Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function

Abstract

The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state.Int. J. Mol. Sci. 2020, 21, 2734 2 of 13 particular, the MTh receives the BG input at the level of the ventral-anterior (VA) and the ventral-medial (VM) nuclei [2]. BG are assumed to inhibit the thalamus under basal conditions because substantia nigra pars reticulata (SNr) and internal globus pallidus (GPi) display high spontaneous spiking rates, releasing GABA in the MTh. However, when the BG network is activated by cortical input, BG output is transiently suppressed and downstream targets, including the MTh, are disinhibited [3,4]. Another source of GABA in the MTh comes from the nucleus reticular thalami (NRT) [5], a thin layer of GABAergic cells adjacent to the relay nuclei of the dorsal thalamus, that we have shown to be able to modulate the oscillatory activity of MTh in dopamine (DA)-depleted animals [6]. On the other hand, the excitatory input to the MTh is classically provided by the cerebellothalamic [7] and corticothalamic synapses [8,9]. Moreover, it has been recently shown that some substantia nigra (SN) neurons project to the NRT and the posterior thalamus, and co-release glutamate (GLU) and DA, while the VA and VM would receive preferential GABAergic SN fibers [10]. GABA, GLU and DA, therefore, may interact when modulating synapse and excitability within the MTh in normal and pathological conditions [11][12][13][14]. Although it is well established that the appearance of the cardinal features of Parkinson's disease (PD) is due to the degeneration of...

Afferent and efferent projections of the rostral anterior cingulate cortex in young and middle-aged mice

“…Our results show that the VAL/VM was the most dominant output-projection brain region of the rACC. Previous studies have shown that the VAL/VM belongs to the motor nucleus of the thalamus and is an internal brain area of the thalamus that encodes and integrates motor information ( Gaidica et al, 2018 ; Di Giovanni et al, 2020 ). The VAL/VM is not only involved in the execution of regulated movements but also in their planning ( Guo et al, 2017 ; Svoboda and Li, 2018 ).…”

Changes in Excitability Properties of Ventromedial Motor Thalamic Neurons in 6-OHDA Lesioned Mice

“…Increased motor thalamic LTS bursting has been found in MPTP-treated primates ( Magnin et al, 2000 ; Devergnas et al, 2016 ) and in the dopamine deficient SPR-KO mouse model ( Kim et al, 2017 ). While assessment of VM bursting in awake rodents is yet lacking, a recent study shows increased bursting following 6-OHDA treatment recorded under urethane anesthesia ( Di Giovanni et al, 2020 ). Interestingly, in this study, an acute dopamine depletion led to a decrease in BGMT firing rate and increase in thalamic GABA transmission, whereas the chronic 6-OHDA depleted state resulted not in a firing rate change, but in increased bursting, supporting the notion of an intervening homeostatic mechanism as dopamine depletion persists.…”

Deep brain stimulation in Parkinson’s disease patients and routine 6‐OHDA rodent models: Synergies and pitfalls

“…Unexpected alterations occurred (Grandi, Kaelin-Lang, et al, 2018) as the two states of DA depletion disclosed a decoupled activity between the MTh and the NRT, unmasking compensatory mechanisms and the putative role of NRT in the interplay between MTh and cortex. Furthermore, we recently observed that the acute TTX-driven DA depletion causes a reduction of MTh activity (Di Giovanni et al, 2020) parallel with the increment of firing activity of NRT (Figure 3); conversely following 6-OHDA, the changes of MTh activity were negligible, suggesting that the development of compensatory mechanisms was likely exerted by NRT in order to counteract the glutamate driven from the cortex.…”

“…Some remarks apply : The progressive induction of a dopaminergic neuron damage in 1–2 weeks allows an assessment of the probable compensatory mechanisms that go along with the dopaminergic deficits which we are not able to look at in PD patients, as they have already been well established. For instance, we demonstrated how the chronic DA depletion causes subtle changes in a crucial and often slightly investigated time point of the disease, that is, the MTh, considerably soon after the rapid interruption of the nigrostriatal pathway (DiGiovanni et al, 2020). Moreover, the effects on the neuronal oscillations, mainly in the β band range, that appear following the chronic denervation, suggest underling compensatory mechanisms which are even extra‐dopaminergic (Salvade et al, 2016).…”