The basal ganglia and Parkinson's disease

The basal ganglia (BG) are a collection of subcortical nuclei that are involved in learning, planning and execution of self-initiated movement, as well as in sensory and affective processing. These nuclei include the striatum, which is the largest input structure of the BG, the globus pallidus, the subthalamic nuclei,  the substantial nigra pars reticulata (SNr, one of the output nuclei) and pars compacta (SNc), that is home to the dopamine cells that innervate the striatum. These BG form two feedforward circuits connecting the entire cortex with the frontal cortex: the direct (“go”) and indirect (“stop”) pathways. Half of the spiny projection neurons (SPNs) in the striatum belong to the direct pathway (dSPNs) and the other half to the indirect pathway (iSPNs).
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Several movement disorders such as Parkinson’s disease (PD, caused by the loss of SNc dopamine neurons) and Huntington’s disease are characterized by a severe dysfunction of BG circuitry. In PD, as dopamine cells are lost the BG circuitry becomes dysfunctional.  In our lab we are interested in understanding the normal physiological function of these circuits and what goes awry in these devastating diseases.

Characterizing the collective dynamics of striatal cholinergic interneurons during naturalistic behavior

The striatum has the highest expression of markers for dopamine and acetylcholine (ACh) in the brain. It has long been thought that for the proper function of the BG the striatum needs to maintain a so-called balance between these two neuromodulators. In our lab we are interested in the collective dynamics of striatal cholinergic interneurons (CINs)  that provide the source of tonic ACh. Cholinergic interneurons (CINs) constitute a tiny fraction of striatal cells, but they are key modulators of striatal circuits and strongly affect SPN excitability and synaptic inputs. 

Microendoscopic calcium imaging of striatal cholinergic interneurons in a freely moving mice

We employ the novel method of microendoscopic calcium imaging, which enables us to record from dozens of genetically defined CINs simultaeously in freely moving mice.  Using this cutting-edge technique, we study the collective dynamics of CINs during naturalistic behaviors in healthy intact animals, as well as in parkinsonian mice prior to and following the induction of levodopa-induced dyskinesias.

Cellular physiological responses to synucleinopathies and non-motor symptoms of Parkinson's disease

PD is known to result from the death of dopamine (DA) cells in the brain. Understanding why these cells are vulnerable in PD is necessary for the development of neuroprotective therapies. Interestingly, in addition to DA cell death, PD is characterized by the appearance of Lewy pathologies (LPs, intracellular inclusions loaded with a toxic form of the protein alpha-synuclein), not only in DA cells, but also in various other cell types in the brain. These other cells exhibit LPs decades before DA cells do, and well before the onset of the disease, but seem to be less vulnerable in PD than DA cells.

One of the first neuronal populations to exhibit these pathologies are gut innervating neurons in the dorsal motor nucleus of the vagus (DMV). It is widely thought that the appearance of LPs in these neurons accounts for one of the most common prodromal (ie, predating diagnosis) symptoms of PD – severe constipation, but the mechanism for this remains unknown. Interestingly, DMV cell loss is milder than that of DA neurons in the substantia nigra pars compacta, and recent work from our lab has shown that this is likely the result of lower levels of oxidative stress. 

Yet, many questions remain unanswered: Why are gut-innervating cells less vulnerable than dopamine cells if they exhibit LPs years earlier? What is the physiological mechanism by which the appearance of LPs in these gut-innervating cells leads to prodromal constipation prior to cell death and what biomarker can be used to identify this pathology? We use slice patch-clamp recordings, juxtacellular in-vivo recordings and histological analysis combined with non-motor behavioral assessment to dissect the physiological mechanisms in DMV neurons under pathological impacts and identify the functional biomarker.

Prodromal symptoms of Parkinson's disease

Our work on vagal alpha-synucleinopathy underscores the importance of studying the mechanisms of prodromal symptoms of PD. First, non-motor prodromal symptoms (e.g., constipation, pain) can be severe and require treatment per se. Moreover, once disease modifying therapies for PD are found it will be essential to achieve early detection based on (currently) prodromal symptoms. Thus, we expand our work to other prodromal symptoms.
In particular, the lab is collaborating with several other labs to test our hypothesis that DA neurons in the dorsal raphe nucleus (dRN) are vulnerable in PD (like nigral DA neurons) and that their functional decline leads to prodromal anxiety and depression in PD (AND-PD) by disrupting the dRN efferent pathways. To investigate this, we will combine endoscopic imaging of serotonin release in the dorsal striatum in mouse models of AND-PD with electrophysiological experiments aimed at studying the mechanism of pacemaking in dRN DA neurons and their vulnerability to calcium influx and oxidative stress.

Combining experimental and computational tools to study BG circuits

Recent seminal studies have shown that striatal dopamine (DA) release is dissociated from the discharge of nigral DA neurons, and that CINs can activate nicotinic receptors on DA fibers to induce DA release.
We are developing a mathematical model to explain how reciprocal coupling between DA release and CINs can give rise to self-organized spatiotemporal patterns. This model could explain how striatal DA release is independent of the midbrain, and provide a dynamical framework for the realization of the famous striatal “DA-acetylcholine imbalance hypothesis” of neurodegenerative diseases such as PD.