The basolateral amygdala and striatum propagate alpha-synuclein pathology causing increased fear response in a Parkinson’s disease model

• BLA and striatum serve as hub regions that rapidly develop alpha-synuclein pathology after PFF injections, spreading quickly in female Thy1-aSyn mice. • PFF injection increased microgliosis and astrogliosis in the nigrostriatal system and reduced Parv interneurons in female Thy1-aSyn mice. • PFF injection into the BLA results in Parv interneuron loss, potentially reducing local inhibitory input across the corticolimbic circuitry. • PFF injection increased regionally-specific enhanced fear response without nigrostriatal dopaminergic degeneration. Alpha-synuclein (aSyn)-related pathology crucially contributes to the pathogenesis of Parkinson’s disease, a frequent and incurable neurodegenerative disease characterized by progressive motor and non-motor symptoms. Anxiety and fear- related neuropsychiatric symptoms develop frequently and early in the disease, but a lack of understanding of pathogenesis hampers rational therapy. This study aimed to decipher whether aSyn pathology in the basolateral amygdala (BLA) is causative of fear and anxiety. Bilateral stereotaxic injections of human aSyn-preformed amyloid fibrils (PFF) in BLA, striatum, or substantia nigra were conducted in female mice overexpressing human aSyn (Thy1-aSyn) and in wildtype littermates (WT). We characterized the propagation of aSyn pathology and related neuropathological changes across brain regions and examined the behavioral and fear responses in mice up to 2 months post-injection of PFF. While PFF injections induced local aSyn fibril pathology close to all respective injection sites in transgenic mice, we observed differences in propagation, downstream pathology and behavioral alterations. The BLA and the striatum, but not the substantia nigra, effectively propagated aSyn pathology to connected brain regions at 2.5 months post injection. This involved enhanced microgliosis and astrogliosis in the nigrostriatal system and loss of GABAergic parvalbuminergic interneurons in the striatum and corticolimbic brain regions. Intra-BLA PFF injections resulted in increased cued fear response in both transgenic mice and WT mice at 1 month post injection. The effect was more pronounced in the transgenic mice. Conversely, intra-striatal PFF injections enhanced contextual fear in WT at 2 months post injection. These findings imply that increased fear is inducible by aSyn pathology, especially if originating in the BLA or striatum. Furthermore, both regions are hub regions of aSyn pathology propagation, thereby contributing to disease progression. These insights provide mechanisms that can guide rational therapeutic development.