Figure 1
Figure 1

Mouse Grooming Behavior: Exploring the Innate and Learned Aspects in Animal Models

Self-grooming, a fundamental and intricate innate behavior, is remarkably prevalent among rodents, characterized by a conserved sequential pattern across evolution. This behavior stands as one of the most frequent activities observed in rodents. This review delves into the neurobiological underpinnings of self-grooming in rodents, with a particular focus on studies utilizing rodent models for neuropsychiatric disorders, notably autism spectrum disorder and obsessive-compulsive disorder, to evaluate self-grooming phenotypes. We propose that rodent self-grooming serves as a valuable metric for assessing repetitive behaviors within such models, offering significant insights for translational psychiatry. Furthermore, the study of rodent self-grooming can enhance our comprehension of the neural circuits governing complex sequential action patterns.

This review is dedicated to the memory of Professor John C. Fentress (1939–2015), a pioneering figure in neurobiology research, whose passing occurred shortly after the initial submission of this manuscript.

In the animal kingdom, self-grooming is an inherent behavior crucial for maintaining hygiene and facilitating various physiologically significant processes. These encompass thermoregulation, social communication, and stress reduction. It is a behavior commonly observed in rodents when they are awake, distinguished by a structured, sequential organization that follows a characteristic head-to-tail progression (FIG. 1). The consistency of self-grooming across diverse species within several taxa is noteworthy. Humans also engage in self-grooming behaviors, exhibiting certain similarities to those observed in other animals. However, in humans, self-grooming can become pathological, particularly under stressful conditions or in the context of specific neuropsychiatric disorders.

Figure 1. Decoding Rodent Self-Grooming Behavior: Syntactic Chains, Neural Lesions, and Stress Effects

Figure 1a: Syntactic Chains in Mouse Self-Grooming. Mouse self-grooming is structured into syntactic chains, comprising stereotyped movements in a sequence. Phase 1 involves bilateral paw strokes near the nose (paw-nose grooming). Phase 2 transitions to unilateral strokes from whiskers to below the eye (face grooming). Phase 3 includes bilateral upward strokes by both paws (head grooming). Phase 4 concludes with body licking, following a head-to-tail postural shift. Tail and genital grooming, while frequent, are not part of the syntactic chain. Chain grooming is vital for studying self-grooming sequencing, though flexible, non-chain grooming makes up about 90% of self-grooming behavior. Figure 1b: Impact of Brain Lesions on Rat Grooming Behavior. Lesions in different brain areas affect rat self-grooming differently. Ventral pallidum (VP) lesions reduce grooming, while anterior dorsolateral striatum (DL) lesions disrupt grooming sequencing. Figure 1c: Stress-Induced Alterations in Rat Self-Grooming. Acute stress from bright light exposure alters self-grooming sequencing in rats, affecting grooming activity, incorrect transitions, and interrupted bouts.

The evaluation of rodent self-grooming holds significant promise for translational neuroscience research. Aberrant self-grooming in rodents can be correlated with human disorders characterized by abnormal self-grooming symptoms. However, it’s crucial to acknowledge that animal self-grooming should not be considered a precise replica of any specific human pathology. Instead, its broader value lies in its capacity to model complex repetitive, self-directed, and sequentially patterned behaviors. Thus, rather than directly equating rodent self-grooming behavior to a particular symptom, it is more appropriate to view it as an indirect indicator of various behavioral phenomena relevant to human brain disorders. These include motor action chains and intricate motor activity patterns. From this wider perspective, analyzing rodent self-grooming can contribute to understanding the neural mechanisms of hierarchical motor control that underlie complex sequential behaviors in general and offer valuable mechanistic insights into their dysregulation.

Neurophysiology, genetics, and pharmacology have been instrumental in investigating this intriguing complex behavior in rodents. This review discusses findings from these studies and emphasizes the potential implications of assessing rodent self-grooming behavior for understanding human brain disorders. We posit that rodent self-grooming is a crucial behavioral phenotype for deciphering the neural basis of complex action patterns across species, including humans, in both normal and abnormal states. This review specifically focuses on self-grooming and does not cover heterogrooming or the peripheral and brainstem or spinal coordination mechanisms that are the ultimate targets of the forebrain control networks involved in grooming.

Unraveling the Neurobiology of Rodent Self-Grooming

Behavioral Complexity: The Intricate Structure of Grooming

Self-grooming in mice and rats exhibits a remarkable degree of behavioral complexity and organization, often referred to as grooming microstructure. This involves a sequence of individual movements forming functional patterns, including highly stereotyped sequences (FIG. 1a). In the initial postnatal days, rodent self-grooming is primarily directed at the face, consisting of either isolated grooming strokes with the front paws or bouts of strokes with varying intensity and symmetry. Over the subsequent weeks, self-grooming behavior evolves to incorporate symmetrical, double-handed movements of lower intensity, eventually maturing into the species-typical sequencing of short and long symmetrical and asymmetrical strokes. During these early developmental stages, grooming is confined to the face, gradually expanding to include the entire head, neck, and trunk. Adult rodents not only exhibit the stereotyped grooming seen in younger animals but also demonstrate more flexible, less stereotyped facial grooming movements.

Mature rodent grooming behavior is characterized by specific and highly stereotyped patterns of sequential movements, known as a syntactic chain pattern. This pattern frequently occurs during the transition from facial to body grooming (FIG. 1a,b). Syntactic chains of self-grooming share similarities with other fixed-action patterns, such as sexual or aggressive behaviors. They are highly stereotyped in order and, once initiated, proceed to completion without requiring sensory feedback. A typical self-grooming syntactic chain in rodents links 20 or more grooming movements into four distinct, predictable phases, following a head-to-tail rule. The serial structure of these chains is repetitive and consistent in order and timing. Once the first phase begins, the entire sequential pattern reliably continues through all four phases. This syntactic chain pattern accounts for approximately 10–15% of all observed self-grooming behaviors in rodents, with the majority following less predictable sequential patterning rules (FIG. 1).

Self-grooming sequencing, chain initiation, and chain completion in rodents are susceptible to bidirectional alterations through experimental manipulations. These include lesions of the dopamine-containing nigrostriatal tract, administration of various dopaminergic drugs, genetic mutations, and psychological stress. The syntactic chains are typically interspersed with more flexible ‘non-chain’ grooming, which constitutes approximately 85–90% of all grooming behaviors. Ethologically based analyses of grooming behaviors, encompassing both chain and non-chain bouts, are widely used in neurobiological research to assess their overall adherence to the head-to-tail rule. Correct and incorrect head-to-tail transitions between stages can be studied, alongside interruptions in grooming bouts (as an indicator of disturbed self-grooming) and their regional distribution across the body. Such analyses highlight the high sensitivity of grooming sequencing to genetic, pharmacological, and psychological challenges.

Neural Circuitry: Mapping the Brain Regions of Self-Grooming

Given its highly patterned nature, grooming is particularly well-suited for investigating how various neural circuits regulate both the motor and sequencing aspects of this behavior. Studies on rats decerebrated at successively lower levels of the neuraxis have revealed that rats with mesencephalic decerebration, where the midbrain remains intact, maintain a normal sequential pattern of self-grooming chains. However, these animals face difficulties in completing the full pattern. In contrast, rats decerebrated at more caudal levels (metencephalic and myelencephalic) exhibit a gradual degradation of the sequential pattern itself. This suggests that the brainstem circuitry is essential for executing fully patterned grooming sequences (FIG. 2).

Figure 2. Key Brain Regions Regulating Rodent Self-Grooming: A Simplified Overview

Figure 2: Brain Regions in Rodent Self-Grooming. This figure simplifies the brain regions involved in rodent self-grooming. The basal ganglia, especially the striatum and its dopamine inputs, control motor behavior and sequencing, even for brainstem-generated sequences. The neocortex modulates grooming movements, projecting to the striatum and receiving projections from the thalamus and amygdala. The cerebellum, with its connections to various brain areas, coordinates and fine-tunes movements. The amygdala modulates grooming in context-specific situations like stress. The hypothalamus regulates grooming through neuroendocrine pathways, with hormones like CRH and ACTH inducing grooming. The brainstem initiates grooming movements and basic sequences but needs striatal input for full pattern implementation.

Within the forebrain, circuits incorporating the basal ganglia and allied nuclei, such as the striatum, globus pallidus, substantia nigra, nucleus accumbens, and subthalamic nucleus, are strongly implicated in hierarchical motor control and behavior sequencing, including self-grooming. The striatum serves as the primary input region of the basal ganglia and is involved in learning, motivation, and motor sequencing. The basal ganglia and particularly the striatum are necessary for executing complete sequential patterns of grooming chains and other sequential behaviors in mice and rats (FIG. 2). Lesions in the striatum result in a permanent deficit in the ability to complete sequential syntactic self-grooming chains (FIG. 1b). Extensive research using localized striatal lesions has pinpointed the anterior dorsolateral striatum as crucial for normal grooming behavior. Damage to this striatal region impairs the completion of syntax patterns of grooming movements but not the initiation. Rats with such striatal lesions completed only about 50% of syntactic chains, similar to rats with mesencephalic decerebration, while control rats completed about 90% of chains. This suggests that the anterior dorsolateral striatum and decerebration lead to similar pattern completion deficits, yet both mesencephalic and pontine decerebrates can still produce the basic sequential self-grooming pattern.

These findings suggest that the brainstem contains the essential pattern generator for syntactic chains, while the dorsolateral striatum acts as a forebrain controller coordinating the normal completion of the chain pattern. In contrast, lesions affecting the major output nuclei of the basal ganglia, including the ventral pallidum and globus pallidus, disrupt the movements necessary for grooming but not the syntax. This indicates that distinct striatal pathways may regulate self-grooming activity and its patterning and sequencing. Neurons in the dorsolateral striatum and substantia nigra pars reticulata exhibit distinct spiking patterns during different grooming types. For instance, some dorsolateral striatal neurons active during syntactic grooming sequences are unresponsive during kinematically similar movements in flexible grooming. Given that striatal neurons can code various types of naturally sequenced behaviors, the basal ganglia likely play a critical role in controlling sequential movement not only in self-grooming but also in other complex sequenced behaviors.

Lesions in the neocortex or cerebellum lead to timing deficits and abnormalities in individual self-grooming movements without affecting the sequential pattern of grooming chains. Other cerebellar manipulations also impact self-grooming. Electrical stimulation of the cerebellum elicits self-grooming in rats, while Lurcher mutant mice with cerebellar degeneration show reduced grooming duration but unaltered sequencing compared to wild-type mice. The interconnectedness of the striatum, neocortex, and cerebellum in movement-control networks suggests that the striatum and its associated neural pathways are particularly important for grooming pattern sequencing. This aligns with evidence supporting the role of striatum-based circuits in sequential behaviors in general.

Self-grooming behavior is also modulated by the limbic circuitry, including the amygdala and hypothalamus (FIG. 2). The amygdala, a limbic brain structure, regulates motivational states like fear, anxiety, and desire. Studies have shown correlations between increased anxiety-like behavior and reduced dopamine release within the amygdala in selectively bred high-grooming versus low-grooming rats. The extended amygdala, a system extending from the amygdala to the bed nucleus of the stria terminalis (BNST) and nucleus accumbens shell, regulates reward and affect. It comprises a medial division (MeA and medial BNST) and a lateral division (CeA and lateral BNST), both implicated in self-grooming and acting in concert. Stimulation of glutamatergic neurons in the posterior dorsal MeA (MeApd) induced repetitive self-grooming and suppressed social interaction in mice, while stimulation of GABAergic neurons in the MeApd inhibited self-grooming and promoted social interaction. Within the lateral extended amygdala, orexin-B microinjections into the CeA increased grooming frequency in hamsters, supporting the role of both MeA and CeA in modulating self-grooming.

Further research is needed to fully understand amygdala-related grooming circuitry. In addition to striatal connections, the amygdala, particularly the basolateral nucleus (BLA), projects to the prefrontal cortex, which, along with other cortical regions, projects to the striatum. While corticostriatal connections modulate self-grooming behavior, the potential functions of indirect amygdalo-corticostriatal networks in grooming remain to be explored. The connectivity between the striatum and amygdala raises the possibility of distinguishing between locomotor and sequencing control of self-grooming (linked to basal ganglia circuits) and self-grooming related to affective states (modulated by amygdala-related limbic circuits). However, affective state is central to striatal state modulation, making this contrast potentially oversimplified. Therefore, the functional and anatomical diversity of both amygdala and striatal circuits must be considered. Complex context-specific modulation of grooming behavior may involve both BLA–CeA–anterior BNST circuits (mediating stress, anxiety, and conditioned defense) and MeA–posterior BNST circuits projecting to the hypothalamus (responsible for innate social and predator-defense behaviors).

The hypothalamus, a forebrain region coordinating neural and endocrine regulation of brain functions and behavior, is another limbic region implicated in rodent self-grooming regulation. Local electrical stimulation or drug injections in the hypothalamus evoke robust self-grooming in rats, suggesting the paraventricular nucleus and dorsal hypothalamus are part of a grooming-specific region. The paraventricular nucleus projects to the MeApd, and glutamatergic neurons in the lateral hypothalamic area adjacent to the MeApd contribute to repetitive self-grooming in mice. Both CeA and MeA project to divisions of the BNST, the main amygdala-hypothalamus connector. Amygdala nuclei, notably the MeApd, also project to the medial hypothalamus. The hypothalamic–pituitary system also modulates self-grooming, with stress-related peptides like corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) inducing self-grooming. The effects of these hormones on grooming partly depend on the mesolimbic dopaminergic system. This evidence collectively indicates that the hypothalamus and its pituitary connections are crucial brain regions integrating neural and endocrine regulation of self-grooming.

Pharmacological Modulation: Neurotransmitters and Grooming Behavior

Pharmacological interventions can significantly alter rodent self-grooming. Dopamine, a key modulator in the nigrostriatal and mesolimbic systems, is crucial for locomotor function, self-grooming, and other complex patterned behaviors. In rodents, systemic administration of dopamine D1 receptor (D1) agonists enhances behavioral super-stereotypy, leading to excessive production and rigidity of self-grooming chains. Systemic co-administration of the dopamine D2 receptor (D2) antagonist haloperidol prevents sequential super-stereotypy induced by the D1 agonist SKF38393. Activation of grooming by SKF83959, a D1 agonist and D2 partial agonist, is eliminated in knockout mice lacking the D1 (but not D2) gene. These findings underscore the importance of balance between the D1 and D2 systems of the striatum in regulating self-grooming.

Striatal circuits are also characterized by the striosome-matrix architecture. Striosomes, chemically specialized macroscopic zones within the striatum, form a distributed labyrinthine system within the extrastriosomal matrix. This architecture governs the distribution of neurotransmitters, receptors, projection neurons, and interneurons in the striatum. Studies show that dopaminergic challenge strongly activates striosomes, expressing early response genes coding for transcription factors. This heightened striosomal activation correlates with increased repetitive behaviors, including self-grooming, in both non-human primates and rodents.

Pharmacological studies also highlight glutamate’s role in self-grooming regulation. Systemic administration of anti-glutamatergic agents, like the NMDA receptor antagonist phencyclidine (PCP), is a well-established method for inducing grooming in rodents. PCP also induces generalized hyperlocomotion and other stereotypic behaviors. While PCP increases experimentally evoked self-grooming duration, it only disrupts self-grooming sequencing under stress, suggesting that self-grooming activity and patterning are differentially controlled by the CNS.

GABAergic neurotransmission also contributes to self-grooming regulation. Drugs enhancing GABAergic tone, such as benzodiazepines and allo-pregnanolone, generally reduce rodent self-grooming at non-sedative doses. Conversely, GABA-inhibiting drugs often increase grooming and can reverse the anti-grooming effects of GABA-enhancing agents. The GABAergic system is a key modulator of stress and anxiety-related behaviors in rodents. GABA-enhancing drugs exert anxiolytic effects and may be useful in treating obsessive-compulsive disorder (OCD). These drugs and other anxiolytics may suppress stress-induced grooming by reducing the perception of anxiogenic stimuli, as anxiety-like states alter rodent self-grooming and its sequencing. Head-to-tail patterning of rodent self-grooming is sensitive to GABAergic drugs: GABA signaling inhibitors generally disrupt head-to-tail patterning, while GABA signaling enhancers tend to normalize this response.

Given the CNS ubiquity of GABA and glutamate, region-specific manipulations are needed for further insights into their grooming roles. For example, injecting the GABAA receptor agonist zolpidem into the hamster CeA did not affect orexin B-evoked grooming, while co-infusion of an NMDA receptor agonist potentiated orexin B’s effect. Injecting the GABAA agonist muscimol into the BNST (but not BLA) strongly reduced self-grooming evoked by cat urine exposure, suggesting this region is crucial for anxiogenic responses, including increased self-grooming. Muscimol administration to the ventral tegmental area potentiates excessive self-grooming evoked by α-melanocyte-stimulating hormone. Conversely, treatment with the NMDA receptor antagonist memantine ameliorates pathological self-grooming in mice lacking astrocyte-specific excitatory amino acid transporter 2 (GLT1), which exhibit aberrant excitatory transmission at corticostriatal synapses. Collectively, this evidence implicates key central neurotransmitters and their circuits in grooming regulation.

Self-Grooming Aberrations in CNS Disorders: Modeling Human Conditions

Rodent self-grooming can model normal or pathological human grooming behaviors, and it is broadly relevant to the neurobiology of complex, repetitive, and sequentially patterned behaviors. Different aspects of rodent self-grooming can mimic phenotypes across human conditions (FIG. 3), some of which manifest as aberrant grooming. In line with Research Domain Criteria (RDoC), we take a dimensional approach, discussing rodent self-grooming dysregulation and its value for modeling dimensions of human psychopathology that cross traditional diagnoses.

Figure 3. Rodent Self-Grooming as a Model for Neuropsychiatric and Neurodegenerative Disorders

Figure 3: Self-Grooming Phenotypes in Rodent Models. This figure illustrates expected self-grooming phenotypes in rodent models of neuropsychiatric and neurodegenerative disorders. The x-axis represents grooming activity amount (low to high frequency/duration), and the y-axis represents sequential patterning (rigid/repetitive to flexible). Wild-type control animals show normal self-grooming centrally. ‘Rigid’ grooming, with high head-to-tail sequence adherence, is maximal in chain grooming. ‘Flexible’ patterning, with head-to-tail rule deviations, is maximal in non-chain grooming. Sapap3−/− mice (OCD model) groom more and repetitively. Anxiety models show increased grooming but impaired patterning. Alzheimer’s and Parkinson’s models likely show progressive grooming deficits due to motor impairments. Huntington’s models may initially show increased grooming, followed by decreased grooming due to motor deficits in later stages.

Autism Spectrum Disorder: Self-Grooming as a Measure of Repetitive Behavior

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex symptoms, including communication difficulties, repetitive behaviors, and social deficits. Developing experimental animal models of ASD is of significant interest. Rodent self-grooming episodes are considered to recapitulate pathological repetitive behaviors, making rodent strains exhibiting these phenotypes valuable for identifying neural circuits and genes relevant to ASD. We discuss rodent self-grooming as a measure of behavioral perseveration rather than a specific ASD phenotype model. Many mouse strains discussed also show other ASD-relevant phenotypes, such as non-grooming behavioral perseverations, social impairments, and anxiety.

The inbred BTBR T+Itpr3tf/J (BTBR) mouse strain, lacking the corpus callosum, exhibits ASD-like symptoms, including social deficits, anxiety, and behavioral inflexibility. Peer rearing with a non-ASD strain improved social deficits but not repetitive self-grooming in BTBR mice, suggesting different ASD behavioral domains may be regulated by distinct brain mechanisms. However, pharmacological interventions can correct increased self-grooming in these animals. Cholinergic agents reduce self-grooming and other ASD-like behaviors in BTBR mice. Repetitive self-grooming in BTBR mice is also rescued by inhibiting glutamatergic metabotropic mGluR5 receptors and stimulating NMDA receptors by d-cycloserine. Environmental enrichment reduces the duration, but not the rigid patterning, of abnormal self-grooming in BTBR mice. The ability to modulate self-grooming quantity and quality in these mice by different interventions suggests distinctions between these aspects of self-grooming behavior at the circuit and molecular pathway levels. This emphasizes the value of nuanced grooming phenotype understanding in preclinical biological psychiatry research, aligning with defining psychiatric diseases as circuit disorders.

Genetic mechanisms underlying ASD have been unclear due to its polygenic nature. Currently, about 700 genes are associated with ASD. Individuals with ASD have heterogeneous behavioral and neuromorphological phenotypes. Assessing self-grooming in transgenic mice can help investigate the role of specific genes associated with autism. SHANK1, SHANK2, and SHANK3 encode postsynaptic scaffolding proteins crucial for brain synaptic function, and mutations in these genes are strongly implicated in ASD. Mice with mutations in different Shank genes show aberrant self-grooming phenotypes (TABLE 1), alongside ASD-like social deficits and repetitive behaviors. For example, Shank1+/− mice show mildly increased self-grooming as adults. Female Shank2−/− mice lacking exon 7 show increased self-grooming bout duration, and male Shank2−/− mice lacking exons 6 and 7 spend more time self-grooming during novel object recognition tests. Increased self-grooming bout duration in Shank3−/− mice has also been reported. These findings link Shank gene disruptions, aberrant brain synaptic function, and ASD-related behaviors in mice, suggesting Shank-mutant mice, and their self-grooming phenotypes, are good ASD models.

Table 1. Selected Rodent Strains Exhibiting Aberrant Self-Grooming Behavior

Model Aberrant self-grooming phenotype Refs
Dat1−/− mice Increased stereotypy 29
Drd1a−/− mice Increased frequency and disrupted sequencing 148
Hoxb8−/− mice Excessive self-grooming 17,25
Sapap3−/− mice Increased frequency and duration* 23,40,39
Shank1+/− and Shank1−/− mice Increased duration 21
Shank2−/− mice Partially increased in females (lacking exon 7) and in males(lacking exons 6 and 7) 16,112
Shank3+/− and Shank3−/− mice Mildly increased duration 88,106,107
Syn2−/− mice Increased duration 22
Hdc−/− mice Increased duration 150
Vdr−/− mice Increased duration and disrupted sequencing 31,158
Astrocyte-specific inducibleGlt1−/− mice Increased duration 85
Striatum-specific Gad1−/− mice Increased duration 118
MAO-ANeo mice Increased frequency and duration 192
BTBR mice Increased duration and repetition 19,33,94
RLA rats Increased duration 159,193,194
LY and HY rats Different patterning in HY rats compared with LY rats 195,196

Table 1: Aberrant Grooming in Rodent Models. This table lists selected rodent strains showing aberrant self-grooming phenotypes, relevant to modeling neuropsychiatric disorders. It includes details on the specific grooming phenotype observed and corresponding references.

Ephrin A ligands and receptors are strongly implicated in neurodevelopment. Ephrin A ligands are membrane-anchored cellular proteins binding to ephrin A receptors, receptor tyrosine kinase superfamily members. Ephrin A-mediated signaling modulates neuronal differentiation and synaptic plasticity during development. Given ASD’s neurodevelopmental nature, ephrin A ligands and receptors may be relevant to ASD and its pathogenesis modeling in animals. Mice lacking both ephrin A2 and A3 receptors show robust repetitive self-grooming, motor retardation, increased prepulse inhibition, and social deficits, paralleling ASD clinical symptoms. Searching for novel molecular anti-ASD drug targets is a priority, and grooming-based analyses are increasingly useful for exploring novel candidate pathways of this disorder, such as ephrin A receptor agonists.

Another example of rodents with specific mutations displaying aberrant self-grooming are mice lacking the GABA-synthesizing enzyme glutamate decarboxylase 1 (GAD1; GAD67) in striatal neurons. These mice exhibit ASD-like behavioral abnormalities, including stereotypic grooming, impaired spatial learning, and social behavior, suggesting striatal GABAergic output may contribute to ASD behavioral deficits.

A deletion on human chromosome 16p11.2, spanning ~30 genes, is associated with ASD and other neurodevelopmental disorders. Mice heterozygous for a deletion of the syntenic region on chromosome 7F3 (16p11+/− mice) show reduced self-grooming but also hyperactivity and behavioral perseverations like increased circling. 16p11+/− mice also have increased striatal medium spiny neurons expressing dopamine D2 receptors, fewer cortical neurons expressing D1 dopamine receptors, and synaptic defects indicating abnormal basal ganglia circuitry. The behavioral phenotype of these mice is notable because decreased self-grooming is observed alongside increased non-grooming stereotypies, suggesting further distinctions between grooming activity and patterning aspects. Studying self-grooming enhances ASD animal model development, as the co-occurrence of a self-grooming phenotype with other ASD-like phenotypes strengthens model validity.

Basal Ganglia Disorders: Self-Grooming in OCD and Tourette Syndrome Models

Excessive self-grooming is a feature of some OCD forms and related illnesses like body dysmorphic disorder, excoriation, and trichotillomania. Studying aberrant rodent self-grooming is relevant to modeling these conditions and OCD-spectrum disorders characterized by excessive behavioral repetitiveness, even without abnormal self-grooming.

OCD is a common heterogeneous psychiatric disorder characterized by obsessions and compulsions. Obsessions are intrusive, recurrent, unwanted thoughts, often causing anxiety. Compulsions include repetitive behaviors or thoughts, conventionally viewed as attempts to relieve obsessions. Compulsions sometimes focus on personal hygiene, involving self-cleaning or grooming behaviors like hand-washing and behaviors to avoid perceived contamination. Evidence from OCD syndrome studies, including neuroimaging, clinical genetics, and animal models of repetitive behavior, suggests basal ganglia-related circuit dysfunction contributes to these syndromes.

A growing number of genetic mutations affect self-grooming behavior in rodents (TABLE 1). Some may model self-grooming-related OCD symptoms, including compulsive hand-washing and obsessive hair-pulling (TABLE 2). Serotonergic drugs effective in treating some clinical OCD symptoms also reduce aberrant self-grooming phenotypes in some mutant mice (TABLE 3). These findings support the value of rodent self-grooming behaviors in mimicking human OCD and suggest the serotonergic system contributes to regulating normal and pathological grooming in humans and rodents. Clinical and experimental evidence continues to implicate serotonergic function in various OCD-like symptoms, although direct support remains elusive.

Table 2. Modeling Human Disease Symptoms with Rodent Self-Grooming Assessment

Human disease Symptom Relevant rodent self- groomingphenotype Refs
OCD Compulsive hand washing Increased self-grooming 37,143145
Trichotillomania Compulsive hair pulling Increased self-grooming 128,199
Body dysmorphic disorder Obsessive cosmetic grooming Increased self-grooming 92
Excoriation Compulsive skin-picking Increased self-grooming 92
ASD Behavioural perseveration Increased self-grooming 16,1922,33
Tourette syndrome Tics Increased self-grooming 29
Anxiety disorders andpanic disorder Stress-induced displacementbehaviour Increased self-grooming 7,27,31,158
Schizophrenia Hyperarousal Increased self-grooming 92
Trichotillomania Compulsive hair-pulling Increased self-barbering* 27,45
ASD Behavioural perseveration Grooming patterning rigidity 8991
Depression Behavioural perseveration Grooming patterning rigidity 92
Anxiety disorders andpanic disorder Hyperarousal Disrupted grooming patterning 27,28,159
Basal ganglia disorders Impaired action sequencing Disrupted grooming patterning 64
Depression Anhedonia and poor hygiene Reduced grooming activity 92
Neurodegenerativedisorders General decline in motor function Reduced grooming activity 160

Table 2: Self-Grooming Phenotypes as Models for Human Disease Symptoms. This table outlines how rodent self-grooming phenotypes can model symptoms of various human diseases, including OCD, ASD, and anxiety disorders. It specifies the human symptom, the corresponding rodent self-grooming phenotype, and relevant references.

Mutations in SAPAP3, encoding synapse-associated protein 90/postsynaptic density protein 95-associated protein 3, are weakly implicated in OCD and self-grooming disorders like pathologic skin picking, nail biting, and hair pulling. SAPAP3 binds to SHANK3, another postsynaptic scaffolding protein linked to ASD. In rodents, SAPAP3 is primarily expressed in striatal neurons, a key region controlling self-grooming. Sapap3−/− mice exhibit robustly increased self-grooming, rescued by Sapap3 re-expression in the striatum. As Sapap3 is expressed in striatal glutamatergic synapses, excitatory neurotransmission in this region is important for regulating normal self-grooming behavior. Interestingly, Sapap3 deletion reduces corticostriatal synaptic transmission but not thalamostriatal activity, providing an opportunity to dissect thalamostriatal versus corticostriatal circuit roles in mediating excessive repetitive behaviors in OCD. The over-grooming phenotype in Sapap3−/− mice can be rescued by optogenetic stimulation of the orbitofrontal cortex corticostriatal pathway. This rescue mechanism involves striatal high-firing interneurons (impaired in this model), directly implicating intrastriatal network activity in compulsive grooming behavior etiology. Repeated daily stimulation of a nearby orbitofrontal cortex part in wild-type mice can evoke prolonged increased self-grooming behavior. These results emphasize corticostriatal circuits and intrastriatal microcircuits’ importance in rodent self-grooming control, potentially relevant to modeling compulsions in OCD.

Tourette syndrome, another common, heritable, childhood-onset neuropsychiatric disorder, is characterized by motor and phonic tics. It is frequently comorbid with OCD and ADHD and can be accompanied by affective disorders like anxiety and depression. Though related to OCD and grooming disorders, Tourette syndrome differs genetically and phenotypically. Rodent self-grooming behavior, due to its complex repetitive nature, is a logical phenotype to investigate in Tourette syndrome models, especially given the nigrostriatal dopaminergic system’s implication in behavioral sequential stereotypy. Rodents with abnormal dopaminergic signaling are good candidates for modeling aspects of these disorders.

Dopamine transporter (DAT)-deficient mice, with elevated dopamine levels, exhibit more stereotyped and predictable syntactic grooming sequences than wild-type counterparts, with fewer syntactic pattern disruptions and sequential ‘super-stereotypy’ in complex fixed-action patterns. Dopamine receptor subtypes may mediate different dopamine effects on self-grooming phenotypes. Mutant mice lacking dopamine D1A receptors exhibit shorter self-grooming bouts and more disrupted, incomplete sequential patterns. This phenotype suggests dopamine D1A receptors specifically modulate rodent grooming behavior sequencing, supporting human studies suggesting distinct dopamine receptor subtype roles in Tourette syndrome and related basal ganglia disorders. Transgenic mice expressing a cholera toxin form that potentiates neurotransmission selectively within corticolimbic D1-expressing neurons exhibit elevated self-grooming and juvenile-onset tics, mimicking comorbid OCD and Tourette syndrome aspects. Similarly, mutations in the histidine decarboxylase gene (HDC) have been implicated in Tourette syndrome, and Hdc−/− mice display tic-like behaviors, including stereotypic self-grooming, recapitulating certain Tourette syndrome aspects.

Rodents with impaired motor behavior and motor sequencing, such as pathologically reduced self-grooming, are also useful for understanding basal ganglia disorders. For example, the weaver (wv/wv) mouse has a natural mutation in the Girk2 gene, encoding a G protein-activated inwardly rectifying potassium ion channel. This mutation significantly affects cerebellar and striatal pathways (crucial for motor performance), resulting in an aberrant self-grooming phenotype with more frequent, shorter grooming bouts, smaller forelimb strokes, and less complete sequences. Due to deficits in these two critical CNS circuits, the context- and age-specific neurological defects in wv/wv mice are useful for examining how these systems control self-grooming during development. Initially, mutant mice groom less, but after day 15, they initiate more frequent, briefer grooming bouts, more likely associated with striatal sequencing control. These models illustrate the basal ganglia’s important role in modulating normal and pathological rodent self-grooming behavior, potentially offering translational insights into human basal ganglia disorders.

Other Disorders: Stress, Neurodegeneration, and Self-Grooming

Acute stressors, like novel environments or predators, can potently modulate self-grooming, often increasing bout frequency and/or duration and inducing displacement activity. Stressors also lead to disorganized grooming patterning by impairing head-to-tail progression, increasing incorrect transitions, evoking incomplete bouts, causing more interruptions, and disrupting regional distribution. High chronic baseline anxiety in certain mouse and rat strains is often accompanied by increased self-grooming and disorganized patterning, while anxiolytic treatments tend to reduce rodent self-grooming activity and normalize sequential organization. The neurobiological bases of stress and self-grooming interaction are poorly understood, but brain regions involved in affect, especially the amygdala, are likely involved. As stress and anxiety modulate rodent self-grooming, abnormal grooming behavior could measure stress or anxiety in experimental models and tests.

Motor deficits are characteristic of major neurodegenerative disorders, and self-grooming, as a complex patterned behavior, is a logical candidate behavior to assess these deficits in rodent models. Parkinson’s disease, characterized by debilitating voluntary movement impoverishment, is neuropathologically marked by Lewy bodies, mostly composed of α-synuclein. The A53T missense mutation in the α-synuclein gene is strongly implicated in parkinsonian state pathogenesis. Transgenic mice expressing the human A53T variant under mouse prion promoter control display progressive motor and cognitive deficits, including impaired grooming observed as early as 1–2 months old, before spatial memory deficits (6–12 months) or abnormal gait (12 months) onset. Combined with aberrant synaptic neurotransmission, self-grooming behavioral analyses in this mouse strain may be useful for assessing novel Parkinson’s disease therapeutic interventions.

Several rodent models of other neurodegenerative diseases also display aberrant self-grooming phenotypes, including recent models of Huntington’s disease, familial Danish dementia, Krabbe disease, and other neurodegeneration types. These studies illustrate self-grooming phenotype utility for modeling neurodegenerative disorders and dissecting pathobiological mechanisms. Interestingly, aberrant hyper-grooming is observed in early disease stages in a Huntington’s disease rat model induced by striatal quinolinic acid injection, and impaired grooming in A53T-mutant mice appears before parkinsonian-like cognitive or gait deficits. Altered self-grooming may represent an early behavioral hallmark in these disease models, although further testing is needed.

Table 3. Pharmacological Sensitivity of Rodent Self-Grooming Behavior

Model Effect on self-grooming behaviour Refs
Chronic fluoxetine
Chronic corticostriatalstimulation in mice Evoked grooming reversed 15
Sapap3−/− mice Over-grooming and facial lesions corrected 40
Slitrk5−/− mice Over-grooming and facial lesions corrected 18
Chronic clomipramine
Rats selectively bred for highanxiety-like behaviour Reduced activity 200
Rats displaying stress-evokedself-grooming Reduced activity 157
Acute memantine
Astrocyte-specific inducibleGlt1−/− mice Over-grooming and body lesions corrected 85
Mice prenatally exposed tovalproate Reduced over-grooming 201
Acute MPEP
BTBR mouse strain Reduced activity 90
Acute risperidone
BTBR mouse strain Reduced activity 90
Acute diazepam*
Wild-type mice and rats Reduced activity, normalized patterningduring novelty-based tests 32,76
Acute clonazepam*
Wild-type mice and rats Reduced activity, normalized patterningduring novelty-based tests 32,76

Table 3: Pharmacological Modulation of Self-Grooming. This table highlights the sensitivity of rodent self-grooming behavior to pharmacological manipulations. It lists different pharmacological agents and their effects on self-grooming in various rodent models, providing insights into potential therapeutic interventions for grooming-related disorders.

Novel Approaches and Future Directions in Grooming Research

Recognizing the importance of neuromorphological endophenotypes related to brain disorders, applying similar approaches and imaging techniques to rodents with aberrant self-grooming phenotypes is logical. For example, functional MRI detected decreased fronto-cortical, occipital, and thalamic gray matter volume and cortical thickness in hyper-grooming BTBR mice compared to low-grooming C57BL/6J mice. Diffusion tensor tractography confirmed callosal agenesis and impaired hippocampal commissure formation in BTBR mice, while resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced corticothalamic function.

Given the complexity and polygenic nature of most brain disorders, research increasingly focuses on identifying gene sets contributing to several CNS disorders. Although repetitive behaviors (including self-grooming) and increased anxiety are both observed in OCD, most clinical and animal studies examine genetic and physiological correlates of these behavioral domains separately. Applying large-scale bioinformatics and pathway analyses to complex behavioral endophenotypes and their interactions, rather than targeting individual endophenotypes, can significantly enrich the landscape of genes related to neuropsychiatric disorders, including those regulating self-grooming-related behaviors.

Optogenetic manipulations are valuable for understanding circuits involved in rodent self-grooming. Repeated (but not acute) stimulation of the medial orbitofrontal cortex-ventromedial striatum pathway in mice can trigger pathological self-grooming lasting weeks, reversible by chronic fluoxetine administration. Stimulating the nearby orbitofrontal cortex (or its intrastriatal terminals) can block compulsive self-grooming in Sapap3−/− mice. These findings provide strong experimental evidence for circuit-level control of repetitive grooming episodes. While optogenetic approaches are not yet clinically translatable, these studies suggest future circuit modulation methods may become valuable therapeutic tools for disorders associated with repetitive behavior.

In-depth self-grooming behavior analyses are now an important part of behavioral phenomics (BOX 1). Several automated tools are available for quantity-based and patterning-based grooming phenotype studies in laboratory rodents. Future refinement is expected to advance this field.

Box 1 | Behavioral Phenomics and High-Throughput Grooming Analyses

Rodent behavioral tests often face problems: they are time-, space-, and labor-consuming, expensive, and low-medium-throughput. Some rodent behaviors need prolonged testing time to emerge, while others require special conditions (e.g., homecage testing) and/or long-term assessment. Behavioral responses to novel drugs or genetic mutations may spontaneously appear when animals are unobserved. These issues are particularly problematic for complex behaviors like grooming, involving movements of multiple body points with elaborate spatiotemporal organization. However, recent advances in behavioral phenotyping offer timely and efficient solutions to empower grooming research. Behavioral phenomics, a rapidly developing field merging phenomics and neuroscience, links behavioral phenotypes to genetic and environmental factors. Automated tools recording force, vibration, or visual signals have been developed for non-invasive self-grooming assessment, implementable without prior animal training to evaluate grooming in different experimental conditions. Current analyses cannot assess all self-grooming stages but can be improved using multiple cameras, 3D spatial imaging of multiple body points, and increased IT-based signal integration. More powerful grooming activity analysis tools are likely to emerge soon. Systems detecting and integrating several different behavioral signals simultaneously (e.g., vibration and image) have already improved rodent self-grooming phenotyping. As better signal detection and behavior recognition capabilities continue to enhance automated grooming analyses, this may lead to increased self-grooming analysis use in high-throughput phenotyping. A typical self-grooming patterning analysis, previously taking days and multiple investigators, can now be performed much faster using these new technologies.

Given the established role of dopamine-containing neurons in movement initiation and sequencing, dopaminergic system regulation (and dysregulation) in numerous brain disorders will be of particular interest for further study. Future research may examine larger molecular interactor networks related to dopaminergic genes, evaluate these genes’ role in rodent self-grooming behavior, and relate these findings to genes implicated in human brain disorders.

Rodent studies have shown that D1-expressing neural circuit activation results in excessively stereotyped but sequentially complex grooming patterns. This suggests that direct output circuits of the basal ganglia are particularly important in compulsive behavioral patterns related to serial perseveration and sequential rigidity. Basal ganglia circuitry, evolutionarily embedded in mammalian self-grooming control, could also contribute to pathological human super-stereotypies. Mesocorticostriatal disorders in humans, resulting in washing rituals or self-purification compulsions to escape perceived contamination, may share similar mechanisms to self-grooming in rodents.

Conclusions: The Broad Implications of Rodent Grooming Studies

Studying rodent self-grooming provides researchers with crucial insights into how the brain regulates complex behaviors under normal conditions and how these are affected in pathological states. Understanding the neural circuitry, genetic determinants, and associated molecular pathways involved in rodent self-grooming can improve our understanding of neurological disorders characterized by repetitive behaviors. It is also possible that the brain circuitry initially evolved to control self-grooming sequence and coordination as an instinctive behavior could have been repurposed throughout human evolution and cultural expansion, extending to ritualistic behaviors, cognitive functions, and even linguistic syntax and serially ordered thought streams. While this speculation remains untested, it is clear that rodent self-grooming studies are likely to have implications extending beyond motor aspects of grooming to include the sequential control of complex behaviors in general.

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Acknowledgments

This Review is a tribute to John C. Fentress (1939–2015), a brilliant scientist, good friend and a true pioneer of ethology and neurobiology research. This study is supported by the ZENEREI Research Center (A.V.K., A.M.S.), Guangdong Ocean University (A.V.K., C.S.), St. Petersburg State University grant 1.38.201.2014 (A.V.K.), as well as by the US National Institutes of Health grants NS025529, HD028341, MH060379 (A.M.G.) and MH63649, DA015188 (K.B.). A.V.K. research is supported by the Government of Russian Federation (Act 211, contract 02.A03.21.0006 with Ural Federal University). The authors thank M. Nguyen, E. J. Kyzar and Y. Kubota for their assistance with this manuscript. They wish to acknowledge helpful suggestions from D. J. Anderson (California Institute of Technology, USA) regarding the roles of amygdala-related circuitry in grooming behaviour. The authors also thank manufacturers of neurophenotyping tools for providing information used in Supplementary information S5 (figure).

Glossary

Cephalocaudal progression: A general direction (or rule) of rodent self-grooming behaviour that begins at the nose, then continues to the face and head, the body, the tail and the genitals.

Grooming microstructure: The complex sequential organization (patterning) of self-grooming movements.

Fixed-action patterns: Instinctive species-specific behavioural sequences that, once begun, run to their completion.

Basal ganglia: A group of subcortical nuclei involved in motor control, motivation and organizing movements into behavioural sequences.

Ventral tegmental area: A midbrain region (implicated in reward, anxiety and aversion) that contains the dopaminergic cell bodies of the mesocorticolimbic system.

Research domain criteria (RDoC): A strategy in translational mental health research that aims to explore the basic mechanisms of brain deficits to understand symptom sets that are observed across multiple disorders.

Behavioural perseveration: The repetition of a specific behaviour that becomes inappropriate in the absence of behaviour-evoking stimuli.

Stereotypies: Repetitive behaviours involving an abnormal or excessive repetition of a behavioural action in the same way over time.

Tics: Sudden, repetitive, involuntary movements or vocalizations with varying intensity and frequency.

Displacement Behaviour: Behaviour that is seemingly irrelevant to the context, which is displayed during a conflict of motivations or when the animal is unable to perform an activity for which it is motivated.

Krabbe disease: (Also known as globoid cell leukodystrophy). A rare, fatal neurodegenerative disorder that is due to genetic defect causing aberrant brain myelination.

Footnotes

Competing interests

The authors declare no competing interests.

DATABASES

Simons Foundation Autism Research Initiative gene database: http://gene.sfari.org/autdb/Welcome.do

SUPPLEMENTARY INFORMATION

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References

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Supplementary Materials

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