Bipolar disorder (BD) is a lifelong severe mental illness affecting up to 2% of the population. BD is unique in that patients switch between extreme states of mania (euphoria, impulsivity, etc.) to depression (sedation, despair, etc.). Poor treatment options contribute to a high rate of suicide. The lack of options is partly due to our limited knowledge of circuitry causing switches between mood states in BD. Identifying this circuitry requires model animals that share biological changes seen in BD patients. Currently, no model animals related to the causes of this switch exist. Elevating dopamine (DA) activity can induce manic episodes. The DA transporter (DAT) serves to reduce synaptic DA. DAT polymorphisms associated with BD reduce the functional expression of DAT (50%) and limit DA clearance. In BD, DAT levels are reduced irrespective of state. Reduced DAT may therefore also be important for depressed moods. Beyond nature, the environment can trigger switches, e.g., mania episodes occur most often as days grow longer while depressive episodes occur in shorter days. Similarly, normal rats housed in high and low activity-inducing photoperiods (summer- and winter-like) switch into modest mania- and depressive-like behaviors respectively. Immunocytochemistry revealed some of the neural chemistry underlying these switches. During long-activity photoperiods, DA was elevated while somatostatin (SST) was reduced in the brain region that receives light input (the hypothalamus). The opposite was true for short-activity photoperiods. The overall hypothesis tested here is that reduced DAT expression in mice confers susceptibility to extreme behavioral switches resulting from altered photoperiods.
Specific Aim 1 will test if mice with 50% DAT expression exhibit mania-like behaviors when housed in long activity-inducing photoperiods and depression-like behaviors in short activity-inducing photoperiods. These behaviors will be measured using ethologically relevant tests for 'mood'and by tests of attention, risk-taking, exploration, and sensorimotor gating that are used in both mice and humans.
Specific Aim 2 will map the brain circuitry hypothesized to underlie these extreme changes in behavior. The working model is that 50% DAT expression causes changes in the neurochemical environment enabling higher DA and SST expression during changing photoperiods. Hence, the hypotheses are that: A) long-activity photoperiods will elevate hypothalamic DA, elevating DA D2 receptor expression and DA in the striatum, and thereby lead to mania-like behaviors;and B) short-activity photoperiods will elevate levels of hypothalamic SST and corticotropin releasing factor, elevating hippocampal acetylcholine levels, and thereby producing depression-like behaviors. These studies will help elucidate the circuitry underlying switching between the extreme poles of BD. This research should facilitate the identification of novel treatments targeted at this neural circuitry. Furthermore, because the animal cognitive and behavioral tasks used have human analogs, any treatments developed for this circuit will have an increased chance of working in the clinic, helping patients with BD.

Public Health Relevance

Bipolar disorder is a complex and debilitating disorder affecting up to 2% of the population, 1 in 3 of whom will attempt suicide. Generating a model animal for bipolar disorder is hampered by our limited understanding of the brain mechanisms underlying switching between depressed and manic mood states. This project will investigate a genetic and environmental model organism that will illuminate the brain mechanisms contributing to the behavioral and cognitive switching that occurs in patients, enabling targeted treatments to be developed.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Winsky, Lois M
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University of California San Diego
Schools of Medicine
La Jolla
United States
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van Enkhuizen, Jordy; Henry, Brook L; Minassian, Arpi et al. (2014) Reduced dopamine transporter functioning induces high-reward risk-preference consistent with bipolar disorder. Neuropsychopharmacology 39:3112-22