Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice

A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.

BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders

Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit

Transmembrane protein 168 (TMEM168) comprises 697 amino acid residues, including some putative transmembrane domains. It is reported that TMEM168 controls methamphetamine (METH) dependence in the nucleus accumbens (NAc) of mice. Moreover, a strong link between METH dependence-induced adaptive changes in the brain and mood disorders has been evaluated. In the present study, we investigated the effects of accumbal TMEM168 in a battery of behavioral paradigms. The adeno-associated virus (AAV) Tmem168 vector was injected into the NAc of C57BL/6J mice (NAc-TMEM mice). Subsequently, the accumbal TMEM168 mRNA was increased approximately by seven-fold when compared with the NAc-Mock mice (controls). The NAc-TMEM mice reported no change in the locomotor activity, cognitive ability, social interaction, and depression-like behaviors; however, TMEM168 overexpression enhanced anxiety in the elevated-plus maze and light/dark box test. The increased anxiety was reversed by pretreatment with the antianxiety drug diazepam (0.3 mg/kg i.p.). Moreover, the NAc-TMEM mice exhibited decreased prepulse inhibition (PPI) in the startle response test, and the induced schizophrenia-like behavior was reversed by pretreatment with the antipsychotic drug risperidone (0.01 mg/kg i.p.). Furthermore, accumbal TMEM168 overexpression decreased the basal levels of extracellular GABA in the NAc and the high K+ (100 mM)-stimulated GABA elevation; however, the total contents of GABA in the NAc remained unaffected. These results suggest that the TMEM168-regulated GABAergic neuronal system in the NAc might become a novel target while studying the etiology of anxiety and sensorimotor gating deficits

Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood. The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats. Nicotine (0, 0.05, 0.2 mg/kg, s.c.) and tranylcypromine (3 mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field. Nicotine (0.2 mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2 mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment. There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors

LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Compounds that activate the 5-HT2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT2A receptors in rats. We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D2/D3 receptor antagonist raclopride (0.1 mg/kg, s.c). The effect of LSD on PPI is mediated by the 5-HT2A receptor, whereas activation of the 5-HT2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT2A agonist

The effects of smoking on whisker movements: a quantitative measure of exploratory behaviour in rodents

Nicotine, an important component of cigarette smoke, is a neurotransmitter that contributes to stress, depression and anxiety in smokers. In rodents, it increases anxiety and reduces exploratory behaviours. However, so far, the measurements of exploratory behaviour in rodents have only been semi-quantitative and lacking in sufficient detail to characterise the temporal effect of smoking cessation. As rodents, such as mice and rats, primarily use whiskers to explore their environment, we studied the effect of 3 months smoking with 1 and 2 weeks smoking cessation on whisker movements in mice, using high-speed video camera footage and image analysis. Both protraction and retraction whisker velocities were increased in smoking mice (p<0.001) and returned to normal following just one week of smoking cessation. In addition, locomotion speeds were decreased in smoking mice, and returned to normal following smoking cessation. Lung function was also impacted by smoking and remained impaired even following smoking cessation. We suggest that the increased whisker velocities in the smoking mice reflect reduced exploration and impeded tactile performance. The increase in whisker velocity with smoking, and its reduction following smoking cessation, also lends support to acetylcholine being involved in awareness, attention and alertness pathways. It also shows that smoking-induced behavioural changes can be reversed with smoking cessation, which may have implications for human smokers

CONSOLIDATION AND RECONSOLIDATION MECHANISMS SUPPORT UPDATING OF CONTEXT RECOGNITION MEMORY IN MICE

International audienceRetrieval during ongoing learning provides a mechanism for integrating a new overlapping events or experiences into existing memories. How such integration takes place and impacts long-term retention of original memory remains poorly understood. Here, we used a new context recognition memory task in mice that provides a way to study memory-updating mechanisms and retroactive interference phenomenon, the most common cause of forgetting. The task is conducted in an operant chamber and involves spontaneous discrimination of novel from familiar nose-poke modules that are distinguishable by their visual feature and spatial location. In the acquisition session, mice are exposed for the first time to the testing chamber with one blinking nose-poke module. In the choice session, a novel non-blinking nose-poke module is inserted into an empty spatial location and the number of pokes in each set of nose-poke module is used as an index of recognition memory. We first verified that recognition performance varies as a function of the length of the acquisition period and the retention delay and is sensitive to conventional amnestic treatments. By manipulating the features of spatial context we show that introduction of new overlapping information during retrieval can impair subsequent recall of original memory and provide evidence that retroactive interference effects reflect a memory updating process that can occur either by a consolidation or a reconsolidation mechanism. We further show that both forms of memory updating do not overwrite previously stored information and that memory deficit may be due to retrieval failure

New Translational Procedure to Study Retroactive Interference and Memory Updating Mechanisms in Mice

International audienceMemories are not fixed entities but change in a course of new experiences. Evidence that memories are subject to modification is supported by a large body of work in cognitive psychology demonstrating that presentation of new competing information at the time of retrieval can lead to distortion or impairment of old memories. Although the constructive nature of memory is now well established, the underlying cellular mechanisms remain poorly understood. Here, we introduce a new translation task for rodents that provides a way to study memory-updating mechanisms and retroactive interference phenomenon, the most common cause of forgetting. The task is conducted in an operant chamber and involves spontaneous discrimination of novel from familiar nose-poke modules that are distinguishable by their visual feature and spatial location. In the acquisition session, mice are exposed for the first time to the testing chamber with one blinking nose-poke module. In the choice session, a novel non-blinking nose-poke module is inserted into an empty spatial location and the preference for novel over the familiar nose-poke modules (number of nose poking) is used as an index of recognition memory. We first demonstrate that recognition performance varies as a function of the length of the acquisition period and the retention delay and is sensitive to conventional amnestic treatments (muscarinic receptor and NMDA receptor antagonists, scopolamine and MK-801, respectively). We next manipulated the features of spatial context during a brief reactivation episode (insufficient for acquiring a new context recognition memory) to study memory updating mechanisms. We show that presentation of new competing information during retrieval impairs subsequent recall of old memory as reported by studies in normal human subjects and provide evidence that mnemonic integration can occur either by a consolidation or a reconsolidation mechanism to update pre-existing memory representation. We further demonstrate that both forms of memory updating do not overwrite previously stored information and that memory impairments are due to retrieval failure caused by retroactive interference

Auditory and visual prepulse inhibition in mice: parametric analysis and strain comparisons.

International audiencePrepulse inhibition (PPI) is a multimodal phenomenon where the prepulse and the startling stimulus can be presented in either the same or the different sensory modalities. The aim of the present study was to characterize intramodal and cross-modal PPI in mice. We first examined the effects of varying prepulse intensity and prepulse duration on auditory and visual PPI in three inbred mouse strains C57BL/6J, 129S2 and BALB/cByJ mice. Increasing the intensity (5-15 dB above the background) and the duration (1-25 milliseconds) of the acoustic prepulse increased auditory PPI, and maximum level of inhibition was reached with each prepulse intensity at specific prepulse duration (between 5 and 15 milliseconds). Varying the intensity (30-300 lux) and the duration (1-25 milliseconds) of the light flashes had similar impact on visual PPI level (optimal durations between 1 and 10 milliseconds). There were also marked strain differences in PPI performances, with 129S2 and BALB/cByJ mice displaying the highest and the lowest scores of auditory PPI, respectively. In contrast, opposite strain ranking was obtained for visual PPI. The temporal expression of PPI was then studied in the same mouse strains using a wide range of interstimulus intervals (2-2000 milliseconds between the prepulse offset and the pulse onset). The time-course of the auditory and the visual PPI were relatively comparable (bell-shaped curve) with optimal lead-times between 10 and 100 milliseconds, but the shape of the temporal function varied between the mouse strains depending on the prepulse modality. These findings demonstrate that PPI has many physiological and genetic determinants that vary greatly across temporal and intensity domain, as well as stimulus modality