Characterization of social behavior in young and middle-aged ChAT-IRES-Cre mouse.

The cholinergic system is an important modulator of brain processes. It contributes to the regulation of several cognitive functions and emotional states, hence altering behaviors. Previous works showed that cholinergic (nicotinic) receptors of the prefrontal cortex are needed for adapted social behaviors. However, these data were obtained in mutant mice that also present alterations of several neurotransmitter systems, in addition to the cholinergic system. ChAT-IRES-Cre mice, that express the Cre recombinase specifically in cholinergic neurons, are useful tools to investigate the role of the cholinergic circuits in behavior. However, their own behavioral phenotype has not yet been fully characterized, in particular social behavior. In addition, the consequences of aging on the cholinergic system of ChAT-IRES-Cre mice has never been studied, despite the fact that aging is known to compromise the cholinergic system efficiency. The aim of the current study was thus to characterize the social phenotype of ChAT-IRES-Cre mice both at young (2-3 months) and middle (10-11 months) ages. Our results reveal an alteration of the cholinergic system, evidenced by a decrease of ChAT, CHT and VAChT gene expression in the striatum of the mice, that was accompanied by mild social disturbances and a tendency towards anxiety. Aging decreased social dominance, without being amplified by the cholinergic alterations. Altogether, this study shows that ChAT-IRES-Cre mice are useful models for studying the cholinergic system's role in social behavior using appropriate modulating technics (optogenetic or DREADD).

Effects of water restriction on social behavior and 5-HT neurons density in the dorsal and median raphe nuclei in mice.

We explored here the hypothesis that temporary chronic water restriction in mice affects social behavior, via its action on the density of 5-HT neurons in dorsal and median raphe nuclei (DRN and MRN). For that, we submitted adult C57BL/6 J mice to mild and controlled temporary dehydration, i.e., 6 h of water access every 48 h for 15 days. We investigated their social behavior in a social interaction task known to allow free and reciprocal social contact. Results showed that temporary dehydration increases significantly time spent in social contact and social dominance. It also expands 5-HT neuron density within both DRN and MRN and the behavioral and neuronal plasticity were positively correlated. Our findings suggest that disturbance in 5-HT neurotransmission caused by temporary dehydration stress unbalances choice processes of animals in social context.

Reduced adolescent risk-assessment and lower nicotinic beta-2 expression in rats exposed to nicotine through lactation by forcedly drinking dams.

Few animal studies focus on consequences of nicotine postnatal exposure, particularly through lactation. We have recently shown that forced nicotine drinking elevates maternal care, paradoxically provoking arousal and stress in pups. Present work aimed to evaluate the specific contribution of altered maternal cares, compared to the sequelae merely due to nicotine effects. Two groups were compared to water-drinking control dams: (i) free-choice dams (H2O+NIC group) drinking from two bottles, containing either nicotine or water; (ii) forced dams (NIC+NIC group) drinking from two bottles, both containing nicotine. We previously demonstrated that nicotine was indeed transferred to the lactating offspring. Regarding behavioural consequences at adolescence, both H2O+NIC and NIC+NIC rats were slower than controls in discovering a novel over a familiar compartment, whilst only NIC+NIC rats exhibited reduced risk-related avoidance and assessment behaviour. Brain analyses at adulthood suggest that, in prefrontal cortex, nicotine per se reduced serotonin, while the maternal overcare reduced CHRN-B2 gene-expression. As a whole, unescapable nicotine-enhanced maternal care could have an impact on the offspring arousal by acting on prefrontal CHRN-B2 gene-expression. When present results are translated to consequences of non-voluntary exposure in humans, we propose that children receiving altered attentions by a smoking caregiver might undergo a neuro-behavioural development biased towards emotional shyness.

Dissociated features of social cognition altered in mouse models of schizophrenia: Focus on social dominance and acoustic communication.

Social and communication impairments are common features of psychiatric disorders. Animal models of schizophrenia display various social deficits due to difference in tests, mouse strains and drugs. Moreover, communication deficits have not been studied. Our objectives were to assess and compare three major features of social cognition in different mouse models of schizophrenia: interest for a social stimulus, organization and acceptance of social contact, and acoustic communication to question whether mouse models for schizophrenia with social dysfunction also exhibit vocal communication defects. To achieve these aims we treated acutely C57BL/6J mice either with MK-801 or ketamine and tested WT and microtubule-associated protein 6 -MAP6- KO mice in two complementary social tasks: the 3-chamber test which measures social motivation and the social interaction task -SIT- which relies on prefrontal cortex activity and measures the ability to organize and respond to a real interaction, and which promotes ultrasonic vocalizations. Our results reveal that schizophrenia models have intact interest for a social stimulus in the 3-chamber test. However, thanks to principal component analyses of social interaction data, we demonstrate that social motivation and the ability to act socially rely on distinct mechanisms in revealing a decrease in dominance and communication in pharmacological schizophrenia models along with social withdraw, classically observed in schizophrenia, in MK-801 model. In this latter model, some social parameters can be significantly improved by aripiprazole, an atypical antipsychotic. Our social protocol, combined with fine-tuned analysis, is expected to provide an innovative framework for testing future treatments in preclinical models. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Social behaviors and acoustic vocalizations in different strains of mice.

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.

Neuronal Nicotinic Receptors Are Crucial for Tuning of E/I Balance in Prelimbic Cortex and for Decision-Making Processes.

RATIONALE: Decision-making is an essential component of our everyday life commonly disabled in a myriad of psychiatric conditions, such as bipolar and impulsive control disorders, addiction and pathological gambling, or schizophrenia. A large cerebral network encompassing the prefrontal cortex, the amygdala, and the nucleus accumbens is activated for efficient decision-making. METHODS: We developed a mouse gambling task well suited to investigate the influence of uncertainty and risk in decision-making and the role of neurobiological circuits and their monoaminergic inputs. Neuronal nicotinic acetylcholine receptors (nAChRs) of the PFC are important for decision-making processes but their presumed roles in risk-taking and uncertainty management, as well as in cellular balance of excitation and inhibition (E/I) need to be investigated. RESULTS: Using mice lacking nAChRs - ß2-/- mice, we evidence for the first time the crucial role of nAChRs in the fine tuning of prefrontal E/I balance together with the PFC, insular, and hippocampal alterations in gambling behavior likely due to sensitivity to penalties and flexibility alterations. Risky behaviors and perseveration in extinction task were largely increased in ß2-/- mice as compared to control mice, suggesting the important role of nAChRs in the ability to make appropriate choices adapted to the outcome.

Modified impact of emotion on temporal discrimination in a transgenic rat model of Huntington disease.

Huntington's disease (HD) is characterized by triad of motor, cognitive, and emotional symptoms along with neuropathology in fronto-striatal circuit and limbic system including amygdala. Emotional alterations, which have a negative impact on patient well-being, represent some of the earliest symptoms of HD and might be related to the onset of the neurodegenerative process. In the transgenic rat model (tgHD rats), evidence suggest emotional alterations at the symptomatic stage along with neuropathology of the central nucleus of amygdala (CE). Studies in humans and animals demonstrate that emotion can modulate time perception. The impact of emotion on time perception has never been tested in HD, nor is it known if that impact could be part of the presymptomatic emotional phenotype of the pathology. The aim of this paper was to characterize the effect of emotion on temporal discrimination in presymptomatic tgHD animals. In the first experiment, we characterized the acute effect of an emotion (fear) conditioned stimulus on temporal discrimination using a bisection procedure, and tested its dependency upon an intact central amygdala. The second experiment was aimed at comparing presymptomatic homozygous transgenic animals at 7-months of age and their wild-type littermates (WT) in their performance on the modulation of temporal discrimination by emotion. Our principal findings show that (1) a fear cue produces a short-lived decrease of temporal precision after its termination, and (2) animals with medial CE lesion and presymptomatic tgHD animals demonstrate an alteration of this emotion-evoked temporal distortion. The results contribute to our knowledge about the presymptomatic phenotype of this HD rat model, showing susceptibility to emotion that may be related to dysfunction of the central nucleus of amygdala.

Temporal sensitivity changes with extended training in a bisection task in a transgenic rat model.

The present study investigated temporal perception in a Huntington disease transgenic rat model using a temporal bisection procedure. After initial discrimination training in which animals learned to press one lever after a 2-s tone duration, and the other lever after a 8-s tone duration for food reward, the bisection procedure was implemented in which intermediate durations with no available reinforcement were interspersed with trials with the anchor durations. Bisection tests were repeated in a longitudinal design from 4 to 8 months of age. The results showed that response latencies evolved from a monotonic step-function to an inverted U-shaped function with repeated testing, a precursor of non-responding on trials with intermediate durations. We inferred that temporal sensitivity and incentive motivation combined to control the transformation of the bisection task from a two-choice task at the outset of testing to a three-choice task with repeated testing. Changes in the structure of the task and/or continued training were accompanied by improvement in temporal sensitivity. In sum, the present data highlight the possible joint roles of temporal and non-temporal factors in the temporal bisection task, and suggested that non-temporal factors may compensate for deficits in temporal processing.

Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease.

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

Desire and dread from the nucleus accumbens: cortical glutamate and subcortical GABA differentially generate motivation and hedonic impact in the rat.

BACKGROUND: GABAergic signals to the nucleus accumbens (NAc) shell arise from predominantly subcortical sources whereas glutamatergic signals arise mainly from cortical-related sources. Here we contrasted GABAergic and glutamatergic generation of hedonics versus motivation processes, as a proxy for comparing subcortical and cortical controls of emotion. Local disruptions of either signals in medial shell of NAc generate intense motivated behaviors corresponding to desire and/or dread, along a rostrocaudal gradient. GABA or glutamate disruptions in rostral shell generate appetitive motivation whereas disruptions in caudal shell elicit fearful motivation. However, GABA and glutamate signals in NAc differ in important ways, despite the similarity of their rostrocaudal motivation gradients. METHODOLOGY/PRINCIPAL FINDINGS: Microinjections of a GABA(A) agonist (muscimol), or of a glutamate AMPA antagonist (DNQX) in medial shell of rats were assessed for generation of hedonic "liking" or "disliking" by measuring orofacial affective reactions to sucrose-quinine taste. Motivation generation was independently assessed measuring effects on eating versus natural defensive behaviors. For GABAergic microinjections, we found that the desire-dread motivation gradient was mirrored by an equivalent hedonic gradient that amplified affective taste "liking" (at rostral sites) versus "disliking" (at caudal sites). However, manipulation of glutamatergic signals completely failed to alter pleasure-displeasure reactions to sensory hedonic impact, despite producing a strong rostrocaudal gradient of motivation. CONCLUSIONS/SIGNIFICANCE: We conclude that the nucleus accumbens contains two functional affective keyboards for amino-acid signals: a motivation-generating keyboard and a hedonic-generating keyboard. Corticolimbic glutamate signals and subcortical GABA signals equivalently engage the motivation keyboard to generate desire and-or dread. Only subcortical GABA signals additionally engage the hedonic keyboard to amplify affective "liking" and "disliking" reactions. We thus suggest that top-down cortical glutamate signals powerfully regulate motivation components, but are relatively unable to penetrate core hedonic components of emotion. That may carry implications of limits to therapeutic regulation of pathological emotions.

Mesolimbic dopamine in desire and dread: enabling motivation to be generated by localized glutamate disruptions in nucleus accumbens.

An important issue in affective neuroscience concerns the role of mesocorticolimbic dopamine systems in positive-valenced motivation (e.g., reward) versus negative-valenced motivation (e.g., fear). Here, we assessed whether endogenous dopamine receptor stimulation in nucleus accumbens contributes to both appetitive behavior and fearful behavior that is generated in keyboard manner by local glutamate disruptions at different sites in medial shell. 6,7-Dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) microinjections (450 ng) locally disrupt glutamate signals in <4 mm(3) of nucleus accumbens, and generate either desire or fear (or both) depending on precise rostrocaudal location in medial shell. At rostral shell sites, local AMPA/kainate blockade generates positive ingestive behavior, but the elicited motivated behavior becomes incrementally more fearful as the same microinjection is moved caudally. A dopamine-blocking mixture of D(1) and D(2) antagonists (raclopride and SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrochloride]) was combined here in the same microinjection with DNQX to assess the role of endogenous local dopamine in mediating the DNQX-motivated behaviors. We report that local dopamine blockade prevented DNQX microinjections from generating appetitive behavior (eating) in rostral shell, and equally prevented DNQX from generating fearful behavior (defensive treading) in caudal shell. We conclude that local dopamine is needed to enable disruptions of corticolimbic glutamate signals in shell to generate either positive incentive salience or negative fearful salience (valence depending on site and other conditions). Thus, dopamine interacts with localization of valence-biased glutamate circuits in medial shell to facilitate keyboard stimulation of both appetitive and fearful motivations.

A standardized method to automatically segment amyloid plaques in Congo Red stained sections from Alzheimer transgenic mice.

Automated detection of amyloid plaques (AP) in post mortem brain sections of patients with Alzheimer disease (AD) or in mouse models of the disease is a major issue to improve quantitative, standardized and accurate assessment of neuropathological lesions as well as of their modulation by treatment. We propose a new segmentation method to automatically detect amyloid plaques in Congo Red stained sections based on adaptive thresholds and a dedicated amyloid plaque/tissue modelling. A set of histological sections focusing on anatomical structures was used to validate the method in comparison to expert segmentation.

Fully automated and adaptive detection of amyloid plaques in stained brain sections of Alzheimer transgenic mice.

Automated detection of amyloid plaques (AP) in post mortem brain sections of patients with Alzheimer disease (AD) or in mouse models of the disease is a major issue to improve quantitative, standardized and accurate assessment of neuropathological lesions as well as of their modulation by treatment. We propose a new segmentation method to automatically detect amyloid plaques in Congo Red stained sections based on adaptive thresholds and a dedicated amyloid plaque/tissue modelling. A set of histological sections focusing on anatomical structures was used to validate the method in comparison to expert segmentation. Original information concerning global amyloid load have been derived from 6 mouse brains which opens new perspectives for the extensive analysis of such a data in 3-D and the possibility to integrate in vivo-post mortem information for diagnosis purposes.

Habit learning dissociation in rats with lesions to the vermis and the interpositus of the cerebellum.

After cerebellar tumors resection, patients show motor skill learning impairments but also cognitive deficits. However, their exact origins remain controversial. Using a rat model of cerebellar injury, we assessed the involvement of two structures often damaged during resection (vermis and interpositus nuclei) on habits development. During extended training of an instrumental task, rats develop response routines that are no longer voluntary or goal-directed but habit-based, evidenced by their insensitivity to changes in the value of the reward. Here we showed that, in contrast to sham or vermis lesioned rats, discrete lesions to interpositus nuclei prevented rats from developing habits with overtraining, without motor difficulties, nor alteration of the instrumental task acquisition. Our results suggest that the role of the cerebellum can be extended from motor skill learning to cognitive routines learning. Similar habit impairment could possibly account for some of the long-term outcome difficulties observed in cerebellar-damaged patients.

Endoneural metastasis of the sciatic nerve disclosing the relapse of a renal carcinoma, four years after its surgical treatment.

METHODS: To report on an exceptional case of renal metastasis. Indeed, endoneural metastases of peripheral nerves are thought to be exceptional, and such an event has not yet been ascribed to a renal carcinoma. RESULTS: We report on a sciatica leading to the discovery of a tumour of the right thigh which proved to be an endoneural metastasis of the sciatic nerve from a renal carcinoma surgically removed 4 years before. CONCLUSION: A thorough palpation of peripheral nerve can help recognise such metastases in patients previously diagnosed with renal carcinoma.

Cervical spondylitis due to Neisseria meningitidis.

The diverse clinical spectrum of meningococcal infections includes frequent clinical forms, such as meningitis or septicemia, and uncommon manifestations, such as septic arthritis. Neisseria meningitidis is not generally considered to be a causative agent of osteoarticular infections. We report the first case of acute primary cervical spondylitis in a 48-year-old man.

Learning-dependent activation of Fra-1: involvement of ventral hippocampus and SNc/VTA complex in learning and habit formation.

Although the effect of overtraining on learning processes in rats has long been studied, only few studies have specifically assessed the differential involvement of brain areas in habit formation. We used the analysis of expression of the immediate early gene Fra-1 as a tool to differentiate the areas involved in training and overtraining. Behavioural experiments showed that instrumental performance (signalled and non-signalled instrumental tasks), but not pavlovian conditioned responses, were no longer under the control of the incentive value of the reward after overtraining. The number of Fra-1 expressing neurons was increased in SNc/VTA and ventral hippocampus after training in all groups independently of behavioural performance. After overtraining, the number of learning-induced Fra-1 immunoreactive neurons remained increased in the SNc/VTA. However, in CA1, it significantly decreased in the signalled instrumental group, whereas it further increased in the pavlovian group, with no modulation in non-signalled instrumental animals. The increase in the number of Fra-1 neurons observed after training in SNc/VTA and ventral hippocampus suggests that a general underlying incentive process regulates Fra-1. Moreover, the sustained increased expression of Fra-1 in the SNc/VTA after instrumental overtraining could reflect a possible role of dopaminergic neurons in habit formation.

Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation.

Acquisition and performance of instrumental actions are assumed to require both action-outcome and stimulus-response (S-R) habit processes. Over the course of extended training, control over instrumental performance shifts from goal-directed action-outcome associations to S-R associations that progressively gain domination over behavior. Lesions of the lateral part of the dorsal striatum disrupt this process, and rats with lesions to the lateral striatum showed selective sensitivity to devaluation of the instrumental outcome (Yin et al., 2004), indicating that this area is necessary for habit formation. The present experiment further explored the basis of this dysfunction by examining the ability of rats subjected to bilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic pathway to develop behavioral autonomy with overtraining. Rats were given extended training on two cued instrumental tasks associating a stimulus (a tone or a light) with an instrumental action (lever press or chain pull) and a food reward (pellets or sucrose). Both tasks were run daily in separate sessions. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. In control animals, one action (lever press) was insensitive to reward devaluation, indicating that it became a habit, whereas the second action (chain pull) was still sensitive to goal devaluation. This result provides evidence that the development of habit learning may depend on the characteristics of the response. In dopamine-depleted rats, lever press and chain pull remained sensitive to reward devaluation, evidencing a role of striatal dopamine transmission in habit formation.

Dynamic effects of a 9 mm missile on cadaveric skull protected by aramid, polyethylene or aluminum plate: an experimental study.

BACKGROUND: Most military helmets are designed to prevent penetration by small firearms using composite materials in their construction. However, the transient deformation of the composite helmet during a non penetrating impact may result in severe head injury. METHOD: Two experimental designs were undertaken to characterize the extend of injuries imparted by composite panels using in protective helmets. In the first series, 21 dry skulls were protected by polyethylene plates, with gaps between the protective plate and skull ranging from 12 to 15 mm. In another design, using 9 cadavers, heads were protected by aluminum, aramid, or polyethylene plates. Specimens were instrumented with pressure gauges to record the impact response. The ammunition used in these experiments was 9 mm caliber and had a velocity of 400 m/s. A macroscopic analysis of the specimens quantified fractures and injuries, which were then related to the measured pressures. RESULTS: Protective plates influenced both the levels of injury and the intracranial pressure. Injuries were accentuated as the plates was changed from aluminum to composite materials and ranged from skin laceration to extensive skull fractures and brain contusion. Fractures were associated with brain parenchymal pressures in excess of 560 kPa and cerebrospinal fluid pressure of 150 kPa. An air gap of a few millimeters between the plate and the head was sufficient to decrease these internal pressures by half, significantly reducing the level of injury. CONCLUSIONS: Ballistic helmets made of composite materials could be optimized to avoid extensive transient deformation and thus reduce the impact and blunt trauma to the head. However, this deformation cannot be completely removed, which is why the gap between the helmet and the head must be maintained at more than 12 mm.

Spontaneous sphenoid sinus mucocele revealed by meningitis and brain abscess in a 12-year-old child.

Sphenoid sinus mucocele is an uncommon lesion related to inflammatory disease that is diagnosed after surgery or a traumatic event. This report describes an unusual case revealed by bacterial meningitis and cerebral abscess in a 12-year-old child. CT and MR imaging allowed precise extension to the skull base in preoperative management and follow-up investigations. Endoscopic transnasal marsupialisation of the mucocele and antibiotic therapy led to complete remission. There was no evidence of recurrence after 6 months, which suggests that sphenoid mucoceles, regardless of size and complications, can be treated by endoscopic sinus surgery.