Hughlings Jackson Lecture - The Basal Ganglia and the Motivation to Act

Abstract: It is universally recognized that the basal ganglia are implicated in major hypokinetic and hyperkinetic extrapyramidal motor disorders. However, a shift in thinking about the basal ganglia is emerging, driven by the realization that their influence extends beyond motor control to the modulation of mood and cognition. In this lecture, Ann Graybiel will highlight experimental work that supports these non-classical views and present evidence suggesting that previously unrecognized links between the striatum and the dopamine-containing neurons of the substantia nigra may be crucial to these broader functions of the basal ganglia.

Foundational research has established that a balance between two principal output pathways of the basal ganglia—the Direct-D1 and Indirect-D2 pathways—is necessary for normal movement. Imbalances favoring the canonical D1 ‘Go’ pathway are associated with hyperkinetic disorders such as Huntington’s disease, whereas dominance of the D2 ‘NoGo’ pathway is linked to hypokinetic disorders like Parkinson’s disease. Operationally, an agonist-antagonist balance between these pathways is thought to regulate and coordinate movements, supplemented by cooperative interactions between them. These pathways project to the motor output nuclei of the basal ganglia.

Outside this classical model lies the nigro-striato-nigral loop, a circuit affected in Parkinson’s disease and implicated in a variety of neuropsychiatric conditions. With the advent of powerful new tools in experimental neuroscience, it has become possible to begin aligning this loop with the classical circuit organization. Remarkably, it appears that the canonical Direct and Indirect pathways are paralleled by a non-canonical pair of pathways that target not the motor output nuclei, but the dopamine-containing neurons of the substantia nigra.

These newly identified pathways originate from specialized, widely distributed compartments in the striatum known as striosomes—structures first identified in the human brain. Current evidence from Graybiel's lab suggests that striosomal pathways closely mirror the canonical Direct and Indirect pathways, yet differ critically in their output targets. They appear to act in opposition to one another and retain the Go-D1 and NoGo-D2 signaling polarities. Though these findings are recent, mounting evidence indicates that striosomes play key roles in reinforcement-based learning, behavioral engagement, cost-benefit decision-making, and the regulation of mood and bodily states—functions aligned with their input from limbic-related brain regions.

Together, these discoveries support the development of new models of basal ganglia function, incorporating motivation and mood as integral elements of forebrain control circuits that interact with dopamine and other neuromodulatory systems to guide behavior and cognition.

Bio: Ann Graybiel is an Institute Professor at the Massachusetts Institute of Technology. She received her undergraduate degree at Harvard University and her PhD at MIT. Her scientific work is focused on the functional analysis of neural circuits related to the basal ganglia. The striatal compartments that she discovered in the human brain (striosomes, within a large matrix) project to the dopamine-containing neurons of the midbrain substantia nigra, thereby forming critical gateways stretching from limbic-related cortical regions inputs through the striosomal system to modulate dopamine.

Established in 1935, the Hughlings Jackson Lecture is The Neuro’s premier scientific lecture. It honours the legacy of British neurologist John Hughlings Jackson (1835-1911) who pioneered the development of neurology as a medical specialty. A reception will follow for registered attendees.

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