Dopamine and Acetylcholine, a Circuit Point of View in Parkinson's Disease

Abstract

Data from the World Health Organization (National Institute on Aging, 2011) and the National Institutes of Health (He et al., 2016) predicts that while today the worldwide population over 65 years of age is estimated around 8.5%, this number will reach an astounding 17% by 2050. In this framework, solving current neurodegenerative diseases primarily associated with aging becomes more pressing than ever. In 2017, we celebrate a grim 200th anniversary since the very first description of Parkinson's disease (PD) and its related symptomatology. Two centuries after this debilitating disease was first identified, finding a cure remains a hopeful goal rather than an attainable objective on the horizon. Tireless work has provided insight into the characterization and progression of the disease down to a molecular level. We now know that the main motor deficits associated with PD arise from the almost total loss of dopaminergic cells in the substantia nigra pars compacta. A concomitant loss of cholinergic cells entails a cognitive decline in these patients, and current therapies are only partially effective, often inducing side-effects after a prolonged treatment. This review covers some of the recent developments in the field of Basal Ganglia (BG) function in physiology and pathology, with a particular focus on the two main neuromodulatory systems known to be severely affected in PD, highlighting some of the remaining open question from three main stand points: - Heterogeneity of midbrain dopamine neurons. - Pairing of dopamine (DA) sub-circuits. - Dopamine-Acetylcholine (ACh) interaction. A vast amount of knowledge has been accumulated over the years from experimental conditions, but very little of it is reflected or used at a translational or clinical level. An initiative to implement the knowledge that is emerging from circuit-based approaches to tackle neurodegenerative disorders like PD will certainly be tremendously beneficial.

Keywords: Parkinson’s disease; acetylcholine; dopamine; optogenetics; sub-circuits.

Figure 1

Recent developments in Basal Ganglia (BG) circuit organization. This figure aims at highlighting the increased knowledge collected in the last years in the network organization of the BG with the Delong model proposed in the late 90’s as a starting point. (A) Schematic representing the Delong rate model of BG organization where activation of the direct (full line) and indirect (dotted line) pathways has opposing effects onto the thalamo-cortical loop. In the direct pathway, dMSNs inhibit the output structures (SNr/GPi), sending a GO motor signal; conversely the iMSNs disinhibit the subthalamic nucleus (STN) via the inhibition of the GPe, ultimately providing a NO GO motor signal. (B) Simplified representation of the connectivity between BG nuclei, showing some of the recently described synaptic contacts (reported in the current review as examples of the advances made in the field), as revealed by monosynaptic rabies anatomical mapping and/or optogenetic and electrophysiological dissection. Green and red connection lines represent the direct inputs and outputs to SNc and VTA, highlighting the parallel between motor and motivation/reward related circuits, respectively. DS, Dorsal striatum; NAc, nucleus accumbens; dMSN, direct pathway medium size spiny neurons; iMSN, indirect pathway medium size spiny neurons; GPe, Globus Pallidus external; GPi, Globus Pallidus internal segment; STN, subthalamic nucleus; SNr, Substantia Nigra pars Reticulata; SNc Substantia Nigra pars Compacta; mPFC, medial prefrontal cortex; M1, primary motor cortex; LH, lateral hypothalamus; PF, parafascicular thalamus; RT, reticular thalamus; VL, ventro-lateral thalamus; LDT, latero-dorsal thalamus; LHb, lateral habenula; DR, dorsal raphe; PPN, Pedunculopontine Nucleus; VTA, ventral tegmental area.

Figure 2

Neuromodulation of MSNs. Schematic representing the convergence of dopamine (DA) and ACh modulation on excitatory inputs onto a dMSN in the dorsal striatum (DS). DA terminals modulate excitatory neurotransmission forming synapses onto the neck of MSN spines; through two molecular mechanisms involving DA and the co-released GABA. These DAergic input is modulated by presynaptic nAChRs and this cholinergic control can itself be fine-tuned via the presence of presynaptic D2Rs. Activation of D1Rs, that are coupled to the Gαs protein, leads to the production of cyclic adenosine monophosphate (cAMP) via the adenylate cyclase (AC). This promotes the protein kinase A (PKA) function, which phosphorylates DARPP32, indirectly driving an increase in neuronal excitability via the activation of Ca²⁺ channels and NMDA receptors as well as the inhibition of K⁺ channels.

Figure 3

Pairing of functionally distinct dopaminergic sub-circuits. A salient external stimulus (blue arrow) can activate different pathways depending on the context and valence of the stimulus. We propose 3 different scenarios speculating on how the BG circuitry can be engaged to produce an appropriate and complex (reward and motor-based) behavioral response. (A) Upstream pairing scenario with a common input (e.g., GP) recruiting both VTA and SNc DA populations. When such a common input is activated, it synchronizes the DA release of VTA and SNc at their specific targets (mPFC and DS, respectively), hence recruiting these complementary pathways to engage both reward and motor programs for the execution of a task. (B) Local pairing via a so far unreported direct DA-DA interaction where the activation of one DA neuronal population induces the modulation of the other, hence engaging both complementary output pathways (mPFC and DS) to produce an elaborated behavioral outcome. (C) Downstream pairing scenario with mutual recruitment of output regions independently of the DA source. For example, the activation of VTA DA cells engages its specific output target (the mPFC) which itself activates the SNc DA neurons’ target (DS) independently of the release of DA from the SNc cells. Blue shading highlights the recruited regions for each scenario. Orange dotted shapes represent the location where the pairing occurs.