Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas

Abstract

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-conditional tryptophan 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.

Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis

“…Young adult mice (∼8 weeks of age) underwent a single survival intracranial surgical procedure to receive adeno-associated virus (AAV) as described in Whitney et al (2016). After induction in isoflurane anesthetic (3.0–3.5% in 1 l/min O 2 ), the mice were mounted into a stereotaxic frame and the anesthetic state was maintained under isoflurane.…”

“…To accomplish this, we used a recently established conditional approach (Whitney et al, 2016) to specifically target adult brain 5-HT synthesis, which nearly eliminates 5-HT from the entire mouse forebrain. Conditional targeting of adult brain 5-HT synthesis, together with well-established operant methods to robustly assay olfactory psychophysics, allowed to us test whether the adult olfactory system requires 5-HT for fundamental aspects of odor-guided operant behaviors, including odor learning and coarse odor discrimination.…”

Serotonin in Neurological Diseases

“…Studies provide evidence that altered availability and metabolism of 5-HT may lead to impulsivity [94]. Moreover, studies indicate that 5-HT deficiency leads to a failure of 5-HT-mediated inhibitory control of aggressive behavior and can occur also in adults [11]. Some of the studies have demonstrated decreased levels of 5-HT and 5-HIAA, in the blood, urine, and CSF in individuals with ADHD compared with in healthy controls, but other studies found no differences.…”

“…Currently, it is believed that disturbances in the level of 5-HT may be associated with the pathogenesis of few neurological diseases such as migraine [7], epilepsy [8], Parkinson's disease (PD) [1], multiple sclerosis (MS) [9], and amyotrophic lateral sclerosis (ALS) [10] and other disorders (attention-deficit hyperactivity disorder (ADHD) [11], autism spectrum disorder (ASD) [12]). …”

Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages

“…Interestingly, serotonin transporter-deficient mice also showed stressinduced alterations in the adrenocortical stress response as measured by corticosterone metabolites excretion levels (40). 5-HT depleted transgenic animals also seem to have disrupted sleep patterns and display altered muscle and bone structure (41,42). While TPH2 −/− animals did not show altered pain sensitivity they show an increased fear learning (38).…”