ReTune Neuroscience Colloquium: Johannes Letzkus

Dec 1, 2022 | 5 pm | Zoom

Circuit mechanisms of neocortical plasticity.

Plasticity and flexibility of information processing in neocortex is fundamentally important for many higher brain functions including learning, perception and action. In addition, deciphering these mechanisms holds great promise for the development of rational, circuit-based strategies for neurmodulatory interventions in neurological and psychiatric diseases. Our work over the last years has identified the outermost layer 1 of neocortex as a central hotspot for processing of experience-related information in the behaving mouse. The discovery of a novel marker gene for interneurons in layer 1 enabled us to show the widespread impact of inhibition from this source during retrieval of memories.

Parallel work in human brain slices revealed that key features of these interneurons are conserved in human neocortex. Moreover, we discovered that afferents from the higher-order thalamus are a highly plastic source of long-range excitation. This pathway selectively targets layer 1, and transmits memory-related information in close correlation with acquired behavioral relevance. Recently, we uncovered a previously little defined afferent pathway to layer 1 which derives from the subthalamic zona incerta. Zona incerta is an inhibitory region, and a target for deep brain stimulation to alleviate motor and potentially mood deficits in patients with Parkinson’s disease. We discover that incertocortical afferents form a disinhibitory circuit within neocortical layer 1.

Moreover, long-range inhibitory transmission along this pathway is necessary for learning, and encodes memories in a unique and bidirectional manner that differs fundamentally from long-range excitatory systems. In conclusion, our research pinpoints layer 1 as a site with unique function, and as a main driver for the flexibility and plasticity of neocortical computations. In addition, the finding that the zona incerta is a key instructor of cortical plasticity may offer a novel entry point for dissecting the therapeutic mechanisms of deep brain stimulation.