Meredith Sorenson Whitney

Background: Bipolar and depressive disorders (bipolar disorder [BD], major depressive disorder [MDD]), as well as menopause affect millions of women. Although there are three known cognitive behavioral group treatment (CBGT) protocols to help women with problematic menopause symptoms, they do not target women on the BD or MDD spectrum. The purpose of this qualitative study was to learn more about the treatment needs and group experiences of women with problematic menopause symptoms and diagnosed on the BD and MDD spectrum, who participated in a CBGT intervention for menopausal symptoms. Methods: Narrative data recorded by clinicians (Interventionists' notes) and participants (Evaluation of Groups Survey) were analyzed using content analyses. Results: Several themes emerged from (n = 11 BD; n = 48 MDD) what women wanted help with (specific symptoms and general aspects of menopause), what women liked about CBGT (specific and general aspects of the program), and changes needed in the CBGT intervention (things wished for and barriers that interfered with the program). The two diagnostic groups differed in their responses, although both groups identified content and delivery gaps they wished would be addressed. Specifically related to their diagnosis, women most commonly talked about problems with worsening mood and mood instability and multiple stressors interfering with their ability to follow through with the intervention. Conclusions: These findings can help refine existing CBGT protocols for women diagnosed on the BD and MDD spectrum seeking help for menopause symptoms. Trial Registry: Parent study ClinicalTrials.gov [identifier: NCT02860910].

Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditionaltryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep–wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior.SIGNIFICANCE STATEMENTSerotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep–wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.

The neurotransmitter serotonin (5-HT) is considered a powerful modulator of sensory system organization and function in a wide range of animals. The olfactory system is innervated by midbrain 5-HT neurons into both its primary and secondary odor-processing stages. Facilitated by this circuitry, 5-HT and its receptors modulate olfactory system function, including odor information input to the olfactory bulb. It is unknown, however, whether the olfactory system requires 5-HT for even its most basic behavioral functions. To address this question, we established a conditional genetic approach to specifically target adult braintryptophan hydroxylase 2(Tph2), encoding the rate-limiting enzyme in brain 5-HT synthesis, and nearly eliminate 5-HT from the mouse forebrain. Using this novel model, we investigated the behavior of 5-HT–depleted mice during performance in an olfactory go/no-go task. Surprisingly, the near elimination of 5-HT from the forebrain, including the olfactory bulbs, had no detectable effect on the ability of mice to perform the odor-based task.Tph2-targeted mice not only were able to learn the task, but also had levels of odor acuity similar to those of control mice when performing coarse odor discrimination. Both groups of mice spent similar amounts of time sampling odors during decision-making. Furthermore, odor reversal learning was identical between 5-HT–depleted and control mice. These results suggest that 5-HT neurotransmission is not necessary for the most essential aspects of olfaction, including odor learning, discrimination, and certain forms of cognitive flexibility.