INTRODUCTION: Circuit Neuroscience methods like chemogenetics, miniscope imaging and electrophysiology in mice undergoing behavioural testing allow the identification of cellular and molecular targets to modify cognitive or affective deficits of psychiatric disorders. We have conducted a series of studies using these techniques to identify potential targets to improve cognitive deficits seen in ADHD and schizophrenia.

AIM(S): Our aim was to identify cortical brain regions, cell types within those regions and signalling cascades within those cell-types that improve impulse control and attention.

METHOD(S): We used chemogenetic modulation of certain inhibitory and excitatory neurons, miniscope imaging and electrophysiological recordings in the 5-choice-serial-reaction-time task (5-CSRTT) which assess impulsivity and sustained attention, in mice. Machine-learning-based decoding and encoding analysis were conducted on opto- and electrophysiological data. Custom-made pyControl-based operant boxes and motorized commutators were developed to allow physiological recordings in operant testing.

RESULTS: Applying those techniques we found that: (1) Among prefrontal regions, the anterior cingulate (ACC) has the most robust influence on 5-CSRTT behaviour. (2) Activation of the Gq-protein cascade in inhibitory parvalbumin (PV) neurons of the ACC improves both impulse control and attention, and decreases gamma-oscillations in ACC - as does the ADHD medication atomoxetine. (3) Activation of the Gi-protein cascade in layer 5 pyramidal neurons (PNs) of the ACC decreases impulsivity, and this can be mimicked by activating mGlu2-receptores expressed in them. (4) ACC-PCs simultaneously encode the spatial motor plan (action) just before the choice and cognitive state during and after the choice during 5-CSRTT behaviour, and this encoding is modulated by reward value. (5) Chronic ketamine exposure increases beta/gamma-band input into ACC.

CONCLUSIONS: ACC controls impulsivity and attention, and could be targetted in ADHD or schizoprenia.

FINANCIAL SUPPORT: Boehringer Ingelheim (BIU1.0 and BIU2.0 schemes), Else-Kröner-Fresenius-Foundation, DFG.