Inhibition in cognition : neurophysiology and connectivity of gabaergic interneurons in the prefrontal cortex

The prefrontal cortex (PFC) is a cortical region involved in higher-order cognitive functions, it is widely connected to the rest of the neocortex and is involved in tasks that require temporal integration of information. The local PFC circuit contains excitatory pyramidal neurons and inhibitory interneurons, and the interplay between these is essential for computations in the PFC.

Parvalbumin (PV) expressing interneurons form a subclass of inhibitory interneurons in the neocortex. PV interneurons are fast spiking interneurons that can control the output of pyramidal neurons. PV interneurons play an important role in maintaining the excitatory/inhibitory balance in the PFC. The PFC, and specifically PV interneurons in the PFC, play an important role in several mental disorders.

This thesis explores the input to excitatory and inhibitory neurons in the PFC, and investigates the local connectivity between these neurons. Study I revealed a whole-brain atlas of inputs to four types of neurons in the PFC. All four neuron types receive similar inputs from the rest of the brain. The connections between local interneurons were also investigated and revealed varying degrees of connectivity between different subtypes. Study II focused on generating a PV-Cre rat and demonstrated that PV interneurons in the rat could be reliably targeted both ex vivo and in vivo. Study III centred around the effect of PV interneurons on BDNF/trkB signaling and how this altered the local PFC circuit. Following overexpressing of a truncated trkB receptor, BDNF/trkB signaling is impaired; this decreased PV inhibition, altered the LFP and was linked to increased aggression in mice. Study IV investigated the connection from the auditory cortex to the PFC and showed that both pyramidal neurons and PV interneurons receive monosynaptic, excitatory input from the auditory cortex.

This thesis sheds light on the inputs to the PFC and in particular on prefrontal PV interneurons. Furthermore, it shows that BDNF/trkB signalling in PV interneurons is important for PFC function and it elucidates the local connectivity patterns in the PFC.

List of scientific papers

I. Ährlund-Richter, S., Xuan, Y.,van Lunteren, J. A., Kim, H., Ortiz, C., Dorocic, I. P., Meletis, K., and Carlén, M. (2019). A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse. Nature Neuroscience. 22(4), 657-668.
https://doi.org/10.1038/s41593-019-0354-y

II. Brünner, H. S., Ährlund-Richter, S., van Lunteren, J. A., Crestani, A. P., Kim, H., Meletis, K., and Carlén, M. Genetic Targeting and Manipulation of Parvalbumin Neurons in the Rat. [Manuscript]

III. Guyon, N., Zacharias, L. R., van Lunteren, J. A., Immenschuh, J., Fuzik, J., Märtin, A., Xuan, Y., Zilberter, M., Kim, H., Meletis, K., Lopes-Aguiar, C., and Carlén, M. (2021). Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics. Journal of Neuroscience. 41(14), 3120-3141.
https://doi.org/10.1523/JNEUROSCI.1848-20.2021

IV. van Lunteren, J. A., Ährlund-Richter, S., Ortiz, C., Carlén, M. (2021). Anatomical mapping and functional characterization of cortical auditory projections to excitatory and inhibitory neurons in the mouse prefrontal cortex. [Manuscript]