Links Between Circadian Rhythms and Mood Disorders

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<p class="Title">''Links Between Circadian Rhythms and Mood Disorders''</p><p class="SubTitle">Presented by [[The Bioclock Studio|http://ccb.ucsd.edu/the-bioclock-studio/index.html]] -- [[Watch our Trailer|https://youtu.be/kc03CDzXOtI]]</p><p class="authors" >//Created 2020, by://</p><p class="authors" style="padding-left:42px;text-indent:-22px;"><span style="color:#223d8e;">//Ximei Ackerman,   Christopher Mason,   Joshua Plum,   Lauren Chun,   Karen Tonsfeldt,   Ben Sheredos  and Susan Golden//</span></p> Research has shown a bidirectional relationship between disruptions in circadian rhythms and mood. Understanding this relationship may lead to better treatment options for mood disorders. Ready to [[get started?|Intro]]

<span style="color:#223d8e;">''Molecular Clock Basics''</span> <div class="flexrow"><div class="flexcolumn1" style="margin:auto">Circadian rhythms are biochemical and physiological processes that have a 24-hour rhythm. Circadian rhythms are found in plants, animals, and even some bacteria. These rhythms influence and regulate body temperature, mood, hormone release, and many other biological functions.</div><div class="flexcolumn2"><img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/01_IntroClock.png" style="max-height: 500px; min-width:300px;" align="center"></div></div> ---- Circadian rhythms are controlled by a molecular clock, which is composed of a network that involves the rhythmic expression of specific clock genes. The body contains many molecular clocks, residing within most cells of the body, which together regulate the observed circadian rhythms. In mammals, the molecular clock mechanism is a transcription/translation feedback loop. This feedback loop consists of the proteins BMAL1 and CLOCK, which dimerize and promote the transcription of the Cryptochrome (Cry) and Period (Per) genes. After translation, CRY and PER proteins move into the nucleus to inhibit their own transcription by interfering with the BMAL1/CLOCK dimer.<img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/01_molecmech.png" style="border-radius:10px;" align="center"> ---- Disruption in circadian rhythms is associated with sleep disorders, metabolic problems, and mood disorders, including Major Depressive Disorder (MDD) and Bipolar Disorder (BD). Continue to learn about [[Major Depressive Disorder.|MDD]]

<span style="color:#223d8e;">''Major Depressive Disorder (MDD)''</span> MDD is a leading cause of disability in the United States, affecting 10-20% of women and 5-10% of men. A diverse set of biological factors contribute to major depression including disruptions of the stress response, neurotransmitters, and inflammatory pathways that lead to alterations in the brain circuits underlying reward and motivation. MDD is diagnosed using criteria laid out in the //Diagnostic and Statistical Manual of Mental Disorders - 5th Edition// (DSM-5). The foundation for a diagnosis of MDD lies in first diagnosing the occurrence of a Major Depressive Episode, which the DSM-5 defines with the following diagnostic criteria: <div class ="flexrow"><div class="flexcolumn1" style="max-width:250px; line-height:1.1em;"> <p style="color:#223d8e; margin-bottom:0em;">''Depressed mood''</p><p style="margin-left:10px;margin-top:0em;margin-bottom:1em;">for most of the day, nearly every day,</p> ''OR '' <p style="color:#223d8e; margin-bottom:0em;">''Anhedonia''</p><p style="margin-left:10px;margin-top:0em;margin-bottom:1em;">i.e., decreased sense of enjoyment in nearly all activities, most of the day, nearly every day</p> ''AND'' at least four of the following additional symptoms: #Significant weight or appetite change #Too much or too little sleep #Increased or decreased restless movements #Loss of energy #Feelings of worthlessness #Difficulty concentrating #Recurrent thoughts of death or suicide. </div><div class="flexcolumn2"><img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/02_MDD.png" style="max-height: 800px;min-width:400px;" align="center"></div></div>For a diagnosis of a Major Depressive Episode, these symptoms must occur within the same 2-week period, must cause clinical distress or impair daily functioning, and must not be attributable to any substance or other medical condition. Finally, and crucially for a diagnosis of MDD, the person must not ever have experienced a manic episode or hypomanic episode. (We will discuss this more fully in a moment, in connection with Bipolar Disorders.) Note that some of these symptoms -- such as ''Depressed Mood'', ''Anhedonia'', or thoughts of suicide -- cannot be assessed //directly// unless the subject has the ability to self-report their experience. As a result, MDD can only be diagnosed and studied directly in humans. However, we can study depressive-like symptoms in non-human animal models. For example, symptoms 1-3 above can be easily assessed in animal models. Research in both humans and non-human animals has found an association between circadian rhythms and the symptoms of depression. Continue to learn about [[Bipolar Disorders.|BD]]

<span style="color:#223d8e;">''Why Do Researchers Use Animal Models to Study Mood Disorders?''</span> Animal models can provide insight into the underlying mechanisms of mood disorders that occur in humans. For instance, disrupting certain clock genes in rodents results in depressive-like behaviors. This sort of intervention cannot reasonably be carried out in humans, but the similarity of biological clocks and brain mechanisms across mammals suggests that disruption of clock gene function may also lead to mood disorders in humans. MDD and BD are diagnoses that depend on self-reporting, so they cannot be studied directly in animals. Instead, researchers focus on depressive-like or manic-like behaviors. Here are the main reasons why some researchers use animal models instead of directly studying humans: *//Ability to do more specific and invasive manipulations:// Researchers are able to do procedures in animals that can’t be done in humans for technological and/or ethical reasons (e.g, genetic manipulation, brain surgeries). *//Environmental consistency and similar genetic background:// Rodents in a laboratory setting are inbred so they have very similar genetics, and are reared in the same controlled environment, limiting confounding variables that may affect experimental outcomes. *//Control of confounding medical variables:// Researchers can avoid comorbid conditions that tend to occur in human subjects, like obesity or cancer.<img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/03_WhyMice.png" style="max-height: 500px; min-width:300px;" align="center"> [[How do researchers determine if an animal exhibits "depressive" behavior?|HowDep]] <div align='left' style='font-size: 75%;'>\ Please note that there are strict guidelines which govern the ethical treatment of animals used in laboratory research. Every experiment must follow these guidelines. To learn more about the humane treatment of laboratory animals, [[click here.|https://www.apa.org/science/leadership/care/guidelines]].</div>

<<set $GeneArray to [["Bmal1",0],["Clock",0],["Cry1",0],["Cry2",0],["Per2",0]]>><span style="color:#223d8e;">''Which Specific Clock Genes Have Been Shown to be Important for Depressive Behavior in Rodents?''</span> Researchers manipulate clock genes and proteins in several ways to test their significance for depressive behavior and mood disorders: *''//Mutation://'' The gene that encodes the protein is altered in some way -- this may affect protein function, protein abundance, or other factors. For example, the ClockΔ19 mutant still expresses the CLOCK protein, but it has altered function that results in a disregulated circadian clock. *''//Knockout (KO)://'' The gene is inactivated or deleted either throughout the body or only in a particular body region. Knockout of a gene means that it cannot be expressed as a protein and is therefore non-functional. *''//Knockdown (KD)://'' Gene expression is reduced, resulting in lower protein levels. As with a KO manipulation, a KD can be full-body or region-specific. Researchers then study the phenotype resulting from these genetic manipulations and compare it to wildtype (WT). A WT animal is genetically unmanipulated and used as a control for the study. If a manipulation of a single clock gene causes significant changes in depressive behavior compared to WT, that is good evidence that the manipulated clock gene is important for depressive behavior. Studies like these have shown that multiple clock genes are important for mood. Click on each to learn more: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>>

<<set $TestArray to [["Forced Swim Test","FSTest",0],["Learned Helplessness Test","LHTest",0],["Sucrose Preference Test","SPTest",0],["Tail Suspension Test","TSTest",0]]>><<set $H to 0>><span style="color:#223d8e;">''How do researchers determine if an animal exhibits "depressive" behavior?''</span> Because rodents are unable to verbally express how they are feeling, researchers use certain behavioral tests to determine the depressive-like symptoms of rodents. There are four behavior assays that we will look at. Click on each to learn more: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>> <<if $H isnot 1>>Are you curious about [[how investigators evaluate the validity of a behavioral assay|HowValid][$H to 1]]?<</if>>

<span style="color:#223d8e;">''Learned Helplessness Test''</span><<if $TestArray === undefined>><<set $TestArray to [["Forced Swim Test","FSTest",0],["Learned Helplessness Test","LHTest",1],["Sucrose Preference Test","SPTest",0],["Tail Suspension Test","TSTest",0]]>><<set $H to 0>><</if>> In the test for learned helplessness, a rodent is first subjected to mild, randomly timed, inescapable electric shocks applied to the tail. Then it is placed in a novel environment and exposed to a different aversive stimulus, such as mild shocks to the foot, but this time ''with'' the opportunity to escape. *A typical rodent will try to escape in the novel situation. *A helpless rodent will not try to escape in the novel situation, even when an escape route is available. The rationale for this test is its similarity in humans, where experiencing a traumatic event can lead to expression of "helpless" behavior. Likewise, if a mouse "gives up" and does not seek escape in the novel situation, this is taken as an expression of depressive-like behavior. <img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/04_LHT.png" style="max-height: 500px" align="center"> ---- <<if $TestArray[0][2] is 1 and $TestArray[1][2] is 1 and $TestArray[2][2] is 1 and $TestArray[3][2] is 1>>You've covered the behavioral assays, let's [[move on|SumAssays]]!<<else>>Continue exploring the different behavioral assays: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>><</if>> <<if $H isnot 1>>//Are you curious about [[how investigators evaluate the validity of a behavioral assay|HowValid][$H to 1]]?//<</if>>

<span style="color:#223d8e;">''Forced Swim Test''</span><<if $TestArray === undefined>><<set $TestArray to [["Forced Swim Test","FSTest",1],["Learned Helplessness Test","LHTest",0],["Sucrose Preference Test","SPTest",0],["Tail Suspension Test","TSTest",0]]>><<set $H to 0>><</if>> In the forced swim test, a rodent is placed in a container of water. The experimenter then measures the amount of time the rodent actively tries to escape the water versus the amount of time it is immobile. *A typical rodent will attempt to escape by swimming around the pool, but will eventually become immobile. *A rodent with depressive-like symptoms will spend less time attempting to escape before becoming immobile. The rationale is that if a rodent does not struggle to escape the water and instead more quickly "gives up," then we may consider this a depressive-like behavior. Thus, the time spent struggling relative to that of control animals is taken as a quantitative measure of depressive-like behavior. <img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/04_FST.png" style="max-height: 500px" align="center"> ---- <<if $TestArray[0][2] is 1 and $TestArray[1][2] is 1 and $TestArray[2][2] is 1 and $TestArray[3][2] is 1>>You've covered the behavioral assays, let's [[move on|SumAssays]]!<<else>>Continue exploring the different behavioral assays: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>><</if>> <<if $H isnot 1>>//Are you curious about [[how investigators evaluate the validity of a behavioral assay?|HowValid][$H to 1]]//<</if>>

<span style="color:#223d8e;">''Tail Suspension Test''</span><<if $TestArray === undefined>><<set $TestArray to [["Forced Swim Test","FSTest",0],["Learned Helplessness Test","LHTest",0],["Sucrose Preference Test","SPTest",0],["Tail Suspension Test","TSTest",1]]>><<set $H to 0>><</if>> In the tail suspension test, a rodent is hung from its tail for a few minutes. The experimenter then measures the amount of time it struggles versus the amount of time it is immobile. #A typical rodent will struggle and try to escape. #A rodent with depressive-like symptoms will spend less time trying to escape, and more time immobile. The rationale is that if a rodent "gives up" quickly, this is an expression of depressive-like behavior. <img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/04_TST.png" style="max-height: 800px" align="center"> ---- <<if $TestArray[0][2] is 1 and $TestArray[1][2] is 1 and $TestArray[2][2] is 1 and $TestArray[3][2] is 1>>You've covered the behavioral assays, let's [[move on|SumAssays]]!<<else>>Continue exploring the different behavioral assays: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>><</if>> <<if $H isnot 1>>//Are you curious about [[how investigators evaluate the validity of a behavioral assay|HowValid][$H to 1]]?//<</if>>

<span style="color:#223d8e;">''Sucrose Preference Test''</span><<if $TestArray === undefined>><<set $TestArray to [["Forced Swim Test","FSTest",0],["Learned Helplessness Test","LHTest",0],["Sucrose Preference Test","SPTest",1],["Tail Suspension Test","TSTest",0]]>><<set $H to 0>><</if>> In the sucrose preference test, a rodent is given the option to drink either plain water or a sucrose solution (sugar water), something that they find pleasurable and would normally be very motivating. #A typical rodent will exhibit preferential behavior towards the sucrose solution, tending to drink it more than the plain water. #A rodent with depressive-like symptoms will not exhibit (or, will exhibit less) preferential behavior toward the sucrose solution. The rationale is that if a rodent does not drink the sugar water, this indicates altered reward processing: it is either not motivated to seek pleasure, or does not find the sugar water pleasurable at all -- a behavioral expression reminiscent of anhedonia in humans, a hallmark of MDD. <img src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/04_SPT.png" style="max-height: 800px" align="center"> ---- <<if $TestArray[0][2] is 1 and $TestArray[1][2] is 1 and $TestArray[2][2] is 1 and $TestArray[3][2] is 1>>You've covered the behavioral assays, let's [[move on|SumAssays]]!<<else>>Continue exploring the different behavioral assays: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>><</if>> <<if $H isnot 1>>//Are you curious about [[how investigators evaluate the validity of a behavioral assay|HowValid][$H to 1]]?//<</if>>

<span style="color:#223d8e;">''Per2 Mutation''</span><<if $GeneArray === undefined>><<set $GeneArray to [["Bmal1",0],["Clock",0],["Cry1",0],["Cry2",0],["Per2",1]]>><</if>> <div class="annot"><div class="margtxt">//[[Need a refresher on the assays?|ReCap]]//</div><div class="maintxt"><img class="AA" src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/05_AssayArray_1000.png"></div></div> When researchers mutated //Per2// (the specific mutation is Per2^^Brdm1^^), they found that in addition to altered circadian rhythms, mutant mice had: *Decreased immobility time in the forced swim test This result suggests that //Per2// is involved in the regulation of depressive-like behavior. The Per2^^Brdm1^^ mutant mice also had increased dopamine levels in brain regions important for mood. These findings suggest that Per2 can influence mood-related behaviors by modulating dopamine levels. ---- <<if $GeneArray[0][1] is 1 and $GeneArray[1][1] is 1 and $GeneArray[2][1] is 1 and $GeneArray[3][1] is 1 and $GeneArray[4][1] is 1>>You've covered all the genetic manipulations, let's [[move on|SUM]]!<<else>>Continue exploring the different genetic manipulations: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>><</if>>

<span style="color:#223d8e;">''Clock Mutant or Knockdown''</span><<if $GeneArray === undefined>><<set $GeneArray to [["Bmal1",0],["Clock",1],["Cry1",0],["Cry2",0],["Per2",0]]>><</if>> Depending on the kind of manipulation of //Clock//, mice can exhibit either manic or depressive behavior. The relevant behavioral assays are highlighted yellow below, and the experimental results are then summarized: <div class="annot"><div class="margtxt">//[[Need a refresher on the assays?|ReCap]]//</div><div class="maintxt"><img class="AA" src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/05_AssayArray_1100.png"></div></div> //ClockΔ19// mutant mice have an altered circadian period under constant dark conditions, and exhibit “mania-like behavior” and less depressive- and anxiety-like behavior. They are considered an animal model for bipolar disorder. They have altered mood-related behaviors, as exemplified by: *Less time immobile in the forced swim test *Fewer escape failures in the learned helplessness paradigm *Shorter latency to approach and eat a cracker in the presence of aversive stimuli When researchers knocked down //Clock// expression in the ventral tegmental area (VTA), a brain region important in reward and motivation, they found that the circadian period (of wheel-running activity rhythms in constant darkness) decreased and depressive-like behavior increased, exemplified by: *More time immobile in the forced swim test *More escape failures in the learned helplessness paradigm These findings suggest that disrupting //Clock// expression specifically in the VTA, a mood-regulating center, affects both mood-related behavior and circadian rhythms. ---- <<if $GeneArray[0][1] is 1 and $GeneArray[1][1] is 1 and $GeneArray[2][1] is 1 and $GeneArray[3][1] is 1 and $GeneArray[4][1] is 1>>You've covered all the genetic manipulations, let's [[move on|SUM]]!<<else>>Continue exploring the different genetic manipulations: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>><</if>>

<span style="color:#223d8e;">''Bmal1 Knockdown''</span><<if $GeneArray === undefined>><<set $GeneArray to [["Bmal1",1],["Clock",0],["Cry1",0],["Cry2",0],["Per2",0]]>><</if>> A manipulation linked to depressive-like behavior is the knockdown of //Bmal1// in the central clock of the brain, the suprachiasmatic nucleus of the hypothalamus. //Bmal1// KD leads to disruptions in circadian rhythms as well as an increase in depressive-like behaviors. The relevant behavioral assays are highlighted yellow below, and the experimental results are then summarized: <div class="annot"><div class="margtxt">//[[Need a refresher on the assays?|ReCap]]//</div><div class="maintxt"><img class="AA" src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/05_AssayArray_0101.png"></div></div> SCN //Bmal1// knockdown mice: *Took longer to escape in a learned helplessness paradigm *More immobility in the tail suspension test *Decreased corticosterone release in response to stress *Greater weight gain ---- <<if $GeneArray[0][1] is 1 and $GeneArray[1][1] is 1 and $GeneArray[2][1] is 1 and $GeneArray[3][1] is 1 and $GeneArray[4][1] is 1>>You've covered all the genetic manipulations, let's [[move on|SUM]]!<<else>>Continue exploring the different genetic manipulations: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>><</if>>

<span style="color:#223d8e;">''Cry1 Knockout''</span><<if $GeneArray === undefined>><<set $GeneArray to [["Bmal1",0],["Clock",0],["Cry1",1],["Cry2",0],["Per2",0]]>><</if>> //Cry1// knockout mice exhibit changes in circadian rhythms and in one type of depressive-like behavior. The relevant behavioral assays are highlighted yellow below, and the experimental results are then summarized: <div class="annot"><div class="margtxt">//[[Need a refresher on the assays?|ReCap]]//</div><div class="maintxt"><img class="AA" src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/05_AssayArray_1010.png"></div></div> //Cry1// knockout mice exhibit: *More time immobile in the forced swim test, but *No difference in the sucrose preference test These results suggest that //Cry1// may be important for behavioral despair, but not for motivation to seek reward. ---- <<if $GeneArray[0][1] is 1 and $GeneArray[1][1] is 1 and $GeneArray[2][1] is 1 and $GeneArray[3][1] is 1 and $GeneArray[4][1] is 1>>You've covered all the genetic manipulations, let's [[move on|SUM]]!<<else>>Continue exploring the different genetic manipulations: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>><</if>>

<span style="color:#223d8e;">''Cry2 Knockout''</span><<if $GeneArray === undefined>><<set $GeneArray to [["Bmal1",0],["Clock",0],["Cry1",0],["Cry2",1],["Per2",0]]>><</if>> Knocking out //Cry2// in mice leads to altered circadian rhythms as well as decreased motivation to seek reward. The relevant behavioral assays are highlighted yellow below, and the experimental results are then summarized: <div class="annot"><div class="margtxt">//[[Need a refresher on the assays?|ReCap]]//</div><div class="maintxt"><img class="AA" src="https://ccb.ucsd.edu/_images/bioclock/hashtagmood/05_AssayArray_1011.png"></div></div> //Cry2// knockout mice exhibit: *No difference in forced swim test *Lower preference for sugar in the sucrose preference test *No difference in tail suspension test These results suggest that //Cry2// may be important for motivation to seek reward, but not behavioral despair. ---- <<if $GeneArray[0][1] is 1 and $GeneArray[1][1] is 1 and $GeneArray[2][1] is 1 and $GeneArray[3][1] is 1 and $GeneArray[4][1] is 1>>You've covered all the genetic manipulations, let's [[move on|SUM]]!<<else>>Continue exploring the different genetic manipulations: *<<if $GeneArray[0][1] is 0>>[[$GeneArray[0][0]|$GeneArray[0][0]][$GeneArray[0][1] to 1]]<<else>>==$GeneArray[0][0]==<</if>> *<<if $GeneArray[1][1] is 0>>[[$GeneArray[1][0]|$GeneArray[1][0]][$GeneArray[1][1] to 1]]<<else>>==$GeneArray[1][0]==<</if>> *<<if $GeneArray[2][1] is 0>>[[$GeneArray[2][0]|$GeneArray[2][0]][$GeneArray[2][1] to 1]]<<else>>==$GeneArray[2][0]==<</if>> *<<if $GeneArray[3][1] is 0>>[[$GeneArray[3][0]|$GeneArray[3][0]][$GeneArray[3][1] to 1]]<<else>>==$GeneArray[3][0]==<</if>> *<<if $GeneArray[4][1] is 0>>[[$GeneArray[4][0]|$GeneArray[4][0]][$GeneArray[4][1] to 1]]<<else>>==$GeneArray[4][0]==<</if>><</if>>

<span style="color:#223d8e;">''Summary of the Results & Future Directions''</span> The studies covered in this tutorial give insight into how circadian rhythms are associated with mood-related behaviors in rodents. Specifically, these studies show that clock genes (//Clock//, //Bmal1//, //Per2//, //Cry1//, and //Cry2//) are involved in the regulation of mood-related behaviors in rodents. Although some interactions between the circadian clock and mood disorders have been well established, the molecular mechanisms that govern the relationship between the circadian clock and mood disorders remain unclear. Like most complex disorders, mood disorders are multifactorial. While animal studies support a role for the circadian clock in mood disorders, it is probably one of many elements. While these experiments give researchers a way to study the biological basis of mood disorders, they can’t reveal how the full complexity of human experience factors into depression and other mood disorders. Thus, studying the link between circadian rhythms and MDD is an ongoing effort involving both human and animal studies. Further understanding of the relationship between circadian rhythms and mood disorders holds promise for more effective treatment interventions. If you are interested in learning more about human MDD and clock genes, take a look at this tutorial by BioClock Studio *LINK MDD PRIMARY PAPER TWINE HERE* Continue on to learn about [[actions people can take to improve their circadian rhythms.|Actions]]

<span style="color:#223d8e;">''Actions People Can Take to Improve Their Circadian Rhythms''</span> Some behavioral changes are shown to help many people improve their circadian rhythms and their mood. Suggestions include: ''Healthy light exposure:'' *Get early morning sunlight **A 10,000-lux light box with broad-wavelength (white) light might be appropriate *Avoid bright light at night *Use filters that block blue light from screens at night *Use night mode on devices and computers ''Regular routines:'' *Keep regular sleep / wake times **Avoid naps in favor of sufficient night-time sleep *Eat meals regularly **Avoid late night snacks *Get regular exercise during the day ''Track your progress:'' *There are apps to help you track your daily: **Activity **Diet **Mood **Light exposure [[Resources|Resources]]

<span style="color:#223d8e;">References</span> # Albrecht, U. (2019). Molecular Connections Between Circadian Clocks and Mood-related Behaviors. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2019.11.021 # Hampp, G., & Albrecht, U. (2008). The circadian clock and mood related behavior. Communicative & Integrative Biology, 1(1), 1-3. https://doi.org/10.4161/cib.1.1.6286 # Haque, S. N., Booreddy, S. R., & Welsh, D. K. (2019, June 27). Effects of BMAL1 Manipulation on the Brain's Master Circadian Clock and Behavior. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31249486 # Kim, M., Peña, J. B., Cheong, J. H., & Kim, H. J. (2018). Neurobiological Functions of the Period Circadian Clock 2 Gene,Per2. Biomolecules & Therapeutics, 26(4), 358-367. https://doi.org/10.4062/biomolther.2017.131 # Krishnan, V., & Nestler, E. J. (2011). Animal Models of Depression: Molecular Perspectives. Molecular and Functional Models in Neuropsychiatry Current Topics in Behavioral Neurosciences, 121-147. https://doi.org/10.1007/7854_2010_108 # Landgraf, D., Long, J. E., Proulx, C. D., Barandas, R., Malinow, R., & Welsh, D. K. (2016). Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice. Biological Psychiatry, 80(11), 827-835. https://doi.org/10.1016/j.biopsych.2016.03.1050 # Li, N., Xu, Y., Chen, X., Duan, Q., & Zhao, M. (2015). Sex-Specific Diurnal Immobility Induced by Forced Swim Test in Wild Type and Clock Gene Deficient Mice. International Journal of Molecular Sciences, 16(12), 6831-6841. https://doi.org/10.3390/ijms16046831 # McCarthy, M. J., & Welsh, D. K. (2012). Cellular Circadian Clocks in Mood Disorders. Journal of Biological Rhythms, 27(5),339-352. https://doi.org/10.1177/0748730412456367 # Mendoza, J., & Vanotti, G. (2019). Correction to: Circadian neurogenetics of mood disorders. Cell and Tissue Research, 377(2), 285-288. https://doi.org/10.1007/s00441-019-03051-5 # Mukherjee, S., Coque, L., Cao, J., Kumar, J., Chakravarty, S., Asaithamby, A., Graham, A., Gordon, E., Enwright, J., DiLeone, R., Birnbaum, S., Cooper, D., & Mcclung, C. (2010). Knockdown of //Clock// in the Ventral Tegmental Area Through RNA Interference Results in a Mixed State of Mania and Depression-Like Behavior. Biological Psychiatry, 68(6), 503-511. https://doi.org/10.1016/j.biopsych.2010.04.031 # Savalli, G., Diao, W., Berger, S., Ronovsky, M., Partonen, T., & Pollak, D. D. (2015). Anhedonic behavior in cryptochrome 2-deficient mice is paralleled by altered diurnal patterns of amygdala gene expression. Amino Acids, 47(7), 1367-1377. https://doi.org/10.1007/s00726-015-1968-3 # Schnell, A., Sandrelli, F., Ranc, V., Ripperger, J. A., Brai, E., Alberi, L., Rainer, G., & Albrecht, U. (2015). Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment. Chronobiology International, 32(8), 1075-1089. https://doi.org/10.3109/07420528.2015.1062024 # Schuch, J. B., Genro, J. P., Bastos, C. R., Ghisleni, G., & Tovo-Rodrigues, L. (2017). The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177(2), 181-198. https://doi.org/10.1002/ajmg.b.32599 # Severus, E., & Bauer, M. (2013). Diagnosing bipolar disorders in DSM-5. International journal of bipolar disorders, 1, 14. https://doi.org/10.1186/2194-7511-1-14 # Wang, Q., Timberlake, M. A., Prall, K., & Dwivedi, Y. (2017). The recent progress in animal models of depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 77, 99-109. https://doi.org/10.1016/j.pnpbp.2017.04.008

<span style="color:#223d8e;">''How do investigators evaluate the validity of a behavioral assay?''</span><<if $TestArray === undefined>><<set $TestArray to [["Forced Swim Test","FSTest",0],["Learned Helplessness Test","LHTest",0],["Sucrose Preference Test","SPTest",0],["Tail Suspension Test","TSTest",0]]>><<set $H to 1>><</if>> In order to assess whether a rodent model is testing what the experimenter thinks it is testing, it is important to address the following criteria: *''//Face Validity://'' Is the behavior of the rat or mouse similar to that of humans who have the condition? *''//Construct Validity://'' Can processes which lead to the human condition also be present in the model? Do human and rodent phenotypes have similar causative factors? *''//Predictive (or Pharmacological) Validity://'' Are interventions that reverse the behavioral phenotype in rodents effective for treating the condition in humans? Here we discuss four behavioral assays used in studies of mood disorders that have each been shown to have high validity based on the criteria above. <<if $TestArray[0][2] is 1 and $TestArray[1][2] is 1 and $TestArray[2][2] is 1 and $TestArray[3][2] is 1>>You've covered the behavioral assays, let's [[move on|SumAssays]]!<<else>>Continue exploring the different behavioral assays: *<<if $TestArray[0][2] is 0>>[[$TestArray[0][0]|$TestArray[0][1]][$TestArray[0][2] to 1]]<<else>>==$TestArray[0][0]==<</if>> *<<if $TestArray[1][2] is 0>>[[$TestArray[1][0]|$TestArray[1][1]][$TestArray[1][2] to 1]]<<else>>==$TestArray[1][0]==<</if>> *<<if $TestArray[2][2] is 0>>[[$TestArray[2][0]|$TestArray[2][1]][$TestArray[2][2] to 1]]<<else>>==$TestArray[2][0]==<</if>> *<<if $TestArray[3][2] is 0>>[[$TestArray[3][0]|$TestArray[3][1]][$TestArray[3][2] to 1]]<<else>>==$TestArray[3][0]==<</if>><</if>>

<span style="color:#223d8e;">''Acknowledgments & Thank You''</span> This project was made possible by the entire BioClock Studio team. Thanks to Drs David Welsh and Michael McCarthy for expertise during the production of this project. [[References|REF]]

<<button "Home" "START">><</button>><<button "Molecular Clock Basics" "Basics">><</button>><<button "MDD Info" "MDD">><</button>><<button "BD Info" "BD">><</button>><<button "Why Use Animal Models?" "WhyRodents">><</button>><<button "Behavioral Assays" "HowDep">><</button>><<button "Clock Genes Affecting Mood" "GENE_OVRVW">><</button>><<button "Summary" "SUM">><</button>><<button "Actions You Can Take" "Actions">><</button>><<button "References" "REF">><</button>>

<span style="color:#223d8e;">''Bipolar Disorders (BDs)''</span> Bipolar Disorders (BDs) are characterized by manic episodes, which may last weeks to months. BD affects 1-2% of the population, and is thought to have a genetic component. There are different varieties of Bipolar Disorders. The starting point for any BD diagnosis is meeting the diagnostic criteria for a major depressive episode -- which we reviewed just a moment ago when discussing MDD -- ''AND'' meeting the diagnostic criteria for either a manic or a hypomanic episode. The DSM-5 defines the following core diagnostic criteria for manic and hypomanic episodes: <div style="margin-left:20px;line-height:1.1em;"><p style= "margin-top:0em;margin-bottom:0.5em;">Persistent increased energy or activity</p><p style= "margin-top:0em;margin-bottom:0.5em;">''AND''</p><p style= "margin-top:0em;margin-bottom:0.5em;">elevated, irregular or irritable mood</p>''AND at least three'' of the following symptoms: #Inflated self-esteem #Decreased need for sleep #More talkative than usual #Racing thoughts #Easily distracted (usually to irrelevant stimuli) #Increase in goal-oriented activity #Excessive impulsiveness in risky, pleasure-seeking activities. </div> For a diagnosis of a ''manic'' episode, these symptoms must be present most of the day, nearly every day, for ''1 week'' (or must be disruptive enough to lead to hospitalization). In addition, the disturbance must be severe enough to cause significant impairment to daily social and occupational life (or must be disruptive enough to lead to hospitalization). Finally, the symptoms must not be attributable to medications, treatment, or another medical condition. For a diagnosis of a ''hypomanic'' episode, the same symptoms must be present most of the day, nearly every day, for ''4 consecutive days''. The disturbance must NOT be so severe as to cause significant impairment to daily social and occupational life, and must NOT be disruptive enough to necessitate hospitalization. Finally, the symptoms must not be attributable to medications, treatment, or another medical condition. The DSM-5 criteria for diagnoses of Bipolar Disorders rely on the foregoing criteria for major depressive episodes, manic episodes, and hypomanic episodes: <div style="margin-left:20px;">For a diagnosis of Bipolar I Disorder (BDI), a subject must meet the criteria above for at least one lifetime ''manic'' episode, ''AND'' must meet the previously-discussed criteria for at least one major depressive episode.</div> <div style="margin-left:20px;">For a diagnosis of Bipolar II Disorder (BDII), a subject must meet the criteria above for at least one lifetime ''hypomanic'' episode, ''AND'' must NOT meet the criteria for any lifetime manic episode, ''AND'' must meet the previously-discussed criteria for at least one major depressive episode.</div> <div style="margin-left:20px;">A third Bipolar Disorder, called cyclothymia, is more subtle. For a diagnosis of cyclothymia, a subject must exhibit numerous episodes of depressive symptoms that never quite qualify as major depressive events, ''AND'' must exhibit numerous episodes of hypomanic symptoms that never quite qualify as hypomanic events. These episodes must last 2 years, must occur at least 50% of the time, and must occur with no longer than a 2-month gap between them at any time.</div> Thus, several varieties of BDs are distinguished on a spectrum in terms of the symptoms required for diagnosis, but this does not mean that some BDs are inherently "more severe" than others. As with MDD, a diagnosis of BDs requires self-reporting, and thus BDs can only be diagnosed and studied directly in humans. Yet, again, it is possible to study mania-like sympotoms and BD-like symptoms in non-human animal models. Continue to learn [[why researchers use animal models to study mood disorders.|WhyRodents]]

<span style="color:#223d8e;">''Resources''</span> *[[National Suicide Prevention Lifeline|https://suicidepreventionlifeline.org/]] **Call 1-800-273-8255 *[[UC San Diego Mental Health Services|https://wellness.ucsd.edu/caps/Pages/default.aspx]] [[Acknowledgements & Thank You|END]]

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<span style="color:#223d8e;">''Non-Behavioral Assays''</span> You're now familiar with four behavioral assays that are commonly used to measure depressive-like behavior in rodents. While we won't discuss them in great detail, a variety of physiological measures are also used in animal research on mood. For example, when placed under stress, rodents typically secrete increased corticosterone -- a steroid hormone synthesized in the adrenal gland. The equivalent adrenal steroid in humans is cortisol. These hormones are key components in the Hypothalamic-Pituitary-Adrenal (HPA) Axis, which is known to be dysregulated in many human mood disorders. Thus, measuring corticosterone release in rodents is one physiological, non-behavioral assay that is often used in mood research. The rationale is that decreased corticosterone release indicates a less pronounced response to respond to stress, indicating a depressive-like alteration in the hormonal system. Got it. [[What about the circadian clock though?|GENE_OVRVW]]

<span style="color:#223d8e;">''Introduction''</span> Studies in both humans and animals have linked circadian rhythms to the symptoms of depressive disorders such as Major Depressive Disorder (MDD) and Bipolar Disorders (BDs). In fact, circadian interventions are used to help alleviate depressed mood in BD patients. In this tutorial, we focus on how researchers study depressive-like behaviors in rodents to gain insights into human diseases. We briefly describe the cellular mechanism of the mammalian circadian clock, which is similar between rodents and humans. We define the criteria that doctors use to diagnose MDD and BDs to indicate that many mood disorders have overlapping symptomatology, and thus may also share some basic underlying mechanisms. Researching depressive-like behavior in rodents may contribute insights into both MDD and BDs in humans. [[Next|Basics]]