Parkinson's disease (PD) is a common and progressive neurodegenerative disorder primarily resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) (Deumens et al., 2002). Although PD is traditionally characterized as a motor disorder, it is also a disease with diverse non-motor symptoms, such as emotional disturbances, sleep disorders and cognitive deficits (Schapira et al., 2017). Anxiety is one of the most common emotional disturbances of PD, but the exact mechanism of anxiety in PD is complex.

The amygdala has long been accepted as a part of the neural circuitry critical for emotion, especially for anxiety (Gallagher and Chiba, 1996). The basolateral amygdaloid nucleus (BL) is a major part of the amygdala and has received attention for its relation to the genesis and maintenance of anxiety-like behaviors (Tovote et al., 2015). Previous studies have shown that the BL manifests hyperexcitability in pathological anxiety (Prager et al., 2016), and pharmacological inactivation of the BL by local administration of GABAA receptor agonist muscimol (Bueno et al., 2005) or glutamate receptor antagonists AP5 and CNQX (Sajdyk and Shekhar, 1997) alleviates anxiety-like response of rats. Moreover, increasing BL activity by administration of GABAA receptor antagonists bicuculline and picrotoxin (Sanders and Shekhar, 1995) or photostimulation (Tye et al., 2011) produces anxiogenic effects in rodents. Further, a large body of evidence indicates that PD patients and parkinsonian animals with anxiety appear extensive abnormalities within the amygdala, such as changes in volume (Vriend et al., 2016), neuronal excitability (Chen et al., 2011a, Chen et al., 2011b; Sun et al., 2018; Tang et al., 2023) and dopamine (DA) level (Du et al., 2018; Sun et al., 2018; Tang et al., 2023). These findings suggest involvement of the BL in PD- related anxiety.

The BL is composed of approximately 90 % excitatory glutamatergic projection neurons (Carlsen, 1988) that receive multiple inputs from other brain areas (Sah et al., 2003), and in turn project to various downstream brain regions, such as the hippocampus (HPC), cortex, bed nucleus of the stria terminalis and nucleus accumbens (Tye et al., 2011). The remaining cell population consists of GABA interneurons, which exert inhibitory control over the glutamatergic neurons (Carlsen, 1988; Muller et al., 2006). The BL receives serotonergic innervations from the dorsal raphe nucleus (DRN), and expresses moderate to high levels of multiple 5-hydroxytryptamine (5-HT) receptor subtypes, such as 5-HT7 receptor (Ma et al., 1991). 5-HT released from the presynaptic terminals in the BL mediates its excitatory action through 5-HT7 receptors, regulating the complex interactions and the input-output relationships of the BL, such as 5-HT-glutamate interactions (Harsing Jr. et al., 2004; Hedlund, 2009; Hedlund and Sutcliffe, 2004). The ventral HPC (vHPC) receives glutamatergic input from the BL and is involved in the regulation of anxiety. A growing body of evidence suggests that hippocampal glutamatergic neurotransmission plays a vital role in the pathogenesis of anxiety. For example, mice lacking glutamate receptor from the HPC have been found to be less prone to anxiety (Barkus et al., 2010). And intra-vHPC injection of glutamate receptor antagonist AP5 has shown anxiolytic-like effects in the elevated plus maze (EPM) test (Nascimento Hackl and Carobrez, 2007). Importantly, optogenetic approaches have found that optogenetic activation or inhibition of monosynaptic glutamatergic anterior part of the BL (BLA) to vHPC inputs (BLAGlu-vHPC) produces robust anxiogenic or anxiolytic effects, respectively (Felix-Ortiz et al., 2013; Yang and Wang, 2017). While whether activation and blockade of BLA 5-HT7 receptors regulate anxiety-like behaviors, particularly in PD-related anxiety, and whether BLAGlu-vHPC pathway is involved are unclear.

In order to address the problem, a series of experiments were conducted to observe the effects of down-regulation of BLA 5-HT7 receptors expression and activation or blockade of BLA 5-HT7 receptors on anxiety-related behaviors in sham and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, and the effects of activation or blockade of BLA 5-HT7 receptors on firing activity of BLA glutamatergic neurons and levels of vHPC extracellular glutamate and GABA in the two groups of rats. Additionally, we also compared the expressions of 5-HT7 receptors on neurons projecting to the vHPC in the BLA of sham and the lesioned rats. Through the above studies, we hope to reveal the role and mechanism of 5-HT7 receptors on the BLAGlu-vHPC pathway in the regulation of PD-related anxiety, and may also provide strategies for the treatment of PD-related anxiety by targeting 5-HT7 receptors.