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Do novel neuroanatomical findings change invasive Parkinson's therapy ?



Parkinson's disease (PD) is caused by a lack of dopamine, which leads to a disruption of neuronal networks, especially in the basal ganglia below the cerebral cortex, and causes the motor problems. However, other abnormalities such as mood swings, anxiety syndromes and cognitive deficits are also found in patients.


The motor symptoms, such as rigor, tremor and bradykinesia, are treated by administering levodopa or using high-frequency deep brain stimulation (DBS), which targets the nucleus subthalamicus (STN) in the diencephalon. However, for many advanced stage patients, even this therapy is not sufficient.


Accurate identification of the neuronal circuits responsible for the various deficits in PD could lead to the development of new therapeutic approaches. The classical model in the following figures shows how loss of neurons in the pars compacta of the substantia nigra (SNc) leads to reduced inhibition of the globus pallidus (pars interna, GPi). Because the GPi itself is inhibitory, the resulting 'double inhibition' that normally occurs to allow motor activation, is severely impaired in PD patients.


View of a frontal section through the brain. The shell nucleus (putamen), tail nucleus (nucleus caudatus), and outer pale spherical nucleus (called globus pallidus or pallidum) are located in the forebrain (telencephalon). The putamen and caudate nucleus together form the striate body (striatum). The corpus callosum connects the two hemispheres of the brain. The inner part of the pallidum and the nucleus subthalamicus originate from the diencephalon, whose essential core area is the thalamus. The substantia nigra is located in the midbrain and thus still in the brainstem. It projects to the striatum (red arrow). The cerebellum, with its dentate nucleus, lies posterior to the brainstem. The dentate nucleus sends signals to the motor nuclei of the thalamus. From the ventral thalamus, signals travel to the motor cortex and from there to the brainstem and spinal cord via the capsula interna (black arrow).

Recent anatomical and physiological data show that the thalamus also regulates the nucleus accumbens, the putamen and the nucleus subthalamicus via its nucleus parafascicularis (PF) (modified Fig. 2.8 from Klimaschewski L.P. Aging and neurodegenerative diseases - why are neurons lost? In: Parkinson's and Alzheimer's today. Springer, 2022).


Schematic control of sensorimotor function by the central nervous system (CNS): The cortex stimulates the striatum via the activating transmitter glutamate. Its neurons express dopamine receptors (D1 and D2). Via the D1 receptors, dopamine transported from the substantia nigra to the striatum stimulates the locomotor programs in a direct way: due to double use of the inhibitory transmitter GABA (gamma-aminobutyric acid), activation occurs. After stimulation of D2 receptors, motor activity is regulated in an indirect way (by activation of the inner pallidum by the nucleus subthalamicus).

The pallidum and striatum also project back to the substantia nigra (inhibitory). The pars reticulata of the substantia nigra, located anterior to the pars compacta, sends inhibitory connections directly into the thalamus. The cerebellum is in parallel to these networks. The final terminal pathway from the thalamic motor nuclei to the motor cortex and on to the motor neurons in the brainstem and spinal cord is the same for both loops, the basal ganglia and the cerebellar loop (Fig. 2.8 from Klimaschewski L.P. Aging and neurodegenerative diseases - why are neurons lost? In: Parkinson's and Alzheimer's today. Springer, 2022).


The STN is therefore part of the so-called indirect pathway, which runs via the external pallidum and the STN to the GPi and activates it. Therefore, the so-called deep brain stimulation (DBS) can be used therapeutically to improve the lack of movement (bradykinesia), but also the stiffness (rigor).


Overall, the effect of an electrode seated in the STN is not easily understood. Both activations and inhibitions of neurons occur, which can be explained, at least in part, by the different neuronal subpopulations and their potentially different functions. Regulation of the STN via neuronal projections from neighboring thalamic nuclei also plays a role.


A relatively central (intralaminar) nuclear area in the thalamus, the nucleus centromedianus parafascicularis (PF), is of crucial importance. Namely, it synchronizes the output of the STN. Already in a previous study it was found that the projection of the PF to the STN can promote movement initiation and thus improve symptoms in PD. A recent paper by Zhang, Roy and colleagues published in Nature now characterizes these projections in more detail in mice and links them to PD.


Retrograde labeling experiments demonstrated that the putamen, STN, and nucleus accumbens (NAc) receive projections from distinct neuronal subpopulations of the PF with different electrophysiological properties. Using chemo- and optogenetic methods, the authors describe three relevant neuronal circuits: Connections from the PF to the caudal putamen (CPu) and to the STN appear to be critical for locomotion and motor learning, and PF projections to the NAc mediate a depression-like state.


Furthermore, the paper shows that modulation of nicotinic acetylcholine receptors (nAChRs) in these three circuits can alleviate parkinsonian symptoms. In particular, the α7-nAChRs (receptors containing the α7 subunit) in STN neurons and the β2-nAChRs in D1 receptor-positive NAc neurons, as well as the α6-nAChRs in CPu-projecting PF neurons, appear to play a crucial role (see figure below). Since these nAChRs are also expressed in macaques, a non-human primate, in a similar pattern to mice, it can be assumed that these neuronal circuits also exist in humans.


Thalamic circuits contributing to Parkinson's disease pathogenesis: neurons of the parafascicular thalamus (PF) project to the caudal putamen (CPu), nucleus subthalamicus (STN), and nucleus accumbens (NAc). Based on the study presented here, these three pathways regulate locomotion, motor learning, and mood in a mouse model of PD. The nicotinic α6-, α7-, and β2-acetylcholine receptors (nAChRs) in the three circuits may represent potential targets for therapy (Fig. 1 from Xiao B, Tan E-K, 2023, Thalamic pathways mediating motor and non-motor symptoms in a Parkinson's disease model. Trends in Neurosciences 46:1)


The present results significantly improve our understanding of the pathogenesis of PD by identifying neuronal circuits that are amenable to targeted therapy. Novel locations for deep brain stimulation (DBS) can thus be determined. However, it should be noted that PF projections to the STN primarily promote motor learning, whereas PF projections to the CPu inhibit locomotion. Thus, nonselective stimulation of the PF could lead to differential effects on these two functions.


Finally, it would need to be determined whether activation of PF-to-NAC circuits can actually alleviate the non-motor symptoms, such as depression. Furthermore, by identifying specific nAChRs that are critical for the function of the aforementioned networks, targets for clinical pharmacological trials should be found. However, this would require the development of highly specific nAChR agonists that can cross the blood-brain barrier to achieve effects in PD patients.


References:


Xiao B, Tan E-K (2023) Thalamic pathways mediating motor and non-motor symptoms in a Parkinson's disease model. Trends in Neurosciences 46:1


Zhang Y, Roy DS, Zhu Y, ..., Feng G (2022) Targeting thalamic circuits rescues motor and mood deficits in PD mice. Nature 607:321


Image credit: iStock

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