Hypothesis

Aging-related dopamine loss does not affect striatal compartments uniformly; instead, early prodromal Parkinson's disease involves preferential D2‑receptor upregulation in striosomal medium spiny neurons, which amplifies indirect‑pathway output within the striosome‑matrix circuit and triggers hyperconnectivity of the somato‑cognitive action network (SCAN) before substantial nigral degeneration.

Mechanistic Reasoning

• Striosomes receive dense limbic and associative cortical input and express higher baseline D2 receptor levels than the surrounding matrix [https://pubmed.ncbi.nlm.nih.gov/2817829/].
• With age‑related dopaminergic decline, striosomal D2 receptors undergo compensatory supersensitivity via reduced receptor internalization, increasing indirect‑pathway gain specifically in this compartment.
• Heightened striosomal indirect‑pathway activity elevates GABAergic inhibition of dopamine neurons in the substantia nigra pars compacta through the striosome‑to‑ nigral feedback loop, creating a local dopamine trough that further drives D2 supersensitivity—a positive feedback loop.
• This compartment‑specific circuit bias disrupts the balance of striosome‑matrix communication, leading to aberrant cortical‑striatal‑thalamic loops that preferentially engage the SCAN, manifesting as early hyperconnectivity observed in functional MRI [https://www.sciencedaily.com/releases/2026/02/260208203013.htm].
• Because striosomal output modulates limbic and associative circuits, the resulting SCAN hyperconnectivity explains concurrent cognitive, autonomic, and mood changes that precede classic motor signs.

Testable Predictions

1. In prodromal PD patients, PET imaging with a D2‑preferring ligand (e.g., [^11C]raclopride) will show significantly higher binding potential in striosomes relative to matrix, even when nigral dopaminergic terminal density (measured with [^18F]DOPA PET) remains >80 % of youthful levels.
2. Resting‑state fMRI will reveal a positive correlation between striosomal D2 binding strength and SCAN hyperconnectivity metrics (e.g., increased degree centrality in nodes such as the dorsal anterior cingulate and insula).
3. Chemogenetic inhibition of D2‑expressing striosomal MSNs in aged mice expressing human α‑synuclein will prevent SCAN‑like hyperconnectivity (measured via wide‑field calcium imaging of cortical‑striatal loops) and preserve motor learning tasks despite comparable nigral dopamine loss.
4. Longitudinal cohorts: individuals exhibiting elevated striosomal D2 binding at baseline will develop clinically diagnosable PD within 3 years at a rate >2‑fold higher than those with normal striosomal D2 binding, independent of baseline matrix binding or overall striatal dopamine loss.

Potential Falsifying Outcomes

• Absence of a striosome‑specific D2 increase in prodromal subjects, or a lack of correlation between striosomal D2 binding and SCAN connectivity, would refute the compartment‑trigger hypothesis.
• If chemogenetic manipulation of striosomal D2 MSNs fails to alter SCAN connectivity or motor phenotypes despite verified target engagement, the proposed causal loop would be unsupported.

This hypothesis integrates compartmental neurochemistry with network‑level dysfunction, offering a concrete biomarker (striosomal D2 PET) and a mechanistic target (striosomal D2 signaling) for early intervention.