The analysis of the biology of neurotropic viruses, notably of their interference with cellular s... more The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on...
Sleep restriction (SR) impairs short term memory (STM) that might be related to different process... more Sleep restriction (SR) impairs short term memory (STM) that might be related to different processes. Neuropeptide S (NPS), an endogenous neuropeptide that improves short term memory, activates arousal and decreases anxiety is likely to counteract the SR-induced impairment of STM. The objective of the present study was to find common cerebral pathways in sleep restriction and NPS action in order to ultimately antagonize SR effect on memory. The STM was assessed using a spontaneous spatial alternation task in a T-maze. C57-Bl/6J male mice were distributed in 4 groups according to treatment (0.1nmol of NPS or vehicle intracerebroventricular injection) and to 20h-SR. Immediately after behavioural testing, regional c-fos immunohistochemistry was performed and used as a neural activation marker for spatial short term memory (prefrontal cortex, dorsal hippocampus) and emotional reactivity (basolateral amygdala and ventral hippocampus). Anxiety-like behaviour was assessed using elevated-plus maze task. Results showed that SR impaired short term memory performance and decreased neuronal activation in cingular cortex.NPS injection overcame SR-induced STM deficits and increased neuronal activation in infralimbic cortex. SR spared anxiety-like behavior in the elevated-plus maze. Neural activation in basolateral nucleus of amygdala and ventral hippocampus were not changed after SR.In conclusion, the present study shows that NPS overcomes SR-induced STM deficits by increasing prefrontal cortex activation independently of anxiety-like behaviour.
The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric ... more The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG (-/-) , PTPRZ (-/-) , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ (-/-) mice demonstrated marked social alteration with increased aggressivity, reminiscent of...
Proposing a framework for the study of core functions is valuable for understanding how they are ... more Proposing a framework for the study of core functions is valuable for understanding how they are altered in multiple mental disorders involving prefrontal dysfunction, for understanding genetic influences and for testing therapeutic compounds. Social and communication disabilities are reported in several major psychiatric disorders, and social communication disorders also can occur independently. Being able to study social communication involving interactions and associated acoustic vocalizations in animal models is thus important. All rodents display extensive social behaviors, including interactions and acoustic vocalizations. It is therefore important to pinpoint potential genetic-related strain differences -and similarities- in social behavior and vocalization. One approach is to compare different mouse strains, and this may be useful in choosing which strains may be best suitable in modeling psychiatric disorders where social and communication deficits are core symptoms. We compared social behavior and ultrasonic acoustic vocalization profiles in males of four mouse strains (129S2/Sv, C57BL/6J, DBA/2, and CD-1) using a social interaction task that we previously showed to rely on prefrontal network activity. Our social interaction task promotes a high level of ultrasonic vocalization with both social and acoustic parameters, and further allows other measures of social behaviors. The duration of social contact, dominance and aggressiveness varied with the mouse strains. Only C57BL/6J mice showed no attacks, with social contact being highly affiliative, whereas others strains emitted aggressive attacks. C57BL/6J mice also exhibited a significantly higher rate of ultrasonic vocalizations (USV), especially during social interaction.
Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicot... more Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicotinic acetylcholine receptor (nAChR) knockout (KO) mice. This study aimed to further assess the role of β2 and coexpressed nAChR subunits in the brain (α4, α6 and α7) to control monoamine-mediated locomotor response, that is, response to novelty, saline, nicotine with tranylcypromine pretreatment, cocaine, d-amphetamine and morphine treatments. Results show that β2 KO mice were hyperreactive to novelty, cocaine and morphine. In contrast, α7 KO mice were hyporeactive to tranylcypromine and cocaine. These results suggest that endogenous nAChR stimulation may exert a tonic control on monoamine-mediated locomotor responses. β2 and α7-containing nAChR may contribute, respectively, to the inhibitory and permissive pathways of this tonic control.
The present work defines a simple behavioral paradigm to evaluate spatial representation in rats.... more The present work defines a simple behavioral paradigm to evaluate spatial representation in rats. In two experimental conditions differing in the richness of distal visual cues, rats learned to locate a food goal in a cross maze from various starting points. We conducted different challenges consisting of (i) reaching the same goal from a modified arrangement of the maze arms (geometric challenge), (ii) reaching the goal within a 90 degrees rotated maze, herein checking the use of a place strategy, and (iii) investigating the effect of central cholinergic blockade over the retention of the task. Results showed that rats needed 12-30 trials to learn a place response, depending upon the richness of the visual environment. The maze rotation did not produce any impairment whereas the geometric challenge affected the performance specifically under the visually richer environment. Scopolamine injection (i.p.) produced a significant impairment in place recognition. Our present work shows that this maze procedure constitutes a useful paradigm to assess learning and processing of a place representation by rats. Similarly to what has been shown in other popular maze paradigms, our results show that rats mostly rely on distal extra-maze cues to solve the task, but also compute intra-maze information.
Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons... more Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of α4 and α7, subunits α4(1-209) and α7(1-208), or injected them with α7(1-208)-specific antibodies. A decrease of α4β2- and α7-nAChRs accompanied with an increase of α4β4-nAChRs in brain membranes of immunized mice was observed. Both α4(1-209)- and α7(1-208)-specific antibodies were detected in the brain membrane lysates of immunized mice. Antibody injection resulted in brain nAChR decrease only if mice were co-injected intraperitoneally with bacterial lipopolysaccharide. Brain sections of immunized ...
ABSTRACT Nicotinic receptors (nAChR) are important targets of the neurotranmitter and modulator a... more ABSTRACT Nicotinic receptors (nAChR) are important targets of the neurotranmitter and modulator acetylcholine. Ten neuronal nAChR subunits have been identified that assemble to form a variety of pentameric oligomers possessing diverse physiological and pharmacological properties and different distributions in the CNS. We investigated the role of the different subunits in knockout mice constructed by homologous recombination. Among other features, in β2−/− mice nicotine no longer stimulates dopamine release in vivo and elicits electrical responses of mesencephalic dopaminergic neurons. Moreover, the β2−/− mice show deficits in nicotine self-administration and in executive functions. Thus the β2 subunit is necessary, but has not yet been shown to be sufficient for these functions. We have therefore developed a novel strategy to selectively re-express the β2 subunit on a knockout background using a lentiviral vector. Fully functional high-affinity nAChRs are recovered in the ventral tegmental area (VTA) and are shown to be sufficient to restore nicotine-elicited dopamine release and nicotine self-administration in vivo. Moreover, slow exploratory behaviour of these mice was restored in a sequential locomotor task testing executive function. These data highlight the critical role of endogenous cholinergic regulation mediated by nicotinic receptors on higher cognitive functions. In a more general manner, the method makes possible the differential analysis of the neuronal circuits involved in nicotine addiction.
Decision-making plays a pivotal role in daily life as impairments in processes underlying decisio... more Decision-making plays a pivotal role in daily life as impairments in processes underlying decision-making often lead to an inability to make profitable long-term decisions. As a case in point, pathological gamblers continue gambling despite the fact that this disrupts their personal, professional or financial life. The prevalence of pathological gambling will likely increase in the coming years due to expanding possibilities of on-line gambling through the Internet and increasing liberal attitudes towards gambling. It therefore represents a growing concern for society. Both human and animal studies rapidly advance our knowledge on brain-behaviour processes relevant for understanding normal and pathological gambling behaviour. Here, we review in humans and animals three features of pathological gambling which hitherto have received relatively little attention: (1) sex differences in (the development of) pathological gambling, (2) adolescence as a (putative) sensitive period for (developing) pathological gambling and (3) avenues for improving ecological validity of research tools. Based on these issues we also discuss how research in humans and animals may be brought in line to maximize translational research opportunities.
Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicot... more Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicotinic acetylcholine receptor (nAChR) knockout (KO) mice. This study aimed to further assess the role of β2 and coexpressed nAChR subunits in the brain (α4, α6 and α7) to control monoamine-mediated locomotor response, that is, response to novelty, saline, nicotine with tranylcypromine pretreatment, cocaine, d-amphetamine and morphine treatments. Results show that β2 KO mice were hyperreactive to novelty, cocaine and morphine. In contrast, α7 KO mice were hyporeactive to tranylcypromine and cocaine. These results suggest that endogenous nAChR stimulation may exert a tonic control on monoamine-mediated locomotor responses. β2 and α7-containing nAChR may contribute, respectively, to the inhibitory and permissive pathways of this tonic control.
The analysis of the biology of neurotropic viruses, notably of their interference with cellular s... more The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on...
Sleep restriction (SR) impairs short term memory (STM) that might be related to different process... more Sleep restriction (SR) impairs short term memory (STM) that might be related to different processes. Neuropeptide S (NPS), an endogenous neuropeptide that improves short term memory, activates arousal and decreases anxiety is likely to counteract the SR-induced impairment of STM. The objective of the present study was to find common cerebral pathways in sleep restriction and NPS action in order to ultimately antagonize SR effect on memory. The STM was assessed using a spontaneous spatial alternation task in a T-maze. C57-Bl/6J male mice were distributed in 4 groups according to treatment (0.1nmol of NPS or vehicle intracerebroventricular injection) and to 20h-SR. Immediately after behavioural testing, regional c-fos immunohistochemistry was performed and used as a neural activation marker for spatial short term memory (prefrontal cortex, dorsal hippocampus) and emotional reactivity (basolateral amygdala and ventral hippocampus). Anxiety-like behaviour was assessed using elevated-plus maze task. Results showed that SR impaired short term memory performance and decreased neuronal activation in cingular cortex.NPS injection overcame SR-induced STM deficits and increased neuronal activation in infralimbic cortex. SR spared anxiety-like behavior in the elevated-plus maze. Neural activation in basolateral nucleus of amygdala and ventral hippocampus were not changed after SR.In conclusion, the present study shows that NPS overcomes SR-induced STM deficits by increasing prefrontal cortex activation independently of anxiety-like behaviour.
The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric ... more The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders. Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG (-/-) , PTPRZ (-/-) , and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry. The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ (-/-) mice demonstrated marked social alteration with increased aggressivity, reminiscent of...
Proposing a framework for the study of core functions is valuable for understanding how they are ... more Proposing a framework for the study of core functions is valuable for understanding how they are altered in multiple mental disorders involving prefrontal dysfunction, for understanding genetic influences and for testing therapeutic compounds. Social and communication disabilities are reported in several major psychiatric disorders, and social communication disorders also can occur independently. Being able to study social communication involving interactions and associated acoustic vocalizations in animal models is thus important. All rodents display extensive social behaviors, including interactions and acoustic vocalizations. It is therefore important to pinpoint potential genetic-related strain differences -and similarities- in social behavior and vocalization. One approach is to compare different mouse strains, and this may be useful in choosing which strains may be best suitable in modeling psychiatric disorders where social and communication deficits are core symptoms. We compared social behavior and ultrasonic acoustic vocalization profiles in males of four mouse strains (129S2/Sv, C57BL/6J, DBA/2, and CD-1) using a social interaction task that we previously showed to rely on prefrontal network activity. Our social interaction task promotes a high level of ultrasonic vocalization with both social and acoustic parameters, and further allows other measures of social behaviors. The duration of social contact, dominance and aggressiveness varied with the mouse strains. Only C57BL/6J mice showed no attacks, with social contact being highly affiliative, whereas others strains emitted aggressive attacks. C57BL/6J mice also exhibited a significantly higher rate of ultrasonic vocalizations (USV), especially during social interaction.
Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicot... more Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicotinic acetylcholine receptor (nAChR) knockout (KO) mice. This study aimed to further assess the role of β2 and coexpressed nAChR subunits in the brain (α4, α6 and α7) to control monoamine-mediated locomotor response, that is, response to novelty, saline, nicotine with tranylcypromine pretreatment, cocaine, d-amphetamine and morphine treatments. Results show that β2 KO mice were hyperreactive to novelty, cocaine and morphine. In contrast, α7 KO mice were hyporeactive to tranylcypromine and cocaine. These results suggest that endogenous nAChR stimulation may exert a tonic control on monoamine-mediated locomotor responses. β2 and α7-containing nAChR may contribute, respectively, to the inhibitory and permissive pathways of this tonic control.
The present work defines a simple behavioral paradigm to evaluate spatial representation in rats.... more The present work defines a simple behavioral paradigm to evaluate spatial representation in rats. In two experimental conditions differing in the richness of distal visual cues, rats learned to locate a food goal in a cross maze from various starting points. We conducted different challenges consisting of (i) reaching the same goal from a modified arrangement of the maze arms (geometric challenge), (ii) reaching the goal within a 90 degrees rotated maze, herein checking the use of a place strategy, and (iii) investigating the effect of central cholinergic blockade over the retention of the task. Results showed that rats needed 12-30 trials to learn a place response, depending upon the richness of the visual environment. The maze rotation did not produce any impairment whereas the geometric challenge affected the performance specifically under the visually richer environment. Scopolamine injection (i.p.) produced a significant impairment in place recognition. Our present work shows that this maze procedure constitutes a useful paradigm to assess learning and processing of a place representation by rats. Similarly to what has been shown in other popular maze paradigms, our results show that rats mostly rely on distal extra-maze cues to solve the task, but also compute intra-maze information.
Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons... more Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of α4 and α7, subunits α4(1-209) and α7(1-208), or injected them with α7(1-208)-specific antibodies. A decrease of α4β2- and α7-nAChRs accompanied with an increase of α4β4-nAChRs in brain membranes of immunized mice was observed. Both α4(1-209)- and α7(1-208)-specific antibodies were detected in the brain membrane lysates of immunized mice. Antibody injection resulted in brain nAChR decrease only if mice were co-injected intraperitoneally with bacterial lipopolysaccharide. Brain sections of immunized ...
ABSTRACT Nicotinic receptors (nAChR) are important targets of the neurotranmitter and modulator a... more ABSTRACT Nicotinic receptors (nAChR) are important targets of the neurotranmitter and modulator acetylcholine. Ten neuronal nAChR subunits have been identified that assemble to form a variety of pentameric oligomers possessing diverse physiological and pharmacological properties and different distributions in the CNS. We investigated the role of the different subunits in knockout mice constructed by homologous recombination. Among other features, in β2−/− mice nicotine no longer stimulates dopamine release in vivo and elicits electrical responses of mesencephalic dopaminergic neurons. Moreover, the β2−/− mice show deficits in nicotine self-administration and in executive functions. Thus the β2 subunit is necessary, but has not yet been shown to be sufficient for these functions. We have therefore developed a novel strategy to selectively re-express the β2 subunit on a knockout background using a lentiviral vector. Fully functional high-affinity nAChRs are recovered in the ventral tegmental area (VTA) and are shown to be sufficient to restore nicotine-elicited dopamine release and nicotine self-administration in vivo. Moreover, slow exploratory behaviour of these mice was restored in a sequential locomotor task testing executive function. These data highlight the critical role of endogenous cholinergic regulation mediated by nicotinic receptors on higher cognitive functions. In a more general manner, the method makes possible the differential analysis of the neuronal circuits involved in nicotine addiction.
Decision-making plays a pivotal role in daily life as impairments in processes underlying decisio... more Decision-making plays a pivotal role in daily life as impairments in processes underlying decision-making often lead to an inability to make profitable long-term decisions. As a case in point, pathological gamblers continue gambling despite the fact that this disrupts their personal, professional or financial life. The prevalence of pathological gambling will likely increase in the coming years due to expanding possibilities of on-line gambling through the Internet and increasing liberal attitudes towards gambling. It therefore represents a growing concern for society. Both human and animal studies rapidly advance our knowledge on brain-behaviour processes relevant for understanding normal and pathological gambling behaviour. Here, we review in humans and animals three features of pathological gambling which hitherto have received relatively little attention: (1) sex differences in (the development of) pathological gambling, (2) adolescence as a (putative) sensitive period for (developing) pathological gambling and (3) avenues for improving ecological validity of research tools. Based on these issues we also discuss how research in humans and animals may be brought in line to maximize translational research opportunities.
Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicot... more Earlier studies reported exacerbated locomotor response to stress and tranylcypromine in β2 nicotinic acetylcholine receptor (nAChR) knockout (KO) mice. This study aimed to further assess the role of β2 and coexpressed nAChR subunits in the brain (α4, α6 and α7) to control monoamine-mediated locomotor response, that is, response to novelty, saline, nicotine with tranylcypromine pretreatment, cocaine, d-amphetamine and morphine treatments. Results show that β2 KO mice were hyperreactive to novelty, cocaine and morphine. In contrast, α7 KO mice were hyporeactive to tranylcypromine and cocaine. These results suggest that endogenous nAChR stimulation may exert a tonic control on monoamine-mediated locomotor responses. β2 and α7-containing nAChR may contribute, respectively, to the inhibitory and permissive pathways of this tonic control.
Uploads
Papers by sylvie Granon