A Signaled Locomotor Avoidance Action Is Fully Represented in the Neural Activity of the Midbrain Tegmentum.

Animals, including humans, readily learn to avoid harmful and threatening situations by moving in response to cues that predict the threat (e.g., fire alarm, traffic light). During a negatively reinforced sensory-guided locomotor action, known as signaled active avoidance, animals learn to avoid a harmful unconditioned stimulus (US) by moving away when signaled by a harmless conditioned stimulus (CS) that predicts the threat. CaMKII-expressing neurons in the pedunculopontine tegmentum area (PPT) of the midbrain locomotor region have been shown to play a critical role in the expression of this learned behavior, but the activity of these neurons during learned behavior is unknown. Using calcium imaging fiber photometry in freely behaving mice, we show that PPT neurons sharply activate during presentation of the auditory CS that predicts the threat before onset of avoidance movement. PPT neurons activate further during the succeeding CS-driven avoidance movement, or during the faster US-driven escape movement. PPT neuron activation was weak during slow spontaneous movements but correlated sharply with movement speed and, therefore, with the urgency of the behavior. Moreover, using optogenetics, we found that these neurons must discharge during the signaled avoidance interval for naive mice to effectively learn the active avoidance behavior. As an essential hub for signaled active avoidance, neurons in the midbrain tegmentum process the conditioned cue that predicts the threat and discharge sharply relative to the speed or apparent urgency of the avoidance (learned) and escape (innate) responses.SIGNIFICANCE STATEMENT During signaled active avoidance behavior, subjects move away to avoid a threat when directed by an innocuous sensory stimulus. Using imaging methods in freely behaving mice, we found that the activity of neurons in a part of the midbrain, known as the pedunculopontime tegmentum, increases during the presentation of the innocuous sensory stimulus that predicts the threat and also during the expression of the learned behavior as mice move away to avoid the threat. In addition, inhibiting these neurons abolishes the ability of mice to learn the behavior. Thus, neurons in this part of the midbrain code and are essential for signaled active avoidance behavior.

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity.

Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.