Circadian Gene Circuitry Predicts Hyperactive Behavior in a Mood Disorder Mouse Model

Area of Science:

• Neuroscience
• Molecular Biology
• Chronobiology

Background:

• Bipolar disorder (manic-depressive illness) is characterized by unpredictable mood and activity swings.
• The molecular underpinnings of these mood fluctuations remain largely unknown.
• Irregular biological rhythms are difficult to predict and manage.

Purpose of the Study:

• To investigate the molecular basis of infradian (longer than a day) cyclic activity levels in a mouse model.
• To identify potential biomarkers for predicting mood-associated behavioral states.
• To explore the role of circadian gene expression in irregular behavioral rhythms.

Main Methods:

• Utilized alpha-calcium/calmodulin-dependent protein kinase II (αCaMKII) mutant mice exhibiting infradian activity cycles.
• Analyzed gene-expression patterns in the hippocampal dentate gyrus.
• Correlated gene expression with locomotor activity (LA) states (high vs. low).
• Examined levels of cyclic adenosine monophosphate (cAMP) and phosphorylated cAMP response element-binding protein (pCREB).

Main Results:

• Gene-expression profiles in the dentate gyrus could retrospectively predict high or low LA states in mice.
• Expression of specific circadian genes correlated with LA.
• Levels of cAMP and pCREB were associated with LA states, suggesting their role as upstream regulators.
• Demonstrated intrinsic molecular circuitry changes accompanying infradian oscillatory LA.

Conclusions:

• Hippocampal gene expression patterns reflect and can predict infradian behavioral oscillations.
• Circadian gene expression, cAMP, and pCREB are implicated in the molecular control of irregular biological rhythms.
• These findings provide a molecular framework for understanding the brain's control over erratic behavior and mood states.