Parkinson's disease (PD) is a neurodegenerative disease, characterized by both motor symptoms like tremors, bradykinesia, and rigidity, as well as non-motor symptoms such as anxiety and depression (Obeso et al., 2017). Approximately 60 % of individuals with PD experience symptoms of anxiety, while about 38 % experience symptoms of depression (Abou et al., 2021; Broen et al., 2016; Cong et al., 2022). These findings underscore the common occurrence of anxiety and depression in PD patients, which can detrimentally impact treatment efficacy for movement disorders, thereby increasing disability and mortality rates (Pagonabarraga et al., 2023).

Up to now, the pathogenesis of anxiety and depression in PD comorbidity is still unclear. Disorder of monoamine neurotransmitter system (Liu et al., 2018), dysfunction of neural circuit, neuroinflammation (Liu et al., 2021) and reduced neuroplasticity (Weina et al., 2018) are all key factors leading to the disease. A large amount of evidence supports that abnormal dopaminergic, 5- hydroxytryptamine and noradrenergic functions can induce anxiety and depression susceptibility (Liu et al., 2018). The progressive loss of dopamine neurons in the substantia nigra and the formation of Lewy bodies are the main pathological features of PD (Jellinger, 2023), and according to braak's PD staging system, Lewy bodies will involve the limbic system (such as amygdala, hippocampus and locus coeruleus) and monoamine nuclei in the brain stem in the first and second stages of PD (Thobois et al., 2017), which may lead to emotional disorders before motor symptoms (Braak et al., 2003). A clinical research report pointed out that depressed PD patients with comorbidities exhibit more severe loss of dopamine neurons in the dense part of the substantia nigra compared to non-depressed PD patients. Additionally, SPECT tracking of dopamine transporters has revealed that depressive symptoms in PD patients correlate with decreased density of dopamine transporters in the caudate nucleus (Vriend et al., 2014a, b). A study inducing selective loss of dopamine neurons in the substantia nigra and the ventral tegmental area in rats, evaluating both motor skills and non-motor symptoms, demonstrated that the loss of dopamine neurons in the substantia nigra led to affective disorders in rats, with no occurrence of motor disorders. This may suggest that emotional deficiency is due to the loss of dopamine neurons in substantia nigra (Drui et al., 2014). Dysfunction of the serotonergic system is associated with depression in the general population, with degeneration of serotonergic neurons in the raphe nucleus occurring during PD progression (Ryan et al., 2019). A significant in vivo study found that alterations in serotonergic system function were linked to higher levels of depression in PD patients not using antidepressants, and cerebrospinal fluid 5-hydroxyindoleacetic acid levels were lower in PD-comorbid depressed patients compared to other depressed patients (Kaiserova et al., 2021). However, some studies have not found differences in serotonergic neuron loss between PD comorbidities and PD patients without depression (Beucke, 2011). Changes in norepinephrine function are closely associated with PD comorbiditic depression. PET tracing of norepinephrine transporters revealed that the severity of PD depression was associated with a specific loss of norepinephrine innervation in the limbic system (Remy et al., 2005). The onset of PD depression may be related to the deficiency of norepinephrine in the locus coeruleus, the primary brain nucleus releasing norepinephrine. The loss of norepinephrine content in the locus coeruleus exceeds 70 % in the early stages of PD (Paredes-Rodriguez et al., 2020).

PD comorbid anxiety disorder is closely associated with the fear circuit and the limbic cortex-striatum-thalamocortical circuit. Dysregulated transmission of both dopaminergic and non-dopaminergic systems within these circuits can precipitate anxiety. Specifically, functional alterations in the striatal dopaminergic system are linked to the severity of anxiety. However, previous studies have yielded conflicting results. Some studies have indicated a reduction in dopaminergic uptake in the right striatum of anxious PD patients (Maillet et al., 2016), while others have reported a positive correlation between dopaminergic uptake in the striatum and patients' social anxiety or personality traits related to anxiety (Picillo et al., 2017; Zhong et al., 2017). In the non-dopaminergic system, serotonergic and noradrenergic neurons release corresponding neurotransmitters to modulate anxiety within regions such as the hippocampus, amygdala, and prefrontal cortex (Bethea et al., 2004; Laurencin et al., 2024). The multifactor and complexity of the pathological mechanism of PD with anxiety and depression suggest that we need more in-depth research to solve this problem.

Constructing relevant disease models is a vital approach to studying the pathophysiological mechanisms of PD. The non-human primate (NHP) model of PD induced by the neurotoxin MPTP is widely acknowledged as a reliable preclinical animal model. Furthermore, NHPs demonstrate highly similar physiological and behavioral responses to anxiety and depression, encompassing genes, physiological activities, brain structure, and the manifestation of anxiety and depression symptoms, making them an ideal animal choice (Barros and Tomaz, 2002). Depressed mood and anhedonia are the core symptoms of depression (Peterson et al., 2017), in which both non-human primates and humans can observe the decrease of social behavior and expected behavior changes accompanied by anhedonia. Among them, the expected behavior changes are characterized by impaired attention control and reduced positive reinforcement response to reward-related stimuli in NHP behavior (van Oosten et al., 2025). Anxiety consists of two basic elements: physical arousal and cognitive anxiety, and is characterized by excessive vigilance against threatening stimuli and social evaluation. Different levels of physical arousal and cognitive anxiety constitute different types of anxiety, corresponding to different behavior response patterns of NHP. On the one hand, it is a reaction mode of attention hyperactivity-behavior avoidance, on the other hand, it avoids threatening stimuli by reducing attention to stimuli(Fajkowska et al., 2017).

In this study, we aimed to detect anxiety-like and depression-like behaviors in a symptomatic PD monkey model and to assess anxiety and depression-related pathological changes in the brain by immunohistochemical methods. On the one hand, it can provide a suitable model and evaluation basis for pre-clinical PD anxiety and depression research. On the other hand, it provides data support for drug research and key targets of neuroregulation.