkinsons disease. Here we review our work in the field and propose a mechanism through which the lack of D2 receptor stimulation in the striatum allows the establishment of fixed routes of information flow in the cortico-striato-pallidal network.

Theta Oscillations in Visual Cortex Emerge with Experience to Convey Expected Reward Time and Experienced Reward Rate

The primary visual cortex (V1) is widely regarded as faithfully conveying the physical properties of visual stimuli. Thus, experience-induced changes in V1 are often interpreted as improving visual perception (i.e., perceptual learning). Here we describe how, with experience, cue-evoked oscillations emerge in V1 to convey expected reward time as well as to relate experienced reward rate. We show, in chronic multisite local field potential recordings from rat V1, that repeated presentation of visual cues induces the emergence of visually evoked oscillatory activity. Early in training, the visually evoked oscillations relate to the physical parameters of the stimuli. However, with training, the oscillations evolve to relate the time in which those stimuli foretell expected reward. Moreover, the oscillation prevalence reflects the reward rate recently experienced by the animal. Thus, training induces experience-dependent changes in V1 activity that relate to what those stimuli have come to signify behaviorally: when to expect future reward and at what rate.

Characterization of 5-HT receptor subtypes mediating contraction in human umbilical vein. 2. Evidence of involvement of 5-HT1B receptors using functional studies

Abstract. Previous studies have shown that a heterogeneous 5-HT receptor population may be involved in vasoconstrictor actions of 5-HT in human umbilical vein (HUV). The aim of the present study was to evaluate whether the 5-HT1B/1D receptor subtype mediates contraction in this tissue.5-HT1B/1D-mediated responses can be enhanced or unmasked after exposure to threshold or sub-threshold KCl concentrations. In HUV rings, when 5-HT, α-Me-5HT or bradykinin concentration-response curves (CRC) were generated in the presence or absence of sub-threshold concentrations of KCl, there were not significant differences between the control and the treated rings. On the other hand, sumatriptan, the classic selective 5-HT1B/1D receptor agonist, produced a concentration-related contraction that was potentiated in the presence of sub-threshold KCl concentration. In addition, L-694,247, the novel selective 5-HT1B/1D receptor agonist, displayed a concentration-dependent contraction with high potency in HUV. The presence of sub-threshold concentrations of KCl produced a marked leftward shift of its CRCs.GR-55562, a 5-HT1B/1D-selective antagonist, competitively blocked sumatriptan CRCs with an estimated pA2 of 8.00 and a slope not different from unity. Likewise, SB-216641, a selective 5-HT1B antagonist, produced a parallel rightward shift of sumatriptan CRCs in HUV. The Schild analysis yielded a pA2 of 9.29, with a slope not different from unity. In addition, L-694,247 contractile responses were competitively blocked by SB-216641 with an estimated pA2 value of 9.12 and a Schild slope not different from unity. On the other hand, ketanserin behaved as a weak antagonist of L-694,247-induced responses, yielding a calculated pA2 value of 6.40.In summary, the results obtained in this study support that the 5-HT1B receptor subtype is involved in vasoconstrictor responses in HUV.

The Timing of Reward-Seeking Action Tracks Visually-Cued Theta Oscillations in Primary Visual Cortex

An emerging body of work challenges the view that primary visual cortex (V1) represents the visual world faithfully. Theta oscillations in the local field potential (LFP) of V1 have been found to convey temporal expectations and, specifically, to express the delay between a visual stimulus and the reward that it portends. We extend this work by showing how these oscillatory states in male, wild-type rats can even relate to the timing of a visually cued reward-seeking behavior. In particular, we show that, with training, high precision and accuracy in behavioral timing tracks the power of these oscillations and the time of action execution covaries with their duration. These LFP oscillations are also intimately related to spiking responses at the single-unit level, which themselves carry predictive timing information. Together, these observations extend our understanding of the role of cortical oscillations in timing generally and the role of V1 in the timing of visually cued behaviors specifically. SIGNIFICANCE STATEMENT Traditionally, primary visual cortex (V1) has been regarded as playing a purely perceptual role in stimulus-driven behaviors. Recent work has challenged that view by showing that theta oscillations in rodent V1 may come to convey timed expectations. Here, we show that these theta oscillations carry predictive information about timed reward-seeking actions, thus elucidating a behavioral role for theta oscillations in V1 and extending our understanding of the role of V1 in decision making.

Converging into a Unified Model of Parkinson’s Disease Pathophysiology

Early models of basal ganglia functional organization pointed at changes in spontaneous activity as the underlying basis of akinesia, the main clinical manifestation of Parkinson’s disease. The ‘‘classical’’ model posits that an imbalance between the direct and indirect pathways results in an increase in the average firing rate of basal ganglia output neurons, tonic inhibition of motor thalamo-cortical circuits, and reduced motor output [1, 2]. However, after nearly 20 years most researchers in the field would probably agree in that there is little evidence to support this hypothesis [3, 4]. Current models posit that dopamine depletion impedes movement by promoting excessive oscillatory synchronization of basal ganglia neurons. According to this view, spontaneous oscillation and synchronization could induce resonance at certain frequencies, precluding the encoding of other frequencies more relevant to movement [5] and/or spatial segregation of information flow [6]. Nevertheless, the mechanism underlying abnormal oscillatory synchronization is a matter of debate. Current models point at intrinsic oscillations in the GP-STN network [7, 8] or at changes in the gain of pathways conveying and reinforcing cortical oscillations [9, 10]. An alternative model puts forward the idea that basal ganglia neurons would not encode correctly action instructions in parkinsonian patients when they try to move [11]. Dopamine depletion would alter the fine temporal and spatial coordination of information flow through trans-striatal and transsubthalamic pathways, resulting in an increased inhibitory influence on the thalamus. Evidence to support this model is scarce, since studying movement in Parkinson’s disease is very difficult. Also, views about the mechanisms involved vary, with focus on either the trans-striatal or trans-subthalamic pathways [11, 12].