Most ontogenetic investigations of cognitive

Most ontogenetic investigations of cognitive processes in laboratory rodents have focused on the pre-weanling and weanling period. However, in recent years adolescence has also gained increasing attention, although longitudinal studies covering the complete adolescent period are still scarce. When testing adolescent animals for cognitive skills, one needs to consider that adolescent individuals differ notably from adults in their thiostrepton reward neuro-circuitry and in the way they process and respond to rewarding and aversive stimuli (Doremus-Fitzwater et al., 2010; Friemel et al., 2010). For the present study we therefore decided to focus on cognitive skills that can be assessed independently from negative/positive reinforcement in rodents and can be measured repeatedly in the same test animal, such as recognition memory and sensorimotor gating. The spontaneous object recognition test was chosen for assessing the developmental trajectory of short-term memory processing. Recognition memory is generally regarded as the ability to discriminate the familiarity of items previously encountered. The test is based on the natural tendency of rodents to investigate and prefer novel objects, odors or social partners over familiar ones (Ennaceur and Delacour, 1988; Goepfrich et al., 2013; Schneider et al., 2008). Short-term recognition memory for objects has been shown to emerge quite early during postnatal development and appears to be completely functional in rats from postnatal day (pd) 17 on (Westbrook et al., 2014; Anderson et al., 2004). However, the development of recognition memory from pre-weaning ages through puberty until late adolescence has only been examined in part and still requires more detailed clarification. Prepulse inhibition (PPI) is the natural reduction in the magnitude of the acoustic startle reflex (ASR) if a weaker, non-startling pre-stimulus is presented shortly before the startling stimulus. Since the ASR can be assessed equally well in humans as in laboratory rodents, modulations of the ASR show a high degree of face validity and translational value (Koch, 1999; Fendt and Koch, 2013). PPI has been suggested to provide a measure of sensorimotor gating, since it reflects the degree to which a motor reflex is gated by a preceding sensory stimulus (prepulse) (for review see Fendt and Koch, 2013). Sensorimotor gating is a fundamental protective mechanism that momentarily prevents or attenuates an overload of higher cortical areas with irrelevant information and hence protects ongoing cognitive processes against external interferences (Cromwell et al., 2008). Similar to recognition memory, comprehensive studies investigating the ontogeny of PPI throughout the complete adolescent period are still missing, since most studies investigated only selective time points during postnatal development and report partially contradictory findings. However, there is some evidence from studies in mice and rats that the ASR, as well as PPI increase with age (Pietropaolo and Crusio, 2009; Rybalko et al., 2015; Schwabe et al., 2007; Fendt et al., 2008). The endocannabinoid (eCB) system is considered to be an ubiquitous regulator of synaptic transmission in the brain that mediates various central and peripheral processes (Kano et al., 2009; Castillo et al., 2012). The eCB signalling system comprises the G-protein coupled cannabinoid receptors (CB1 and CB2 receptor), the two main endogenous ligands N-arachidonoylethanolamide and 2-arachidonoylglycerol, as well as their synthetic and metabolic enzymes. This evolutionarily ancient and widely distributed neuromodulatory system is crucial for sustaining and restoring neuronal homeostasis (Kano et al., 2009) and in particular CB1 receptor signalling has emerged as a critical mechanisms for mediating cognitive behavior and neuroplasticity (Wotjak, 2005; Castillo et al., 2012). Moreover, a transient increase in CB1 receptor signalling has been reported to occur during adolescent brain development, which may provide increased plasticity and behavioral flexibility required specifically during this developmental stage (Schneider et al., 2015). In line with these observations, pharmacological interference with the eCB system during puberty induces pronounced and persistent deficits in cognitive skills (e.g. Schneider and Koch, 2003; Schneider and Koch, 2007; Schneider et al., 2008). Given the modulatory role of CB1 receptor signaling on adolescent behavior, neuroplasticity, and cognition, the eCB system represents an interesting target system for mediating potential developmental changes in cognitive abilities such as object recognition and prepulse inhibition.