Layer 1 NDNF interneurons are specialized top-down master regulators of cortical circuits

Area of Science:

• Neuroscience
• Cellular Neuroscience
• Cortical Circuitry

Background:

• Inhibitory interneurons (INs) are crucial for neocortical circuit function, with diverse subtypes identified in layers 2-6 (L2-L6).
• Layer 1 (L1) INs, particularly those expressing neuron-derived neurotrophic factor (NDNF), have remained less understood due to a lack of selective markers.
• Key aspects of NDNF L1INs, including their connectivity, input-output conversion, and potential subtypes, were largely unknown.

Purpose of the Study:

• To investigate the connectivity of NDNF L1INs with other IN types in the superficial neocortex.
• To characterize the physiological properties and potential subtypes of NDNF L1INs.
• To elucidate the role of NDNF L1INs in regulating cortical circuit activity.

Main Methods:

• Utilized intersectional genetics to identify and study NDNF L1INs and their subpopulations.
• Investigated the physiological properties, including persistent firing, of NDNF L1INs.
• Mapped the inhibitory connectivity of NDNF L1INs onto other IN types in L2/3.

Main Results:

• NDNF L1INs were found to pervasively inhibit L2/3 INs, including parvalbumin and vasoactive intestinal peptide expressing subtypes.
• A subpopulation of NDNF L1INs co-expressing neuropeptide Y displayed similar physiology and connectivity.
• NDNF L1INs selectively and prominently exhibited persistent firing, decoupling their output from immediate input.

Conclusions:

• NDNF L1INs are specialized regulators of superficial neocortical circuits, exerting widespread top-down inhibition.
• The persistent firing property suggests a distinct role in modulating network states independent of rapid synaptic input.
• This study identifies NDNF L1INs as key players in cortical computation, offering new avenues for understanding circuit dynamics.