Extended fear training can lead to initially low fear expression that grows over time, termed fear incubation. Conversely, a single fear conditioning session typically results in high fear initially that is sustained over time. Fear expression decreases across extended training, suggesting that a fear extinction-like process might be responsible for low fear observed soon after training. Because of the prominent role medial prefrontal cortex (mPFC) plays in fear conditioning and extinction, we decided to examine Fos expression resulting from a cued fear retrieval test to gain insight into possible mechanisms involved in extended training fear incubation. Male Long-Evans rats received 1 or 10 days of tone-shock pairings or tone-only exposure (while lever-pressing for food). Two days after the end of fear training, rats received a cued fear test, with perfusions timed to visualize Fos expression during test. As expected, the limited fear conditioning group exhibited higher fear in the test than any of the other groups (as measured with conditioned suppression of lever-pressing). Interestingly, we found that extended training animals (whether they received tone-shock pairings or tone-only exposure) expressed higher levels of Fos in both prelimbic and infralimbic cortices than limited training animals. There was no association between fear expression and mPFC Fos expression. These results suggest we may have visualized Fos expression related to operant overtraining rather than conditioned fear related processes. Further research is needed to determine the neurobiological basis of extended training fear incubation and to determine processes represented by the pattern of Fos expression we observed.

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO) in 129S2 mice. During 14 days after surgery, a classical sensorimotor assessment was conducted using hanging wire test, negative geotaxis test, grip strength test, accelerated rotarod test and locomotor activity-meter. In order to provide a technique for the assessment of more resistant consequences of ischemia on fine psychomotor control, the peak procedure (a modified version of the operant fixed-interval schedule of reinforcement) was used. This procedure also helped to objectify temporal perception in mice five weeks following surgery. On several sensorimotor tests, ischemic mice showed some degree of impairment which rapidly tended to improve after stroke, a profile of results substantially consistent with previous studies. Five weeks post-surgery, ischemic mice tested with the peak procedure exhibited a moderate but yet significant temporal regulation impairment along with a reduced response rate compared to control mice. The present results suggest that the peak procedure and other derived operant schedules of reinforcement may provide useful and sensitive tools for the long-term assessment of both behavioural and cognitive aspects of the consequences of an experimental ischemia.

Effective treatments for the cognitive symptoms of schizophrenia are critically needed. Positive allosteric modulation (PAM) of metabotropic glutamate receptor subtype 5 (mGluR5) is one strategy currently under investigation to improve these symptoms. Examining cognition using touchscreen-equipped operant chambers may increase translation between preclinical and clinical research through analogous behavioral testing paradigms in rodents and humans. We used acute CDPPB (1-30mg/kg) treatment to examine the effects of mGluR5 PAM in the touchscreen paired associates learning (PAL) task using well-trained rats with and without co-administration of acute MK-801 (0.15mg/kg). CDPPB had no consistent effects on task performance when administered alone and failed to reverse the MK-801 induced impairments at any of the examined doses. Overall, the disruptive effects of MK-801 on PAL were consistent with previous research but increasing mGluR5 signaling is not beneficial in the PAL task. Future research should test whether administration of CDPPB during PAL acquisition increases performance.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load.

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.

Moderate reduction of dietary protein (from 25% to 8% casein) in pregnant rats, calorically compensated by carbohydrates, gives rise to 'hidden prenatal malnutrition' (HPM) in the offspring since it does not alter body and brain weights of pups at birth. However, this dietary treatment leads to decreased β-adrenoceptor signaling and brain derived neurotrophic factor (BDNF) levels in the pup' brain, altogether with defective cortical long-term potentiation (LTP) and lowered visuospatial memory performance. Since early postnatal environmental enrichment (EE) has been shown to exert plastic effects on the developing brain and neuroprotection both on cognition and on structural properties of the neocortex, in the present study we addressed the question of whether early postnatal EE during the lactation period could exert compensatory changes in the expression of ®-adrenergic receptors and BDNF in the neocortex of HPM rats, and if these effects are associated with an improvement or even a restore of both neocortical LTP in vivo and cognitive performance induced by HPM. The results obtained show that EE restored β-adrenoceptor density, BDNF expression and the ability to support LTP at prefrontal and occipital cortices of HPM rats. Besides, EE improved learning performance in visuospatial and operant conditioning tasks. The latter support the notion that adequate maternal protein nutrition during pregnancy is required for proper brain development and function. Further, the results highlight the role of environmental enrichment during early postnatal life in increasing later brain plasticity and exerting neuroprotection against brain deficits induced by prenatal malnutrition.

The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self-administration and blocked yohimbine-induced reinstatement of ethanol self-administration. LHb lesions also attenuated ethanol-induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol-directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol-directed behaviors. Our results show that the LH-LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.