Investigating the neuromodulatory potential of the caudal zona incerta across species: a review

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Abstract Submission 

Violet Liu¹, Alaa Taha², Mohamed Abbass³, Abrar Ahmed⁴, Jason Kai⁵, Roy Haast⁶, Ali Khan², Jonathan Lau⁷

¹Western Univeristy, London, MT, ²University of Western Ontario, London, Ontario, ³Western Univeristy, London, Ontario, ⁴Department of Clinical Neurological Sciences, Division of Neurosurgery, London, Ontario, ⁵Robarts Research Institute, Western University, London, Ontario, ⁶Aix-Marseille University, Marseille, Provence, ⁷Department of Clinical Neurological Sciences, Division of Neurosurgery, London, ON

Violet Liu  
Western Univeristy
London, MT

Alaa Taha  
University of Western Ontario
London, Ontario

Mohamed Abbass, MD  
Western Univeristy
London, Ontario

Abrar Ahmed  
Department of Clinical Neurological Sciences, Division of Neurosurgery
London, Ontario

Jason Kai  
Robarts Research Institute, Western University
London, Ontario

Roy Haast  
Aix-Marseille University
Marseille, Provence

Ali Khan  
University of Western Ontario
London, Ontario

Jonathan Lau  
Department of Clinical Neurological Sciences, Division of Neurosurgery
London, ON

The zona incerta (ZI), situated between the subthalamic nucleus and ventral thalamus, has emerged as a promising neuromodulatory target for Parkinson's Disease (PD) and essential tremor (ET). Its role as a therapeutic target has been investigated in both animal models and clinical studies of deep brain stimulation (DBS; Plaha et al. 2006; Ossowska 2020; Plaha et al. 2011). Notably, the caudal region of ZI (cZI) is uniquely enriched in glutamatergic neurons, characterized by its extensive projection to the motor cortex and other subcortical regions implicated in motor control(Yang et al. 2022; Ossowska 2020). This intricate pattern of connectivity underscores its role in modulating postural and locomotion(Ossowska 2020; Wang et al. 2020), which is similarly reflected in a clinical setting, as DBS targeting of the cZI shows significant alleviation of motor symptoms in PD patients(Plaha et al. 2006; 2011; Blomstedt et al. 2018). Although rodent studies offer valuable insights into cZI organization, the neuroanatomical, cytoarchitectural, and genetic disparities between rodent and primate brains are substantial(Belmonte et al. 2015; Herculano-Houzel 2009; Molnár and Clowry 2012). The extent of neurochemical cross-species conservation of this structure remains poorly understood, insights into which could help to reveal the mechanism of action of cZI neuromodulation.

Articles published in English were identified using PubMed. Keywords included combinations of "zona incerta" with "non-human primate", "marmoset", "rhesus monkey", "macaque", "rodent", "mouse", "rat", "human". Inclusion criteria were: 1) studies investigating the connectivity, cyto- or chemo-architecture of the ZI; 2) animal models of rodents, non-human primates, PD or ET patients; 3) direct visualization of the ZI for the treatment of neurological disorders.

This review summarizes and compares the anatomical, cellular, and molecular landscapes of the ZI between rodents, non-human primates, and humans, exploring their implications for the treatment of neurological disorders. Briefly, rodents have a larger ZI to brain ratio than primates, potentially driven by differential expansion patterns during brain development across species. The primate ZI also expresses different immunomarkers in its caudal region comparing to rodents, suggesting potential difference in cellular composition (Figure 1). Although connectivity patterns and molecular composition are largely conserved, rodents have an additional intermediolateral region of connectivity that has not been observed in primates (Figure 2). Key projection areas, such as the thalamus and motor cortex, of the primate cZI also demonstrate distinct genetic profiles when compared to rodents, indicating functional differences.

We found the cZI is a highly conserved structure across rodents and primates, with subtle yet important molecular, connectomic, and anatomical inter-species differences. Improving our understanding of the neurochemical architecture of the cZI across species is critical for neuromodulatory advancements. An understanding of both electrode placement and molecular variations in cZI organization has the potential to impact treatment, enhance accurate interpretation of animal study findings in a clinical context, and ultimately improve patient outcome.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)

Anatomy and Functional Systems ²

Microcircuitry and Modules

Subcortical Structures ¹

Physiology, Metabolism and Neurotransmission Other

CHEMOARCHITECTURE

Cross-Species Homologues

Degenerative Disease

Dopamine

GABA

Glutamate

Movement Disorder

Neurotransmitter

NORMAL HUMAN

Sub-Cortical