Malfunctional Behaviors

Malfunctional behaviors are a class of behaviors that occur as a result of abnormal physiology or hardwiring. An abnormal physiology, including genetic predispositions to disease or genetic mutations, are causes for malfunctional behavior.

Malfunctional behaviors are a type of abnormal behavior that can occur in mice which are not physiologically normal. Thus, malfunctional behaviors are abnormal behaviors occurring in mice that are themselves abnormal and have genetic mutations and are physiologically malwired.

Mice that are abnormal genetically are likely to be abnormal behaviorally, as well. For example, such is predominantly the case with barbering wherein mice compulsively groom themselves or another mouse. There are many genetically abnormal mice that demonstrate higher levels of barbering behavior than normal wild-type mice. Thus, abnormalities that are observed with a genetic cause are most likely to be categorized as a malfunctional behavior.

Is the Behavior Malfunctional or Maladaptive?

Malfunctional behaviors stand in contrast to maladaptive behaviors. Maladaptive behaviors are largely due to environmental causes or triggers. When mice are placed in an environment that is not natural for them, they are likely to react and develop maladaptive behaviors.

Thus, the main difference lies in the fact that malfunctional behaviors are essentially inappropriate responses by abnormal mice while maladaptive behaviors are inappropriate responses by otherwise normal mice.

Malfunctional behaviors are composed of several other behaviors. The following behaviors drive and enable specific malfunctional behaviors to occur:

• Biting: Biting is a behavior that involves using the teeth to contact piercingly an object or the skin such that it leads to a break, nick, or scratch. Biting can be observed in a variety of contexts, including social biting, predatory biting, and food biting. Impulsive aggression and impulsive eating are comprised of high instances of biting.
• Jumping: A mouse will use its limbs to push off the ground and suspend itself momentarily in the air. High levels of repetitive jumping is a commonly observed stereotypy in mice.
• Chewing: Chewing is the repeated biting motion done in the context of feeding behaviors. As a stereotypy, chewing is performed in excess and under inappropriate circumstances.
• Scratching: A mouse uses its hind-limbs to vigorously or quickly scratch its back, head, or neck. Scratching bouts are usually short-lived, resolve quickly, and do not last long. When a mouse is scratching itself repeatedly and continuously, it can be considered as an abnormal behavior because it ends up causing skin lesions.
• Nose-poking: Nose-poking refers to the behavior of using the nose to press something, typically a food dispenser’s lever in laboratory conditions. This behavior is crucial to many tests and tasks which use the operant chamber. When performed in excess or at inappropriate moments, nose-poking is associated with impulsivity.
• Grooming: Grooming refers to the cleaning that a mouse does on its (or another mouse’s) fur and body. Grooming behaviors are typically classified as maintenance behavior since they serve to keep a mouse’s appearance, homeostasis, and cleanliness.
• Route-tracing: Route-tracing is a less common form of stereotypy, but it still happens. When route-tracing, a mouse is essentially following or running over the same cage pattern three times or more.
• Climbing: Climbing is also displayed as a stereotypy. A mouse climbs by using props in its environment to move vertically in space in an upwards direction.

The following behaviors can be classified as being malfunctional behaviors:

• Impulsivity/Compulsive behaviors: Impulsive behaviors, also referred to as compulsive behaviors are characterized by repeating flexible behaviors driven by an inappropriate goal.
• Stereotypies: Stereotypy is a general term that refers to any behavior that is performed in excessive repetition without a clear goal.
• Ulcerative dermatitis: Ulcerative dermatitis is a type of skin disorder that is associated with bacterial flora. The disorder occurs due to excessive scratching.
• Barbering: Barbering, often referred to as the Dalila effect, is a grooming behavior displayed by a mouse on itself or other cagemates which involve the plucking of fur, hairs, or whiskers.

None. Since malfunctional behaviors are considered to manifest as a result of physiological and genetic abnormalities, they have no clear function.

Malfunctional behaviors are likely to be observed under the following conditions:

• Genetic reasons: Since genetics are at the core of malfunctional behaviors, genetic mutations, abnormalities, or susceptibilities are likely to be the causes of malfunctional behaviors.
• Environmental conditions interacting with genetic predispositions: Related to the point above, genetic susceptibility combined with environmental factors can lead to malfunctional behaviors.

The following research techniques have been used to study malfunctional behaviors:

• Behavioral studies: Behavioral studies are very useful for studying malfunctional behaviors. With the various types of behavioral studies and assays, researchers can profile and quantify the nature of malfunctional behaviors.
• Pharmaceutical studies: Pharmaceutical studies are used when studying the effect of certain drugs or supplements on malfunctional behaviors. Such studies are important because they show that physiological abnormalities can be amended via pharmaceutical interventions. Pharmaceutical studies are especially common when disease models are the focus of the research. Thus, in order to see how malfunctional behaviors can be manipulated or reduced, pharmaceutical studies are of the essence.
• Genetic studies: Genetic studies are useful for identifying potential genes and interactions involved behind the scenes of malfunctional behaviors. Through genetic studies, a better understanding can be acquired as to how malfunctional behaviors form. In order to study the intertwined relationship between genes and the environment, genetic studies may also include an environmental component.

Behavioral tests are crucial for assessing malfunctional behaviors, in order to establish the relationship between behavior and genetics and/or physiology.

• The five-choice serial reaction time task (5CSRTT): The 5CSRTT is a type of operant conditioning chamber that has a platform with 5 holes/apertures. It is used for measuring compulsive behaviors. During this test, a mouse will receive a sugar reward only if it identifies correctly from which hole a briefly presented light stimulus originated. Between each trial, there is a short pause where the mouse is expected to withhold any behavioral response. Response during this short interval is indicative of a mouse’s tendency to be impulsive and is classified as a failure of inhibitory control.
• The delay-discounting task (DDT): DDT is also sometimes referred to as the delayed-reinforcement task. Delay discounting is a process where delayed outcomes, such as postponed food delivery, are valued less than outcomes that are delivered immediately or with a short delay. When challenged to complete this task, mice are presented with a choice between either a 20- or 100-ul drop of milk (to be delivered after a 1-second delay). After this initial training, the task’s parameters change. Now, the 100-ul drop of milk is given 100 seconds later. When this delay occurs, mice will shift to demonstrate an increasing preference for the more immediate, but smaller, reward. The DDT is usually administered using an operant chamber, but recent advances and modifications have made it possible to run it using T-Mazes as well.
• Visual cliff avoidance test: In this test, mice are placed on a plexiglass surface. On one half of the plexiglass, it looks like there is a stable floor, but on the other half, there is nothing underneath the plexiglass. So, to a mouse, it appears like an illusion, as if there is a ‘cliff.’ This test measures visual depth perception, the ability to perceive barriers and avoid a dangerous situation. Mice that have an intact vision but still move over the visual cliff are considered to be impulsive.
• Automated Systems: The use of automated behavioral monitoring systems, such as the SmartCage System, is becoming more and more popular in behavioral neuroscience. Automated systems make it easy to quantify and categorize behaviors. This is especially true for studies that focus on malfunctional behaviors such as stereotypy where successive behaviors are rapid and repetitive.
• Tube Dominance Test: This test can measure malfunctional instances of barbering in mice. Thus, the Tube Dominance Test is used to assess dominance in a confrontational setting between two mice. Two mice are placed in a single tube, one at each end. The mice have limited motion (and cannot escape the confrontation) and can only move forward (a sign of dominance) or backward (a submissive sign) since the tube is narrow and not spacious. Thus, the only way to reach the other side is by moving forwards and by being confrontational with the other mouse.
• Resident-Intruder Test: In this test, when an unknown mouse is placed in the cage in which a single mouse resides, an agonistic encounter is extremely likely to occur. In this case, barbering may be performed by the more dominant mouse.

In this section, we will see what pharmaceutical studies have established for the different malfunctional behaviors. The mice being used for these studies all display some form of genetic predisposition for malfunctional behaviors, making them ideal for pharmaceutical studies.

Barbering and Pharmaceutical Studies

• Estradiol injections reduce barbering in trichotillomania mice. In mice, barbering is a hair-plucking behavior that has been validated as a model for trichotillomania. There is a correlation between the onset of trichotillomania and changes in reproductive physiology. This led to the hypothesis that reproductive hormones may influence trichotillomania and barbering. Doses of estrogen can influence the brain’s catecholamines and endogenous opiates, known for regulating and interacting with corticostriatal loops that are involved in planning and motor behavior. Injections of 17β-estradiol significantly reduce barbering in females when compared to vehicle-treated females. Thus, since estrogen injections have an effect on barbering behavior, this suggests that hormones are very likely to be involved in influencing the onset of trichotillomania.
• Clomipramine reduces barbering in trichotillomania mice. Clomipramine is a tricyclic antidepressant that inhibits the serotonin reuptake systemMice that lacks the nitric oxide synthase (NOS2) gene is used as an animal model of trichotillomania since they exhibit high levels of barbering behavior. When these mice are given clomipramine, there will be a significant decrease in their barbering levels significantly after 10-20 days of treatment when compared with untreated NOS2 mice.

Impulsive Behaviors and Pharmaceutical Studies

• Brexpiprazole Reduces Impulsivity. Brexpiprazole is a drug that can alter serotonin levels due to its capability of modulating serotonin-dopamine activity. Brexpiprazole acts on D2/3 and 5-HT1A receptors as a partial dopamine agonist. Recently, in the USA, brexpipraole has received approval as a therapeutic option for schizophrenia and adjunctive treatment in major depressive disorder for patients that are not responding well to monotherapy. When given to mice that model mania (due to their excessively high circulating dopamine levels) that exhibit high levels of impulsivity, brexpiprazole reduces impulsive behaviors.
• Milnacipran Can Reduce Impulsivity. Serotonin/noradrenaline reuptake inhibitors (SNRIs) are a class of drugs commonly used for treating major depressive disorder. Serious side effects come with taking SNRIs like higher impulsivity and aggression. These behavioral side effects are ultimately serious risk factors that ultimately could lead to substance abuse and criminal involvement. In order to address this tension between SNRI treatment and serious side effects, milnacipran can be used. Since milnacipran is both an antidepressant and an SNRI, it may be able to divert some of the serious side effects associated with SNRIs. In mice that are challenged with the 3CSRTT task, milnacipran significantly reduces impulsivity as shown by the reduction in the number of premature responses.

Stereotypy and Pharmaceutical Studies

• Fluoxetine Decreases Stereotypy. Fluoxetine is a drug that is used for treating obsessive-compulsive disorder (OCD). Deer mice (which are a natural model of stereotypy) display high levels of functionless, repetitive behavior. Treating deer mice for 21 consecutive days with fluoxetine (20 mg/kg/day i.p.) reduces stereotypic behavior. Saline-treated deer mice are expected to display about 3250 counts of stereotypic behavior per hour while chronically fluoxetine-treated deer mice display about 2300 counts of stereotyped behavior per hour.
• Chronic Escitalopram Treatment Reduces Stereotypy. Escitalopram is a serotonin inhibitor that is more potent than fluoxetine. Escitalopram can be administered orally to mice through drinking water at 50 mg/kg/day. After chronic treatment over a 4-week period, deer mice’s natural stereotypical behavior significantly decreases. Such a reduction is not visible in a subchronic treatment approach (one-week long treatment) but is visible only after chronic, 4-week long treatment.

Ulcerative Dermatitis and Pharmaceutical Studies

• Lithium Supplementation. Ulcerative dermatitis has an unknown etiology. But, pharmaceutical studies have helped to show that ulcerative dermatitis may be somehow caused or influenced by the insulin signaling pathway. Lithium acts as an insulin-mimetic. Thus, pharmaceutical studies can use lithium in order to study to what extent insulin affects behavior. Healthy wild-type mice following a lithium enriched-diet have been shown to have increased susceptibility for developing ulcerative dermatitis. This suggests that insulin (which lithium mimics) is somehow involved in the development of ulcerative dermatitis in mice. Thus, malfunctionalities in insulin-related pathways could be somehow responsible for the manifestation of ulcerative dermatitis in mice.

Malfunctional behaviors can be observed across various mice and genetically modified strains. By studying malfunctional behaviors across mouse strains, links between genetics and behavior can be established.

Barbering Across Mouse Strains

• 129S1 Mice: 129S1/SvImJ mice, simply known as 129S1 mice, are frequently used as a background strain in behavioral neuroscience research. 129S1 mice are characterized by their anxiety-like behaviors. When it comes to malfunctional behaviors, 129S1 female mice display barbering amongst each other more frequently than males when placed under group housing conditions since weaning.
• BALB/cJ mice: BALB/cJ male mice also display barbering as a malfunctional behavior. Male BALB/cJ mice begin to demonstrate whisker-picking at 10 weeks old, while female BALB/cJ mice begin at 12 weeks old (on average). This suggests that barbering may have a genetic component associated with BALB/cJ mice and a gender difference between BALB/cJ male and female mice with respect to the first manifestation of barbering behavior.

Compulsive Behaviors Across Mouse Strains

• C3H/HeJ mice: The C3H/HeJ mouse strain is frequently used in behavioral research, but is a strain that has been around since the 1920s. It was created by crossing a Bagg albino and a DBA mouse. Over the years, this strain developed a mutation for Toll-like receptor 4 for which they ultimately became known for. C3H/HeJ mice are amongst the most impulsive mouse strains. C3H/HeJ mice have been reported to have a premature responsivity rate as high as 10%. In the Go/No-Go task, this mouse strain averages approximately a 50% false alarm response rate. By comparison, C57BL/6 mice average about 25%.
• 5-HT knockout mice: Serotonin (5-HT) knockout mice lack one of the key serotonin receptors, namely, the 5-HT_1B Compared with wild-type mice, 5-HT knockout mice respond to positive reinforcement by acquiring cocaine via self-administration faster and drinking more alcohol. 5-HT knockout mice also show higher levels of impulsive aggression, a particular type of malfunctional behavior. Thus, this strain shows the importance of intact serotonin receptors for normal behavior.
• TRβ1 mice: Transgenic mice with a mutant β1 thyroid receptor (TRβ1) display all behavioral symptoms associated with attention deficit hyperactivity disorder (ADHD). Their behavioral profile includes inattention, hyperactivity, and impulsivity. When tested for impulsivity, TRβ1 mice display poor impulse control when it comes to tasks that measure the delay of gratification.

Stereotypy Across Mouse Strains

• DBA/2 mice: When DBA/2 (DBA) mice are subjected to food restriction for 9 consecutive days, they begin to show behavioral stereotypy. Specifically, these mice show abnormally high levels of climbing stereotypy as their response to receiving no food. Since this behavioral response is very notable in DBA mice, it suggests that there is a genetic component interacting with an environmental factor (food restriction) which brings about this malfunctional behavior. This behavioral stereotypy is also observable in C57BL/6 mice when subjected to food-restriction, but the subsequent stereotypy is more severe in DBA mice.
• Deer mice: Deer mice (Peromyscus maniculatus) are natural models of OCD and are known to exhibit various forms of stereotypy. Thus, deer mice are used frequently in behavioral research for the purposes of modeling OCD and stereotyped behaviors. The malfunctional stereotypy behaviors that deer mice perform include backward somersaulting or backflipping and jumping. These malfunctional behaviors can be observable as early as postnatal day 20 and are already well developed by postnatal day 30.

Ulcerative Dermatitis Across Mouse Strains

• IRs1 mice: Mice that are deficient for the insulin receptor substrate 1 (IRs1) gene have been found to be completely resistant to the development of ulcerative dermatitis. IRs1 is a key component of the insulin-like growth factor-1 (IGF) signaling pathway. Thus, if mice that lack this receptor do not develop ulcerative dermatitis, it indicates that IRs1 may somehow be implicated in the etiology of this inflammatory skin disorder.
• iNOS-deficient mice: iNOS-deficient mice lack the gene for the inducible nitric oxide synthase (iNOS) enzyme and will develop significantly more ulcerative dermatitis when compared to other strains. This suggests a genetic component of ulcerative dermatitis. It is estimated that iNOS-deficient mice have about 50% incidence of ulcerative dermatitis, significantly higher than the 5% incidence in C57BL/6 strain. Ulcerative dermatitis begins to appear in iNOS-deficient mice at around 16 to 20 months of age. iNOS is involved in the skin repair process. Its absence in iNOS-deficient mice combined with the subsequent high prevalence of ulcerative dermatitis in this strain suggests that it may be involved in the etiology of this malfunctional behavior.

Malfunctional behaviors can be observed in multiple disease models, including the models highlighted in this section. These disease models depend on malwired mice.

Trichotillomania and Barbering

Trichotillomania is modeled by NOS2 knockout mice. These mice naturally display high levels of barbering behavior. As described previously, NOS2 mice have nitric oxide synthase knocked out which consequently leads to decreased levels of microtubule-associated protein 2 levels in PC12 cells. Also, nitric oxide is involved in regulating glutamate, as well as in the migration and maturation of the cortex’s neurons. Thus, NOS2 mice have limited neuronal maturation which may ultimately lead to inadequate inhibition of the brain’s motor programs, ultimately resulting in the inability to stop trimming or barbering. Since trichotillomania and OCD are generally associated with the malfunction of the cortico-striato-thalamo-cortical circuitry, it is expected to see malfunctions within these regions lead to behavioral abnormalities.

ASDs and Stereotypy

ASDs in humans are characterized by cognitive symptoms such as lower social behaviors, but also by repetitive behaviors, such as hand-flapping. BTBR T+tf/J mice are used as a genetic model of ASDs. The stereotypies that these mice demonstrate include repetitive bar-mouthing and repetitive self-grooming. Compared to C57BL/6J mice, the way BTBR self-groom involves higher frequencies and duration of paw licking, head washing, body grooming, leg licking, and tail/genital licking, indicating that these behaviors are performed in excessive amounts.

Obsessive-Compulsive Disorder and Stereotypies

Around the world, OCD 6-month prevalence is estimated to be as high as 2.1%. OCD is a psychiatric condition where a patient exhibits obsessions and compulsions. People with OCD have been characterized to follow and display rigid patterns of language, thought, and/or action.

In behavioral neuroscience research studies, OCD animal models are used for inspecting the disease’s biological features and to identify possible treatment options. Currently, OCD models are most commonly presented in research using mice with a specific genetic background.

Commonly used strains that model OCD include: DAT KO mice, 5-HT_2C mice, and deer mice.

ADHD and Impulsive Behaviors

ADHD is a developmental disorder characterized by impulsivity, hyperactivity, and inattention. In mice, ADHD can be modeled in multiple ways, including genetic manipulation. Two strains that link malfunctional impulsive behavior with ADHD are the DAT KD and TRβ1 transgenic mice.

Mania and Impulsive Behaviors

Mania is modeled by e, mice that have reduced levels of the dopamine transporter. These mice have hyper-exploratory behavior which is a key behavioral characteristic of mania. These mice also demonstrate higher levels of impulsive behaviors.

Yes. All malfunctional behaviors mentioned are known to affect behavioral assessment. Barbering, ulcerative dermatitis, impulsivity/compulsive behaviors, and stereotypy all influence behavioral assessment to a significant extent.

• Malfunctional behaviors are behaviors that manifest as a result of abnormal physiology, such as genetic mutations.
• When mice are placed in an environment that is not natural for them, they are likely to react and develop Malfunctional behaviors.
• The following behaviors drive and enable specific malfunctional behaviors to happen: nose-poking, biting, scratching, jumping, chewing, grooming, route-tracing, and climbing.
• The following behaviors can be classified as being malfunctional behaviors if their cause is rooted in physiological abnormalities: impulsive behaviors, stereotypes, barbering, and ulcerative dermatitis.
• Since malfunctional behaviors occur as a result of mal-wiring, they are believed to not have a function.
• Genetic causes and exposure to environmental conditions (with a genetic predisposition) are contexts for developing malfunctional behaviors.
• Behavioral studies, pharmaceutical studies, and genetic studies are all used to study the nature of malfunctional behaviors.
• Behavioral tests that are used to study malfunctional behaviors include the 5CSRTT, the DDT, visual cliff avoidance test, the tube dominance test, and the resident-intruder test.
• The following findings on malfunctional behaviors have been established by pharmaceutical studies:
  • Estradiol injections reduce barbering in trichotillomania mice.
  • Clomipramine reduces barbering in NOS2 KO mice.
  • Brexpiprazole reduces impulsive behaviors in manic mice.
  • Milnacipran can reduce impulsive behaviors in mice.
  • Fluoxetine decreases stereotypy in genetically predisposed OCD deer mice.
  • Chronic escitalopram treatment reduces stereotypy in deer mice.
  • Lithium supplementation increases ulcerative dermatitis in mice.
• Malfunctional behaviors manifest in one way or another in the following mouse strains: 129S1, BALB/cJ, C3H/HeJ, TRβ1, DBA/2, IRs1, 5-HT KO mice, Deer mice, and iNOS-deficient mice.
• The following disease models display malfunctional behaviors at their core:
  • Trichotillomania as a disease model utilizes barbering as a malfunctional behavior when it is modeled by NOS2 KO mice.
  • Stereotypy is the malfunctional behavior in ASD models observed in BTBR mice.
  • In the disease model for OCD modeled by DAT KO mice, 5-HT KO mice, and deer mice, stereotypy is the malfunctional behavior displayed.
  • In ADHD as modeled by DAT KD and TRβ1 transgenic mice, impulsive behaviors are the malfunctional behaviors of interest.
  • In the disease model for mania, modeled by DAT KD mice, impulsive behaviors are also of interest.
• Researchers need to beware of their rodents displaying malfunctional behaviors as these are known to influence behavioral assessment.

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