Investigating the contributions of cortical disinhibitory microcircuits to familiarity and novelty detection

The ability to distinguish between familiar and novel stimuli is fundamental to cognition, allowing greater neural resources to be allocated to novel, potentially salient, environmental cues. Electrophysiological (local field potential) markers of familiarity recognition and novelty detection have been robustly observed over varying timescales, such as 'mismatch negativity' (MMN), which emerges over minutes, and 'stimulus-selective response plasticity' (SRP), which emerges over days. Both forms of plasticity require various classes of inhibitory interneurons. These GABA-ergic cells directly inhibit excitatory neurons but also inhibit other interneurons, leading to a disinhibitory effect on the network. Disinhibitory connections have been identified between somatostatin-expressing (SOM+) neurons and parvalbumin-expressing (PV+) neurons, as well as between vasoactive intestinal polypeptide-expressing (VIP+) neurons and SOM+/PV+ neurons.

This project aims to investigate these disinhibitory networks by examining whether manipulations to disinhibitory cortical microcircuits affect electrophysiological measures of familiarity and novelty detection over both short and long timescales.

To achieve this, the first step will be to test the hypothesis that SOM+ interneurons play a causal role in SRP and to verify their previously reported involvement in MMN. This will be accomplished through the chemogenetic inactivation of SOM+ neurons using the recently developed actuator PSAM. Similarly, the role of VIP+ interneurons in SRP and MMN will be assessed using the same approach. Furthermore, this PhD will explore whether NMDAR-dependent plasticity in SOM+ neurons is necessary for SRP and MMN by evaluating these effects in a knockout mouse model lacking NMDAR in SOM+ neurons.

In addition, this project aims to investigate a case where these circuits could go awry in a mouse model of a neurodevelopmental disoder, neurofibromatosis 1 (NF1) by assessing SRP and MMN in this model.