A central framework in basal ganglia neuroscience is that the cerebral cortex sends excitatory information to the striatum, where it is integrated with thalamic and neuromodulatory signals to shape action selection, learning, and behavioral flexibility. In this classical view, the striatum acts as the major input structure of the basal ganglia, whereas processed output returns to the cortex indirectly through pallidal, nigral, and thalamocortical pathways. However, recent evidence indicates that striatal and pallidal circuits can influence cortical processing through more direct, specialized, and neurochemically diverse routes than previously appreciated , revealing an unexpected diversity of basal ganglia return pathways. In particular, the identification of a previously uncharacterized cholinergic projection from the dorsal tail of the striatum to the auditory cortex suggests that specialized striatal circuits can directly modulate cortical sensory processing. These findings provide a new entry point for reconsidering basal ganglia-cortical communication beyond the classical indirect loop model. In this review, we use this striato-cortical cholinergic pathway as a recent example, considered alongside the more established pallidocortical literature, to discuss the emerging concept of striato-pallidal-cortical return signaling. We first revisit the historical organization of corticostriatal and basal ganglia-thalamocortical loops, discuss the dorsal tail of the striatum as a sensory-associated basal ganglia node, and finally integrate recent evidence for direct and reciprocal pallidocortical pathways. Together, we propose an expanded model in which basal ganglia circuits may influence cortical gain, timing, sensory salience, and behavioral relevance through multiple return channels. Rather than replacing the classical model, this emerging view expands it: the striatum is not only a recipient of cortical input, but also a participant in return pathways that can contribute to shaping cortical computation.
Parkinson's Disease (PD) is a common neurodegenerative disorder. Existing clinical interventions merely relieve symptoms and cannot reverse progressive neuronal injury. Neuroinflammation and dysregulated programmed cell death are central pathological drivers of PD. PANoptosis is an integrated pan-programmed cell death, can simultaneously trigger apoptosis, pyroptosis and necroptosis, with the NOD‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome serving as a core molecular hub for PANoptosis initiation. Apart from its well‑characterized role in mitophagy, Parkin directly interacts with NLRP3 and mediates K63‑linked ubiquitination at the NLRP3‑K353 residue. This post‑translational modification targets NLRP3 for degradation through chaperone‑mediated autophagy (CMA), which suppresses excessive PANoptosis and preserves dopaminergic neuron survival. This review systematically delineates the molecular framework of the Parkin‑CMA‑NLRP3‑PANoptosis signaling axis. We further discuss its functional crosstalk with canonical PD‑associated pathological events, including α‑synuclein (α‑syn) aggregation and mitochondrial dysfunction, and summarize translational progress of small‑molecule compounds and gene therapies targeting individual components within this cascade. Critical bottlenecks are also addressed, such as unresolved molecular regulatory details, limitations of preclinical animal models, poor blood‑brain barrier permeability of candidate agents, and obstacles for early therapeutic intervention. This work intends to uncover promising targets for PD disease‑modifying treatments and support the advancement of precision therapeutic strategies.
