Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends, we developed pyControl, a system of open-source hardware and software for controlling behavioural experiments comprising a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high-throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier, and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Here, we outline the system’s design and rationale, present validation experiments characterising system performance, and demonstrate example applications in freely moving and head-fixed mouse behaviour.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

Operant boxes enable the application of complex behavioural paradigms to support circuit neuroscience and drug discovery research. However, commercial operant box systems are expensive and often not optimised for combining behaviour with neurophysiology. Here we introduce a fully open-source Python-based operant-box system in a 5-choice design (pyOS-5) that enables assessment of multiple cognitive and affective functions. It is optimized for fast turn-over between animals, and for testing of tethered mice for simultaneous physiological recordings or optogenetic manipulation. For reward delivery, we developed peristaltic and syringe pumps based on a stepper motor and 3D-printed parts. Tasks are specified using a Python-based syntax implemented on custom-designed printed circuit boards that are commercially available at low cost. We developed an open-source graphical user interface (GUI) and task definition scripts to conduct assays assessing operant learning, attention, impulsivity, working memory, or cognitive flexibility, alleviating the need for programming skills of the end user. All behavioural events are recorded with millisecond resolution, and TTL-outputs and -inputs allow straightforward integration with physiological recordings and closed-loop manipulations. This combination of features realizes a cost-effective, nose-poke-based operant box system that allows reliable circuit-neuroscience experiments investigating correlates of cognition and emotion in large cohorts of subjects.

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM). NMDARs have been suggested to mediate sustained firing in excitatory neurons of the prefrontal cortex (PFC) that might underlie WM storage. However, if NMDAR-hypofunction in prefrontal excitatory neurons may indeed entail WM impairments is unknown. We here investigated this question in mice, in which NMDARs were genetically-ablated in PFC excitatory cells. This cell type-selective NMDAR-hypofunction caused a specific deficit in a delayed-matching-to-position (DMTP) 5-choice-based operant WM task. In contrast, T-maze rewarded alternation and several psychological functions including attention, spatial short-term habituation, novelty-processing, motivation, sociability, impulsivity, and hedonic valuation remained unimpaired at the level of GluN1-hypofunction caused by our manipulation. Our data suggest that a hypofunction of NMDARs in prefrontal excitatory neurons may indeed cause WM impairments, but are possibly not accounting for most other deficits in schizophrenia.

Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1, might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1-knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice. We found that virally induced reduction of GluA1 across multiple hippocampal subfields impaired spatial working memory. Transgene-mediated ablation of GluA1 from excitatory cells of CA2 impaired short-term memory for conspecifics and objects. Gria1 knockout in CA3 pyramidal cells caused mild impairments of object-related and spatial short-term memory, but appeared to partially increase social interaction and sustained attention and to reduce motor impulsivity. Our data suggest that reduced hippocampal GluA1 expression—as seen in some patients with schizophrenia—may be a central cause particularly for several short-term memory deficits. However, as impulse control and sustained attention actually appeared to improve with GluA1 ablation in CA3, strategies of enhancement of AMPAR signalling likely require a fine balance to be therapeutically effective across the broad symptom spectrum of schizophrenia.