Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural signals during unrestrained behavior and their open-source versions have made them affordable. Often, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight miniscope with a small footprint that integrates a high-sensitivity image sensor, an inertial measurement unit and an LED driver for an external optogenetic probe. We use it to perform the first concurrent cellular resolution recordings from cerebellum and cerebral cortex in unrestrained mice, demonstrate its optogenetic stimulation capabilities to examine cerebello-cerebral or cortico-striatal connectivity, and replicate findings of action encoding in dorsal striatum. In combination with cross-platform acquisition and control software, our miniscope is a versatile addition to the expanding tool chest of open-source miniscopes that will increase access to multi-region circuit investigations during unrestrained behavior.

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Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural activity during unrestrained behavior and their open-source versions have helped to distribute them at an affordable cost. Generally, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight, small footprint open-source miniscope that incorporates a high-sensitivity image sensor, an inertial measurement unit (IMU), and an LED driver for an external optogenetic probe. We highlight the advantages of NINscope by performing the first simultaneous cellular resolution (dual scope) recordings from cerebellum and cerebral cortex in unrestrained mice, revealing that the activity of both regions generally precede the onset of behavioral acceleration. At the same time, we demonstrate the optogenetic stimulation capabilities of NINscope and show that cerebral cortical activity can be driven strongly by cerebellar stimulation. Finally, we combine optogenetic stimulation of cortex with imaging in the dorsal striatum and replicate previous studies that show action space is encoded by neurons in this subcortical region. In combination with cross-platform control software NINscope is a versatile addition to the expanding toolbox of open-source miniscopes and will aid multi-region circuit investigations during unrestrained behavior.

Obsessive‐compulsive disorder (OCD) is characterized by obsessive thinking, compulsive behavior and anxiety, and is often accompanied by cognitive deficits. The neuropathology of OCD involves dysregulation of cortical‐striatal circuits. Similar to OCD patients, SAPAP3 knockout mice 3 (SAPAP3 −/− ) exhibit compulsive behavior (grooming), anxiety and dysregulated cortical‐striatal function. However, it is unknown whether SAPAP3 −/− display cognitive deficits and how these different behavioral traits relate to one another. SAPAP3 −/− and wild‐type (WT) littermates were trained in a Pavlovian conditioning task pairing visual cues with the delivery of sucrose solution. After mice learned to discriminate between a reward‐predicting conditioned stimulus (CS+) and a non‐reward stimulus (CS−), contingencies were reversed (CS+ became CS− and vice versa). Additionally, we assessed grooming, anxiety and general activity. SAPAP3 −/− acquired Pavlovian approach behavior similarly to WT, albeit less vigorously and with a different strategy. However, unlike WT, SAPAP3 −/− were unable to adapt their behavior after contingency reversal, exemplified by a lack of re‐establishing CS+ approach behavior (sign tracking). Surprisingly, such behavioral inflexibility, decreased vigor, compulsive grooming and anxiety were unrelated. This study shows that SAPAP3 −/− are capable of Pavlovian learning, but lack flexibility to adapt associated conditioned approach behavior. Thus, SAPAP3 −/− not only display compulsive‐like behavior and anxiety, but also cognitive deficits, confirming and extending the validity of SAPAP3 −/− as a suitable model for the study of OCD. The observation that compulsive‐like behavior, anxiety and behavioral inflexibility were unrelated suggests a non‐causal relationship between these traits and may be of clinical relevance for the treatment of OCD.

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There is active debate on the role of dopamine in processing aversive stimuli, where inferred roles range from no involvement at all, to signaling an aversive prediction error (APE). Here, we systematically investigate dopamine release in the nucleus accumbens core (NAC), which is closely linked to reward prediction errors, in rats exposed to white noise (WN, a versatile, underutilized, aversive stimulus) and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, this dopamine signal was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine response shifted only partially toward its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings demonstrate that instead of an APE, NAC dopamine primarily tracks prediction and duration of aversive events.

The role of dopamine in processing aversive stimuli is under debate: Credits range from no involvement at all, to acting as a punishment-prediction error (PPE) signal. Here, we systematically investigated dopamine release in the nucleus-accumbens core (NAC), which is closely linked to reward-prediction errors, in rats that were exposed to white noise (WN), a versatile, underutilized aversive stimulus, and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, dopamine was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine-response shifted only partially towards its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings indicate that instead of a PPE, NAC dopamine primarily tracks prediction and duration of punishment.