Excessive Grooming Research Articles

Implication of the social function of excessive self-grooming behavior in BTBR T+ltpr3tf/J mice as an idiopathic model of autism

Autism spectrum disorder (ASD) is defined by two core behavioral characteristics, namely, restricted repetitive behaviors and impaired social-communicative functioning. BTBR T+ltpr3tf/J (BTBR) mice provide a valuable animal model for ASD to elucidate the underlying mechanisms of these two behavioral characteristics of ASD. This study examined the social function of excessive grooming behavior in BTBR mice as a phenotype of restricted repetitive behaviors. Compared to the control C57BL/6 J (B6) strain, BTBR mice showed increased self-grooming when placed alone in a test apparatus, and this behavior was even more evident when confronted with a stimulus mouse (either B6 or BTBR) in a three-chamber test apparatus. While B6 mice tended to groom their face/snout region on the empty side of the chamber, BTBR mice showed excessive grooming with frequent transitions among grooming body regions on the side of the chamber containing a social stimulus. Acute systemic injection of buspirone,a serotonin 1A receptor agonist, as an anxiolytic, facilitated approach behavior toward social stimuli in the three-chamber setting in both B6 and BTBR mice. However, this treatment did not affect grooming behavior in B6 mice and significantly enhanced self-grooming in BTBR mice. These behaviors in BTBR mice suggest a potential signaling function of grooming in response to social stimuli, in which bodywide grooming of BTBR mice expressed in the proximity of social opponents may stimulate the release of olfactory (possibly dismissive) signals. Consequently, the putative neural mechanisms underlying excessive grooming may differ from those regulating social approaches that are associated with anxiolytic mechanisms.

Prevalence of Body Dysmorphic Disorder Among a Group of College Students in Shiraz

Background: Body dysmorphic disorder (BDD) is a relatively common and often severe psychiatric disorder. This disorder is a highly distressing disorder associated with poor quality of life. In addition, it is characterized by persistent and intrusive preoccupation with perceived defects or flaws in one’s physical appearance accompanied by repetitive behaviors such as mirror checking, excessive grooming, and reassurance seeking. Objectives: The purpose of this study was to examine the prevalence of BDD symptoms and body dissatisfaction among college students. Furthermore, the current study examined students’ checking behaviors and the parts of the body that they were most concerned about. This research also sought to examine the comorbidities associated with BDD symptoms, such as eating disorders, obsessive-compulsive disorder, depression, and social anxiety. Methods: A total of 750 college students were recruited from different schools of the Shiraz University, including Social Science, Engineering, Art, Education and Psychology, and Science and Art, using the cluster sampling method. Two classes were randomly selected in each school, and those who were volunteers took part in this study. Participants completed several questionnaires, including the Body Dysmorphic Disorder Questionnaire, Beck Depression Inventory, Maudsley Obsessive-Compulsive Disorder Scale, Social Phobia Inventory, and Eating Attitude Test. To analyze the data, statistics methods, such as frequency, percentage, mean, standard deviation and chi-squared test were used. Results: The results of this study showed that about 77% of college students were dissatisfied with at least one part of their bodies. The findings also revealed that the prevalence of BDD symptoms among college students was 4.5%. Furthermore, our results indicated that college students were mostly concerned about the appearance of their skin followed by hair, nose, weight, stomach, height, teeth, breast, and other parts of the body. In terms of checking behaviors, checking in front of a mirror, reassurance seeking, seeking treatment, and comparing themselves with others were the most common behaviors. The most prevalent comorbidity associated with BDD symptoms was obsessive compulsive disorder followed by social anxiety, depression, and eating disorders. Conclusions: This study highlighted that the majority of college students were dissatisfied with their bodies. This research also showed that college students are at high risk of mental health problems.

Why do zombies clean themselves? An initial test of the antimicrobial hypothesis in a parasite‐host relationship

The emerald jewel wasp Ampulex compressa attacks the cockroach Periplaneta americana which serves as the host of the parasite and injects venom directly into the cockroach’s central nervous system. The cockroach responds by excessive grooming and cleaning its entire body with its legs and mandibles. The antimicrobial hypothesis suggests that self-grooming is adaptive for the parasite because it decreases ectoparasite and fungal infection rates from the cockroach’s cuticle in order to prevent infection of the wasp’s larvae. We demonstrated under laboratory conditions that microbial prevalence was not higher in stung cockroaches experimentally prevented from self-grooming than in self-groomed ones.

Gender differences in anxiety response to high intensity white noise in rats

Prolong exposure to high intensity white noise (HIWN), defined as a heterogeneous mixture of sound waves extending over a wide frequency range, has detrimental peripheral and central consequences including cardiovascular and emotional effects. Anxiety is a common manifestation of HIWN. Although gender-dependent differences in manifestation of anxiety and/or response to treatment of this condition has been amply documented, potential differences in response to HIWN, a common exposure in combat, construction and rave disco, has not been adequately investigated. In this study, both male and female Wistar rats were subjected to HIWN for 10 consecutive days, 1 h/day. On day 11, a day after the last exposure, the performance of the rats in open field (OF) and elevated plus maze (EPM) was evaluated. Male rats showed a higher anxiety-like response to HIWN as evidenced by: lower number of entries into the open arm of the EPM, lower number of entries into central zone of OF, excess grooming in OF and more boluses in closed arm of EPM. These results indicate that gender-related differences in anxiety in general, and in response to HIWN, in particular, has to be taken into consideration when investigating the neurobiological components and/or treatment modalities.

Spontaneous motor-behavior abnormalities in two Drosophila models of neurodevelopmental disorders

Mutations in hundreds of genes cause neurodevelopmental disorders with abnormal motor behavior alongside cognitive deficits. Boys with fragile X syndrome (FXS), a leading monogenic cause of intellectual disability, often display repetitive behaviors, a core feature of autism. By direct observation and manual analysis, we characterized spontaneous-motor-behavior phenotypes of Drosophila dfmr1 mutants, an established model for FXS. We recorded individual 1-day-old adult flies, with mature nervous systems and prior to the onset of aging, in small arenas. We scored behavior using open-source video-annotation software to generate continuous activity timelines, which were represented graphically and quantitatively. Young dfmr1 mutants spent excessive time grooming, with increased bout number and duration; both were rescued by transgenic wild-type dfmr1+ . By two grooming-pattern measures, dfmr1-mutant flies showed elevated repetitions consistent with perseveration, which is common in FXS. In addition, the mutant flies display a preference for grooming posterior body structures, and an increased rate of grooming transitions from one site to another. We raise the possibility that courtship and circadian rhythm defects, previously reported for dfmr1 mutants, are complicated by excessive grooming. We also observed significantly increased grooming in CASK mutants, despite their dramatically decreased walking phenotype. The mutant flies, a model for human CASK-related neurodevelopmental disorders, displayed consistently elevated grooming indices throughout the assay, but transient locomotory activation immediately after placement in the arena. Based on published data identifying FMRP-target transcripts and functional analyses of mutations causing human genetic neurodevelopmental disorders, we propose the following proteins as candidate mediators of excessive repetitive behaviors in FXS: CaMKIIα, NMDA receptor subunits 2A and 2B, NLGN3, and SHANK3. Together, these fly-mutant phenotypes and mechanistic insights provide starting points for drug discovery to identify compounds that reduce dysfunctional repetitive behaviors.

Making a Tiger's Day: Free-Operant Assessment and Environmental Enrichment to Improve the Daily Lives of Captive Bengal Tigers (Panthera tigris tigris).

There are more captive tigers in the United States than there are wild tigers in the entire world. Many animals under human care engage in problem behaviors such as excessive grooming and aggression, although the origin of these behaviors is typically unknown. Environmental enrichment may mitigate these issues in captive animals of all kinds. In order to individualize enrichment experiences, the current study used a free-operant assessment procedure to establish a menu of most preferred play items and scents among 7 Bengal tigers (Panthera tigris tigris) housed at a sanctuary in southwest Missouri. Each tiger was tested 3 times with scents (cinnamon and Calvin Klein Obsession perfume) and play items (boxes, balls, leaves, and pumpkins). The importance of rigorous assessment of presumed reinforcers among captive wild animals, as well as the difficulty of effectively assessing tigers while ensuring the safety of both the participants and researchers, is discussed.

Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder

Nighttime light pollution is linked to metabolic and cognitive dysfunction. Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycle, and may be particularly vulnerable to the impact of circadian disruptors. In this study, we examined the impact of exposure to dim light at night (DLaN, 5 lx) in a model of ASD: the contactin associated protein-like 2 knock out (Cntnap2 KO) mice. DLaN was sufficient to disrupt locomotor activity rhythms, exacerbate the excessive grooming and diminish the social preference in Cntnap2 mutant mice. On a molecular level, DLaN altered the phase and amplitude of PER2:LUC rhythms in a tissue-specific manner in vitro. Daily treatment with melatonin reduced the excessive grooming of the mutant mice to wild-type levels and improved activity rhythms. Our findings suggest that common circadian disruptors such as light at night should be considered in the management of ASD.

Genetic Basis of Natural Variation in Spontaneous Grooming in Drosophila melanogaster.

Spontaneous grooming behavior is a component of insect fitness. We quantified spontaneous grooming behavior in 201 sequenced lines of the Drosophila melanogaster Genetic Reference Panel and observed significant genetic variation in spontaneous grooming, with broad-sense heritabilities of 0.25 and 0.24 in females and males, respectively. Although grooming behavior is highly correlated between males and females, we observed significant sex by genotype interactions, indicating that the genetic basis of spontaneous grooming is partially distinct in the two sexes. We performed genome-wide association analyses of grooming behavior, and mapped 107 molecular polymorphisms associated with spontaneous grooming behavior, of which 73 were in or near 70 genes and 34 were over 1 kilobase from the nearest gene. The candidate genes were associated with a wide variety of gene ontology terms, and several of the candidate genes were significantly enriched in a genetic interaction network. We performed functional assessments of 29 candidate genes using RNA interference, and found that 11 affected spontaneous grooming behavior. The genes associated with natural variation in Drosophila grooming are involved with glutamate metabolism (Gdh) and transport (Eaat); interact genetically with (CCKLR-17D1) or are in the same gene family as (PGRP-LA) genes previously implicated in grooming behavior; are involved in the development of the nervous system and other tissues; or regulate the Notch and Epidermal growth factor receptor signaling pathways. Several DGRP lines exhibited extreme grooming behavior. Excessive grooming behavior can serve as a model for repetitive behaviors diagnostic of several human neuropsychiatric diseases.

Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila.

Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model. Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during development. Furthermore, intact Nf1 Ras GAP-related domain signaling was required to maintain normal grooming. The requirement for Nf1 was distributed across neuronal circuits, which were additive when targeted in parallel, rather than mapping to discrete microcircuits. Overall, these data suggest that broadly-distributed alterations in neuronal function during development, requiring intact Ras signaling, drive key Nf1-mediated behavioral alterations. Thus, global developmental alterations in brain circuits/systems function may contribute to behavioral phenotypes in neurofibromatosis type 1.

Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice.

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

A limbic circuitry involved in emotional stress-induced grooming

Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour.

Evidence for Distinct Forms of Compulsivity in the SAPAP3 Mutant-Mouse Model for Obsessive-Compulsive Disorder.

The specific mechanisms underlying compulsive behavior in obsessive-compulsive disorder (OCD) are unknown. It has been suggested that such compulsivity may have its origin in cognitive dysfunction such as impaired processing of feedback information, received after the completion of goal-directed actions. The signal attenuation (SA) task models such a processing deficit in animals by attenuating the association strength between food reward and audiovisual feedback (signal) presented after performance of an operant response. The compulsive-like responding resulting from SA is well characterized in rats, but was so far not established in mice, a species for which powerful genetic OCD models exist. Thus, first, we demonstrate that the SA task can be implemented in mice and show that attenuation of reward-associated response feedback produces similar behavior in C57BL/6 mice as previously reported in rats. Second, we tested the hypothesis that SAPAP3 knock-out mice (SAPAP3-/-), prone to exhibit several OCD-like abnormalities including excessive grooming, show enhanced compulsive-like behavior in the SA task compared with their wild-type (WT) littermates. However, task-related compulsivity measures in SAPAP3-/- and WT did not yield significant differences, neither following SA nor during “regular” extinction of operant behavior. Thus, compulsive-like instrumental behavior following feedback distortion was not potentiated in compulsively grooming mice, implicating specifically that (1) a general deficit in feedback processing is not related to excessive grooming in SAPAP3-/- and (2) different manifestations of compulsivity may be driven by independent mechanisms.

Neuromedin U induces self-grooming in socially-stimulated mice

Emerging evidence suggest that appetite-regulating peptides modulate social behaviors. We here investigate whether the anorexigenic peptide neuromedin U (NMU) modulates sexual behavior in male mice. However, instead of modulating sexual behaviors, NMU administered into the third ventricle increased self-grooming behavior. In addition, NMU-treatment increased self-grooming behavior when exposed to other mice or olfactory social-cues, but not when exposed to non-social environments. As the neuropeptide oxytocin is released during social investigation and exogenous oxytocin induces self-grooming, its role in NMU-induced self-grooming behavior was investigated. In line with our hypothesis, the oxytocin receptor antagonist inhibited NMU-induced self-grooming behavior in mice exposed to olfactory social-cues. Moreover, dopamine in the mesocorticolimbic system is known to be a key regulator of self-grooming behavior. In line with this, we proved that infusion of NMU into nucleus accumbens increased self-grooming behavior in mice confronted with an olfactory social-cue and that this behavior was inhibited by antagonism of dopamine D2, but not D1/D5, receptors. Moreover repeated NMU treatment enhanced ex vivo dopamine levels and decreased the expression of dopamine D2 receptors in nucleus accumbens in socially housed mice. On the other hand, the olfactory stimuli-dependent NMU-induced self-grooming was not affected by a corticotrophin-releasing hormone antagonist, and NMU-treatment did not influence repetitive behaviors in the marble burying test. In conclusion, our results suggest that NMU treatment and, social cues - potentially triggering oxytocin release - together induce excessive grooming behavior in male mice. The mesolimbic dopamine system, including accumbal dopamine D2 receptors, was identified as a crucial downstream mechanism.

Behavioural Differences in Dogs with Atopic Dermatitis Suggest Stress Could Be a Significant Problem Associated with Chronic Pruritus.

Simple SummaryCanine atopic dermatitis (cAD) is a common allergic skin condition in dogs that causes long-term itching; it is similar to eczema in people. The overall quality of life in dogs with cAD is known to be reduced, and humans with eczema report significant psychological burdens from itching that increase stress levels and can lead to the development of additional mental health problems. We tested whether dogs with cAD would display more problem behaviours (that could be indicative of stress) than would healthy controls. Behavioural data were gathered directly from owners using a validated dog behaviour questionnaire for 343 dogs with a diagnosis of cAD and 552 healthy controls, and scores were also provided for the severity of itching experienced by their dog. The results showed that itch severity in dogs with cAD was associated with increased frequency of behaviours often considered problematic, such as: mounting, chewing, hyperactivity, coprophagia (eating faeces), begging for and stealing food, attention-seeking, excitability, excessive grooming and reduced trainability. Whilst we cannot know whether itching directly caused these differences, the behaviours that were associated with itch severity are of a type that are often considered by behavioural biologists to be indicative of stress. Further investigation is warranted, and stress reduction could be helpful when treating dogs with cAD.Canine atopic dermatitis (cAD) is a common allergic skin condition in dogs that causes chronic pruritus. The overall quality of life in dogs with cAD is known to be reduced, and human patients with pruritic conditions report significant psychological burdens from pruritus-induced stress, and atopic dermatitis is associated with significant psychopathological morbidities. We tested the hypothesis that dogs with cAD would display more problem behaviours that could be indicative of stress than would healthy controls. Behavioural data were gathered directly from owners using a validated dog behaviour questionnaire for 343 dogs with a diagnosis of cAD and 552 healthy controls, and scores were also provided for their dog’s pruritus severity. Regression modelling, controlling for potential confounding variables (age, sex, breed, neuter status or other health problem(s)) showed for the first time that pruritus severity in dogs with cAD was associated with increased frequency of behaviours often considered problematic, such as mounting, chewing, hyperactivity, coprophagia, begging for and stealing food, attention-seeking, excitability, excessive grooming, and reduced trainability. Whilst causality cannot be ascertained from this study, the behaviours that were associated with pruritus severity are redirected, self/environment-directed displacement behaviours, which are often considered indicative of stress. Further investigation is warranted, and stress reduction could be helpful when treating dogs with cAD.

T34. Effects of Repeated Cortico-Striatal Optogenetic Stimulation on OCD-Like Behaviors in Rats

Accumulating evidence points to orbitofrontal cortex-ventromedial striatum (OFC-VMS) circuitry hyperactivity in Obsessive-Compulsive Disorder (OCD). Hyper-activating this pathway in inbred mice produces excessive grooming and other perseverative behaviors that outlast the stimulation. We aim to replicate these findings in outbred rats, where there are few reliable models of OCD-related behavior.

3293 Region Specific Dysregulation of Dopaminergic Signaling in Mice Displaying Excessive Over-Grooming

OBJECTIVES/SPECIFIC AIMS: The objective of this study was to determine if dopamine signaling is altered in a mouse model displaying excessive self-grooming and further elucidate the potential utility of compounds targeting the striatal DA system in modulating repetitive behaviors. METHODS/STUDY POPULATION: Here, we report studies using fast-scan cyclic voltammetry (FSCV) in mice lacking the postsynaptic protein SAP90/PSD95-associated protein (SAPAP3 KO mice) as well as control littermates. Rodent self-grooming provides a behavioral output with which one can monitor repetitive, self-directed, patterned behavior that has great translational value to OCD-like disorders. Total time spent grooming was monitored in SAPAP3KO mice and control littermates. To further examine the role of DA in regulating repetitive grooming behaviors the magnitude and kinetics of DA transients were assessed using FSCV in ex vivo slice preparations as well as in anesthetized mice in vivo. DA transients were elicited in the dorsolateral striatum (DLS), dorsomedial striatum (DMS); and nucelus accumbens core (NAcc). In some experiments mice were crossed with DAT-Cre animals and channelrhodopsin 2 (ChR2) was virally expressed in DA neurons to allow optical stimulation of DA transients. RESULTS/ANTICIPATED RESULTS: As previously reported, SAPAP3 KO mice showed excessive grooming compared to control littermates at the age assessed (4-5 months). DA transients evoked by a single electrical pulse in slices from SAPAP3 KO mice were not significantly different from those observed in slices from control littermates in any of the regions tested including the DLS, DMS and NAcc. However, when four electrical pulses were applied at a frequency of 10Hz to mimic DA neuron bursting, the magnitude of DA transients observed in the DMS and NAcc of SAPAP3 mice were greater than those evoked in control littermates.Interestingly, phasic stimulation produced similar DA transients in the DLS of both genotypes suggesting that phasic DA signaling was not globally altered. To confirm this finding we crossed SAPAP3 KO mice with DAT-Cre mice and injected ChR2 containing virus into the midbrain to selectively express ChR2 in DA neurons. Transients were then optically evoked resulting in selective activation of DA neurons. Optical stimulation produced a pronounced enhancement of DA release in SAPAP3 KO mice specifically in the DMS and only following phasic-like stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: These exciting findings suggest that DA signaling in SAPAP3KO mice is dysregulated in a very precise manner that is sub-region specific as well as dependent on the pattern of stimulation. These results suggest that targeted therapies that can modulate these specific modes of dopaminergic signaling in these distinct striatal subregions could provide improved efficacy in OCD patients that are resistant to SSRI treatment.

Self-induced dermatoses: A great imitator

The self-induced dermatoses represent about 2% of dermatology patient visits, and include the recurrent body-focused repetitive behaviors (BFRB) (skin-picking or excoriation disorder, trichotillomania, onychophagia and onychotillomania), dermatitis artefacta, and features of other psychiatric disorders, for example, secondary to excessive grooming in body dysmorphic disorder, skin picking in delusional infestation, or secondary to self-harm in depressive disease. Among the BFRBs, onychophagia and onychotillomania are most likely to be associated with lesions that mimic other dermatologic conditions (eg, nail psoriasis, lichen planus, vasculitis, onychomycosis, melanoma). Dermatitis artefacta (DA) describes lesions that are self-inflicted with the intention of assuming a sick role in the absence of obvious external rewards. DA lesions can be bizarre-appearing or may be created intentionally to mimic dermatologic disease (eg, Munchausen syndrome). The manipulation of the integument can have a focused obsessive-compulsive behavioral style which is more responsive to the standard behavior therapies, or an impulsive-dissociative style where patients have partial or no recollection of having self-induced their lesion; dissociative patients tend to have more severe BFRBs and DA, and greater psychopathology. Self-induced dermatoses may both imitate and co-occur with primary dermatologic disease, and may not be readily identified unless the clinician maintains an index of suspicion.

Mutually‐induced traumatic alopecia responsive to husbandry modification in two cohabiting donkeys

SummaryCutaneous expression of behavioural processes remains unexplored in donkeys. This case report describes a case of traumatic alopecia in two donkeys secondary to mutual hair plucking behaviour. Two genetically unrelated, male castrated, 4‐year‐old Cotentin donkeys living together were presented for a 2‐year history of alopecic, mainly nummular, nonpruritic lesions developing on the back, loin and croup. The general physical examination and behavioural assessment were unremarkable. Trichoscopy, scrapings and cytology were performed. Superficial bacterial infection was diagnosed but a 2‐week course of antibacterial treatment showed no improvement. Histopathological examination showed features compatible with traumatic alopecia and consistent with several behavioural causes of alopecia resembling human trichotillomania or acute traction alopecia, canine traction alopecia, feline self‐induced alopecia and murine barbering. Separation of the donkeys led to complete long‐term remission. Clinical and histopathological findings in our case share lots of similar features with the different mechanical traumatic alopecic disorders mentioned above, making it impossible to simply classify the described affection. Whether alopecic lesions resulted from an exclusive behavioural process (either abnormal excessive mutual grooming or other social interactions) or were associated with underlying causes of pruritus is uncertain. Mechanical alopecia secondary to a behavioural process should therefore be suspected in cases of permanent patchy alopecic nummular lesions on donkeys living in groups.

Tsix–Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2+/- heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix-Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix-Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5-10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.

Differential Effects of Deep Brain Stimulation of the Internal Capsule and the Striatum on Excessive Grooming in Sapap3 Mutant Mice

BackgroundDeep brain stimulation (DBS) is an effective treatment for patients with obsessive-compulsive disorder (OCD) that do not respond to conventional therapies. Although the precise mechanism of action of DBS remains unknown, modulation of activity in corticofugal fibers originating in the prefrontal cortex is thought to underlie its beneficial effects in OCD. MethodsTo gain more mechanistic insight into DBS in OCD, we used Sapap3 mutant mice. These mice display excessive self-grooming and increased anxiety, both of which are responsive to therapeutic drugs used in OCD patients. We selected two clinically relevant DBS targets through which activity in prefronto-corticofugal fibers may be modulated: the internal capsule (IC) and the dorsal part of the ventral striatum (dVS). ResultsIC-DBS robustly decreased excessive grooming, whereas dVS-DBS was on average less effective. Grooming was reduced rapidly after IC-DBS onset and reinstated upon DBS offset. Only IC-DBS was associated with increased locomotion. DBS in both targets induced c-Fos expression around the electrode tip and in different regions of the prefrontal cortex. This prefronto-cortical activation was more extensive after IC-DBS, but not associated with behavioral effects. Furthermore, we found that the decline in grooming cannot be attributed to altered locomotor activity and that anxiety, measured on the elevated plus maze, was not affected by DBS. ConclusionsDBS in both the IC and dVS reduces compulsive grooming in Sapap3 mutant mice. However, IC stimulation was more effective, but also produced motor activation, even though both DBS targets modulated activity in a similar set of prefrontal cortical fibers.