Physical weight loading induces expression of tryptophan hydroxylase 2 in the brain stem.

Sustaining brain serotonin is essential in mental health. Physical activities can attenuate mental problems by enhancing serotonin signaling. However, such activity is not always possible in disabled individuals or patients with dementia. Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2) that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive) control, and a 90-min tail suspension was used as a stress (negative) control. Expression of tph2 was determined 30 min - 2 h in three brain regions --frontal cortex (FC), ventromedial hypothalamus (VMH), and brain stem (BS). We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.

5-HT2 receptor distribution shown by [18F] setoperone PET in high-functioning autistic adults.

The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.

Effects of prenatal alcohol exposure on the development of the vibrissal somatosensory cortical barrel network.

We have previously shown that the serotonin (5-HT) and its thalamocortical afferents are compromised by prenatal alcohol exposure (PAE). The development of the sensory cortical barrels is regulated by 5-HT-rich thalamocortical afferents. Therefore, it is hypothesized that PAE will deleteriously affect the postnatal development of the cortical barrel formations. On embryonic day (E)7, C57BL/6 mice were grouped into: Alcohol (Alc), Pair-fed (PF), or Chow, and maintained on diet until E18. On postnatal day 7, cortices were stained with 5-HT for thalamocortical fibers, and a NeuN for identification of mature neurons. The area of the posterior medial barrel subfield (PMBSF), was measured as well as the number of NeuN+ neurons within the barrel patches. Though brain weight and brain volume were similar among the three groups, a significant reduction was seen in total area of the PMBSF, and in the average individual barrel area in the Alc group as compared to Chow. Furthermore, the volumes of the B, but not C row barrels were significantly reduced. Barrels were found missing in layer IV, specifically in the posterior aspects of the A, B, and straddler row in the Alc group. Cell counts demonstrated a nearly 50% reduction in NeuN+ neuron number in both rows. This reduction in size of the PMBSF and fewer neurons within these sensory barreloids may underlie a change in the development of the discriminatory sensitivity of the whiskers and serves as an excellent model for the study of a compromised sensory modality following PAE.

Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development.

To further investigate the role of the transiently expressed serotonin (5-HT) transporter (5-HTT) in the development of thalamic fibers projecting to cortical barrels and the potential developmental changes in neuronal circuitry caused by a selective serotonin reuptake inhibitor (SSRI), paroxetine (5 mg/kg, twice daily, s.c.) or saline was administered to rat pups from postnatal day 0 (P0) to P8. Pups were perfused on P8 for 5-HT immunostaining (-im) to confirm the 5-HT uptake blockade, and 5-HTT-im and phospholipase C-beta1 (PLC-beta1)-im to label the thalamic afferents to barrels and barrel cells respectively. Paroxetine treatment completely blocked 5-HT uptake into the thalamocortical fibers as indicated by the negative 5-HT-im in cortical barrel areas. Organization of thalamic afferents to barrels, indicated by 5-HTT-im or PLC-beta1, was altered in paroxetine-treated pups in the following manners: (1) segregation of thalamocortical fibers was partially disrupted and thalamocortical fibers corresponding to anterior snouts and row A mystacial vibrissae were fused; (2) sizes of the unfused thalamocortical fiber patches related to the long caudal vibrissae in rows B, C, D and E were significantly decreased without changes in the brain weights and cortical areas representing these vibrissae; and (3) thalamocortical fibers corresponding to C4 and D4 vibrissae tended to be closer to each other along the arc while the relative positions of thalamocortical fibers related to the rest of the vibrissae were normal. Our study demonstrated that 5-HTT plays an important role in the refinement, but not the formation, of barrel-like clusters of thalamocortical fibers and that the development of neural circuitry in rodent somatosensory cortex was affected by exposure to a SSRI during thalamocortical synaptic formation.