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The hippocampus is a critical component of a mammalian spatial navigation system, with the firing sequences of hippocampal place cells during sleep or immobility constituting a “replay” of an animal's past trajectories. A novel spatial navigation task recently revealed that such “replay” sequences of place fields can also prospectively map onto imminent new paths to a goal that occupies a stable location during each session. It was hypothesized that such “prospective replay” sequences may play a causal role in goal-directed navigation. In the present study, we query this putative causal role in finding only minimal effects of muscimol-induced inactivation of the dorsal and intermediate hippocampus on the same spatial navigation task. The concentration of muscimol used demonstrably inhibited hippocampal cell firing in vivo and caused a severe deficit in a hippocampal-dependent “episodic-like” spatial memory task in a watermaze. These findings call into question whether “prospective replay” of an imminent and direct path is actually necessary for its execution in certain navigational tasks.

FIGURE S1. Behavioral apparatus and histology. (A) The open arena for the Home-Random navigation task with wall-placed and hanging 3D extramaze cues, and four start boxes (black) on each perimeter wall. (B and C) Histological identification of the cannula placement in the dorsal hippocampus (B) and mPFC (C). The numbers above each picture represent the distance (in mm) of the section from bregma (Paxinos & Watson, 2007) THE RAT BRAIN: In stereotaxic coordinates, 6th Ed, Netherlands, Elsevier., FIGURE S2. Histological assessment of the spread of fluorophore-conjugated muscimol (FCM) in the hippocampus. (A–C) Schematic of bilateral hippocampal cannula positions (A), representative images (B) and average fluorescence distribution of FCM (C) in the hippocampus (HPC) as well as two representative areas of the dorsal neocortex: parietal association cortex (PtA) and retrosplenial cortex (RSC). Means ± S.E.M., FIGURE S3. Hippocampal inactivation with muscimol did not prevent the animals to successfully navigate to the known home location. (A–D) Latency (A and B) and path length (C and D) to goal during Random and Home phases after vehicle (A and C) and muscimol infusions (B and D) into the hippocampus. Means ± S.E.M., FIGURE S4. Histological assessment of the spread of FCM in mPFC. (A–C) Schematic of bilateral mPFC cannula positions (A) representative images (B) and average fluorescence distribution of FCM (C) in the prelimbic region of mPFC (PrL) as well as two representative areas of the frontal cortex: secondary motor cortex (M2) and frontal cortex area 3 (Fr3). Means ± S.E.M.

Major psychiatric disorders such as attention-deficit/hyperactivity disorder and schizophrenia are often accompanied by elevated impulsivity. However, anti-impulsive drug treatments are still limited. To explore a novel molecular target, we examined the role of dopamine D-5 receptors in impulse control using mice that completely lack D-5 receptors (D5KO mice). We also measured spontaneous activity and learning/memory ability because these deficits could confound the assessment of impulsivity. We found small but significant effects of D-5 receptor knockout on home cage activity only at specific times of the day. In addition, an analysis using the q-learning model revealed that D5KO mice displayed lower behavioral adjustment after impulsive actions. However, our results also showed that baseline impulsive actions and the effects of an anti-impulsive drug in D5KO mice were comparable to those in wild-type littermates. Moreover, unlike previous studies that used other D-5 receptor-deficient mouse lines, we did not observe reductions in locomotor activity, working memory deficits, or severe learning deficits in our line of D5KO mice. These findings demonstrate that D-5 receptors are dispensable for impulse control. Our results also indicate that time series analysis and detailed analysis of the learning process are necessary to clarify the behavioral functions of D-5 receptors.

Purkinje cells (PCs) are principal cerebellar neurons, and several classes of interneurons modulate their activity. Lugaro cells (LCs) are one such inhibitory interneuron with distinctive cytology and location, but still most enigmatic among cerebellar neurons. Here we serendipitously produced a novel transgenic mouse line, where a half of Yellow Cameleon (YC)(+) cells in the cerebellar cortex were judged to be LCs, and YC(+) LCs were estimated to constitute one-third of the total LC populations. Neurochemically, two-thirds of YC(+) LCs were dually GABAergic/glycinergic, with the rest being GABAergic. Beneath the PC layer, they extended a sheet of somatodendritic meshwork interconnected with neighboring LCs by adherens junctions, and received various inputs from climbing fibers, mossy fibers, granule cell axons, recurrent PC axons, Golgi cell axons, LC axons, and serotonergic fibers. Intriguingly, somatodendritic elements of individual LCs preferentially extended within a given cerebellar compartment defined by aldolase C expression. In turn, YC(+) LCs projected a dense lattice of ascending and transverse axons to the molecular layer, and innervated molecular layer interneurons (basket and stellate cells) and Golgi cells, but not PCs. Of note, ascending axons profusely innervated individual targets within a cerebellar compartment, while transverse axons ran across several compartments and innervated targets sparsely. This unique circuit configuration highlights that LCs integrate various excitatory, inhibitory, and modulatory inputs coming to the belonging cerebellar compartment and that, as an interneuron-selective interneuron, LCs can effectively disinhibit cerebellar cortical activities in a compartment-dependent manner through inhibition of inhibitory interneurons selectively targeting PCs and granule cells.