Salmeterol, a \u3b22 Adrenergic Agonist, Promotes Adult Hippocampal Neurogenesis in a Region-Specific Manner.

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (\u3b2-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of \u3b22-AR by norepinephrine and \u3b22-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective \u3b22-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult na\uefve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior

Effects of total sleep deprivation on sensorimotor gating in humans

Sensorimotor gating is a measure of pre-attentional information processing and can be measured by prepulse inhibition (PPI) of the startle reflex. Sleep deprivation has been shown to disrupt PPI in animals and humans, and has been proposed as an early phase 2 model to probe antipsychotic efficacy in heathy humans. To further investigate the reliability and efficacy of sleep deprivation to produce PPI deficits we tested the effects of total sleep deprivation (TSD) on PPI in healthy controls in a highly controlled sleep laboratory environment. Participants spent 4 days and nights in a controlled laboratory environment with their sleep monitored with polysomnography. Participants were randomly assigned to either normal sleep on all 4 nights (N = 17) or 36 h of TSD on the 3rd or 4th night (N = 40). Participants were assessed for sleepiness using the Karolinska Sleepiness Scale (KSS) and underwent a daily PPI task (interstimlulus intervals 30-2000 ms) in the evening. Both within-subject effects (TSD vs. normal sleep in TSD group alone) and between-subject effects (TSD vs. no TSD group) of TSD on PPI were assessed. TSD increased subjective sleepiness measured with the KSS, but did not significantly alter overall startle, habituation or PPI. Sleep measures including duration, rapid eye movement and slow wave sleep duration were also not associated with PPI performance. The current results show that human sensorimotor gating may not be reliably sensitive to sleep deprivation. Further research is required for TSD to be considered a dependable model of PPI disruption for drug discovery in humans

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that β-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics

The neurogenic effects of exogenous neuropeptide Y: early molecular events and long-lasting effects in the hippocampus of trimethyltin-treated rats.

Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 \ub5g/2 \ub5l, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit

A monosynaptic pathway links the vestibular nuclei and masseter muscle motoneurons in rats

Physiological evidence indicates that vestibular signals modulate the activity of motoneurons innervating the masseter muscle. Recently, experiments using transynaptic retrograde transport of pseudorabies virus provided anatomical evidence that many neurons concentrated in the dorsomedial part of the parvicellular division of the medial vestibular nucleus (MVePC) and the caudal prepositus hypoglossi (PH) provide inputs to motoneurons innervating the lower third of the superficial layer of the masseter muscle. However, it was not clear whether this vestibulo-trigeminal projection was monosynaptic or polysynaptic. The present study sought to determine whether neurons in the MVePC or PH project directly to motoneurons controlling the masseter muscle in rats. For this purpose, an anterograde tracer (biotinylated dextran amine, BDA) was injected into vestibular nuclei (mainly MVePC) or PH and a retrograde tracer (the beta-subunit of cholera toxin, b-CT) was injected into the masseter muscle ipsilateral or contralateral to the BDA injection site. Following injections of BDA into the vestibular nuclei or PH, anterogradely labeled axon terminals were observed bilaterally in the motor trigeminal nucleus (Mo5), particularly in the ventral, medial, and lateral portions of the nucleus; projections to dorsal Mo5 were sparse. In addition, retrogradely labeled motoneurons were located in the ventral and lateral portions of the ipsilateral Mo5. Moreover, anterogradely labeled terminals were observed to be in close proximity to motoneurons in the Mo5 that were retrogradely labeled from b-CT injections into the masseter muscle. This study provides direct evidence that a monosynaptic pathway exists between the MVePC and PH and masseter motoneurons

Salmeterol, a β2 adrenergic agonist, promotes adult hippocampal neurogenesis in a region-specific manner

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (β-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of β2-AR by norepinephrine and β2-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective β2-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult naïve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/ NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior