Serotonin Neurons Research Articles

Chronic-Stress-Induced Behavioral Changes Associated with Subregion-Selective Serotonin Cell Death in the Dorsal Raphe.

The current study examined the neurochemical mechanisms and neuroanatomical changes underlying coexisting behavioral effects associated with chronic-stress-induced alterations in serotonin (5HT) neurons. Chronic unpredictable stress (CUS) to adult male rats produced depression-like changes with cognitive dysfunction and selective cell death in the interfascicular nucleus of the dorsal raphe (DRif), resulting in decreased 5HTergic innervation of medial prefrontal cortex (mPFC). Twenty-one days of CUS decreased basal plasma levels of corticosterone and produced a shorter latency to immobility and longer durations of immobility in the force-swim test that persisted for 1 month after CUS. Deficits in acquisition, recall, perseveration, and reversal learning were evident 1 month after CUS. MK801 treatment during CUS blocked the changes in the forced-swim test and deficits in memory recall. These behavioral changes were associated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive soma and the eventual loss of 5HT neurons in the DRif and its projections to the mPFC as evidenced by fewer labeled cells in the DRif after retrograde tracer injections into the mPFC of stressed rats. Similar to the effects of MK801 on behavior, MK801 pretreatment during stress blocked the CUS-induced decreases in 5HT soma within the DRif and its projections to the mPFC. Finally, the depression-like behaviors were blocked by acute injection of the 5HT2A/C agonist (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride into the mPFC before forced-swim testing. These results identify a cause and mechanism of 5HTergic dysfunction of the mPFC and associated mood and cognitive behaviors.SIGNIFICANCE STATEMENT Chronic stress causes persistent mood and cognitive changes typically associated with dysregulated serotonin (5HT) transmission in the medial prefrontal cortex (mPFC), but the cause of this dysregulation is unknown. Prior studies have focused on 5HTergic terminals in this region, but this study shows that chronic stress causes NMDA-receptor-dependent and subregion-specific cell death of 5HT neurons in the dorsal raphe. The consequent decreased 5HT innervation of the mPFC was associated with mood and cognitive changes that persisted long after the termination of stress. These findings identify a mechanism of subregion-selective death of 5HT neurons in the dorsal raphe, a defined neuroanatomical pathway, and a behavioral phenotype that mirror stress-associated diseases such as major depressive disorder.

ANTI- OBSESSIVE COMPULSIVE ACTIVITY OF HONEY

Objective: The present study aim to investigate the anti-obsessive compulsive disorder potential of honey in mice.Methods: The honey was given orally in two concentrations of 17.5 ml/kg and 35 ml/kg to mice for 21 days. The anti-obsessive compulsive activity was assessed on 21th day by in-vitro methods viz flickering-light induced obsessive- compulsive behaviour model developed in our laboratory (Patent No. 3087/DEL/2012) and marble-burying behaviour model. The biochemical estimation was also done on 21 days.Results: When honey was administered chronically for 21 days significantly reduced gnawing behaviour and marble-burying behaviour of mice. Interestingly in our biochemical estimations, both, brain serotonin and GABA level were significantly increased by honey. The anti-Obsessive compulsive activity of honey may be due to the presence of Tryptophan, which is an important precursor of serotonin in the serotonergic neurons thereby enhancing the biosynthesis of serotonin to facilitate the anti- obsessive compulsive activity.Conclusion: The present study revealed that honey possessed significant anti-OCD activity.Keywords: Honey, Anti-obsessive–compulsive disorder, Antioxidant, Serotonin.

GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing-Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus.

The dorsal raphe nucleus (DRn) receives glutamatergic inputs from numerous brain areas that control the function of DRn serotonin (5-HT) neurons. By integrating these synaptic inputs, 5-HT neurons modulate a plethora of behaviors and physiological functions. However, it remains unknown whether the excitatory inputs onto DRn 5-HT neurons can undergo activity-dependent change of strength, as well as the mechanisms that control their plasticity. Here, we describe a novel form of spike-timing–dependent long-term potentiation (tLTP) of glutamate synapses onto rat DRn 5-HT neurons. This form of synaptic plasticity is initiated by an increase in postsynaptic intracellular calcium but is maintained by a persistent increase in the probability of glutamate release. The tLTP of glutamate synapses onto DRn 5-HT is independent of NMDA receptors but requires the activation of calcium-permeable AMPA receptors and voltage-dependent calcium channels. The presynaptic expression of the tLTP is mediated by the retrograde messenger nitric oxide (NO) and activation of cGMP/PKG pathways. Collectively, these results indicate that glutamate synapses in the DRn undergo activity-dependent synaptic plasticity gated by NO signaling and unravel a previously unsuspected role of NO in controlling synaptic function and plasticity in the DRn.

660. Effect of Combining Aripiprazole with Escitalopram on Serotonergic and Noradrenergic Neurotransmission in the Rat Hippocampus

Aripiprazole is an atypical antipsychotic approved as an adjunct for inadequate response to antidepressants in the treatment of major depressive disorder. Addition of aripiprazole to escitalopram reverses the inhibitory actions of escitalopram on firing activity of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) neurons. This study investigated the postsynaptic neurotransmission of the previously studied monoamines systems.

What Gene Mutations Affect Serotonin in Mice?

Although serotonin neurotransmission has been implicated in several neurodevelopmental and psychological disorders, the factors that drive dysfunction of the serotonin system are poorly understood. Current research regarding the serotonin system revolves around its dysfunction in neuropsychiatric disorders, but there is no database collating genetic mutations that result in serotonin abnormalities. To bridge this gap, we developed a list of genes in mice that, when perturbed, result in altered levels of serotonin either in brain or blood. Due to the intrinsic limitations of search, the current list should be considered a preliminary subset of all relevant cases. Nevertheless, it offered an opportunity to gain insight into what types of genes have the potential to impact serotonin by using gene ontology (GO). This analysis found that genes associated with monoamine metabolism were more often associated with increases in brain serotonin than decreases. Speculatively, this could be because several pathways (and therefore many genes) are responsible for the clearance and metabolism of serotonin whereas only one pathway (and therefore fewer genes) is directly involved in the synthesis of serotonin. Another contributor could be cross talk between monoamine systems such as dopamine. In contrast, genes that were associated with decreases in brain serotonin were more likely linked to a developmental process. Sensitivity of serotonin neurons to developmental perturbations could be due to their complicated neuroanatomy or possibly they may be negatively regulated by dysfunction of their innervation targets. Thus, these observations suggest hypotheses regarding the mechanisms underlying the vulnerability of brain serotonin neurotransmission.

How Studies of the Serotonin System inMacaque Models of Menopause Relate toAlzheimer's Disease1.

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior

Dysfunction of cholinergic signaling in the brain has long been believed to be associated with depressive disorders. However, the functional impact of habenular cholinergic signaling on the specified depressive behaviors is not well understood. Here, we demonstrated that the expression levels of cholinergic signaling genes (CHAT, VACHT, CHT, CHRNA3, CHRNB3 and CHRNB4) were down-regulated in a chronic restraint stress (CRS) rat model of depression, in which rats display depression-like behaviors such as anhedonia and mood despair. Moreover, knockdown of CHAT in the rat habenula was sufficient to evoke anhedonia-like behavior. The anhedonia-like behavior induced by CHAT knockdown was not reversed by chronic administration of the selective serotonin reuptake inhibitor fluoxetine. To determine whether habenular cholinergic signaling is associated with regulation of dopamine neurons in the ventral tegmental area (VTA) and serotonin neurons in the dorsal raphe nucleus (DRN), we used CHAT::cre transgenic mice expressing the Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Pharmacogenetic activation of habenular cholinergic neurons induces the excitation of dopamine neurons in the VTA and reduces the immunoreactivity of 5-hydroxytryptamine (5-HT) in the DRN. Habenular cholinergic gene down-regulation was recapitulated in the postmortem habenula of suicide victims diagnosed with major depressive disorder (MDD).

Effect of Physical Exercise and Acute Escitalopram on the Excitability of Brain Monoamine Neurons: In Vivo Electrophysiological Study in Rats.

BackgroundThe antidepressant effect of physical exercise has been reported in several clinical and animal studies. Since serotonin, norepinephrine, and dopamine play a central role in depression, it is possible that the beneficial effects of physical exercise are mediated via monoamine pathways. This study investigates the effects of voluntary wheel running on the excitability of monoamine neurons.Materials and MethodsMale Sprague-Dawley rats were used in the study. Voluntary wheel running (VWR) rats were housed in individual cages with free access to a running wheel, while control animals were housed in standard laboratory cages. After three weeks, the rats were anesthetized, and in vivo electrophysiological recordings were taken from dorsal raphe nucleus serotonin neurons, locus coeruleus norepinephrine neurons, and ventral tegmental dopamine neurons.ResultsVWR stimulated activity in serotonin, but not in norepinephrine or dopamine neurons. Subsequently, acute administration of the selective serotonin reuptake inhibitor escitalopram in control rats led to complete suppression of serotonin neurons; this suppression was reversed by subsequent administration of selective antagonist of serotonin-1A receptors, WAY100135. Escitalopram induced only partial inhibition of serotonin neurons in the VWR rats while WAY100135 increased the firing activity of serotonin neurons above the baseline value.ConclusionsThe beneficial effect of physical exercise on mood is mediated, at least in part, via activation of serotonin neurons. Physical exercise can potentiate the response to selective serotonin reuptake inhibitors by increasing the basal firing activity and diminishing selective serotonin reuptake inhibitor-induced inhibition of serotonin neurons.

Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

Tryptase potentiates enteric nerve activation by histamine and serotonin: Relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients.

We previously showed that mucosal biopsy supernatants from irritable bowel syndrome patients activated neurons despite low concentrations of tryptase, histamine, and serotonin which individually would not cause spike discharge. We studied the potentiating responses between these mediators on excitability of enteric neurons. Calcium-imaging was performed using the calcium-sensitive dye Fluo-4 AM in human submucous plexus preparations from 45 individuals. Histamine, serotonin, and tryptase were applied alone and in combinations to evaluate nerve activation which was assessed by analyzing increase in intracellular Ca2+ ([Ca2+ ]i ), the proportion of responding neurons and the product of both defined as Ca-neuroindex (NI). Protease activated receptor (PAR) 2 activating peptide, PAR2 antagonist and the serine protease-inhibitor FUT-175 were used to particularly investigate the role of proteases. Histamine or serotonin (1μmol/L each) evoked only few small responses (median NI [25%/75%]: 0 [0/148]; 85 [0/705] respectively). Their combined application evoked statistically similar responses (216 [21/651]). Addition of the PAR2 activator tryptase induced a significantly higher Ca-NI (1401 [867/4075]) compared to individual application of tryptase or to coapplied histamine and serotonin. This synergistic potentiation was neither mimicked by PAR2 activating peptide nor reversed by the PAR2 antagonist GB83, but abolished by FUT-175. We observed synergistic potentiation between histamine, serotonin, and tryptase in enteric neurons, which is mediated by proteolytic activity rather than PAR2 activation. This explained neuronal activation by a cocktail of these mediators despite their low concentrations and despite a relatively small PAR2-mediated response in human submucous neurons.

Joint symposium: How long do we have to wait for the antidepressant effect? Mechanisms of action for delay of onset response to antidepressants

Major depressive disorder (MDD) is a severe psychiatric syndrome with very high prevalence and socioeconomic impact. Monoamine-based antidepressant drugs (AD) display slow onset of action and limited efficacy. Preclinical studies show that ADs trigger a series of slow adaptive mechanisms that limit the clinical response. These mechanisms result from the pharmacological blockade of monoamine transporters (SERT, NET) and involve presynaptic, such as autoreceptor desensitization (e.g., 5-HT1A and 5-HT1B for serotonin neurons) as well as postsynaptic mechanisms, such as increased neurogenesis and expression of trophic factors, increased dendritic complexity, etc.Given the strong homeostasis of serotonin and noradrenaline neurons, a way to improve antidepressant action is to prevent self-inhibitory presynaptic mechanisms mediated by auto- and heteroreceptors after reuptake blockade. This strategy was used in the past with the non-selective 5-HT1A antagonist pindolol and has been incorporated by two recently developed AD (vilazodone and vortioxetine). Likewise, new molecular strategies using RNA interference (RNAi) show that the modulation of gene expression in serotonin neurons offers a great potential. Hence, local or intrnasal administration of small interfering RNA (siRNA) molecules targeting SERT or 5-HT1A autoreceptors evokes rapid and robust antidepressant-like effects in rodents.Moreover, glutamatergic drugs such as the non-competitive NMDA receptor antagonist ketmaine, offer a potential for the development of fast-acting AD due to its rapid and persistent antidepressant effects in treatment-resistant unipolar and bipolar patients after single i.v. infusion, an effect that likely involves the activation of AMPA receptors in ventral areas of the cingulate gyrus and the subsequent fast activation of serotonergic function.Disclosure of interestF.A. has received consulting honoraria on antidepressant drugs from Lundbeck and he has been PI of grants from Lundbeck. He is also co-author of the patent WO/2011/131693 for the siRNA and ASO (antisense oligonucleotides) molecules.

Impact of Gestational Chronic Intermittent Hypoxia and Hypertension on the Serotonergic System and Autoresuscitation in the Developmental Rat

Sudden infant death syndrome (SIDS) is characterized by the sudden death of a seemingly healthy infant during a sleep period under the age of 12 months. Abnormalities in the medullary serotonin (5HT) system, e.g. decreased tissue levels of 5HT and 5HTT, and increased immature 5HT neurons, have been identified in approximately 70% of infants that died of SIDS. Failed autoresuscitation (inability to recover breathing and heart rate following hypoxic apnea) is considered a possible mechanism of SIDS deaths, and animal studies have shown that 5HT neurons are critical for neonatal mice and rats to survive repeated episodes of severe hypoxia/asphyxia. Gestational chronic intermittent hypoxia (CIH) and preeclampsia both are risk factors for SIDS. In this study we asked whether the stressors, e.g. gestational/prenatal chronic intermittent hypoxia (CIH) and/or hypertension, would increase stress hormone levels, impair the maturity and integrity of medullary 5HT neurons and the ability to autoresuscitate from repetitive asphyxia in developing rat pups. The pregnant dams of normotensive Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR) were exposed to CIH or room air (RA) from gestation E4‐21, and then the serum corticosterone level (ELISA), the number and integrity of the medullary serotonin neurons (immunostainings), and in vivo autoresuscitation were assessed in the offspring pups at Postnatal (P) days 5–15.We found 1) SHR‐CIH pups have significantly higher serum corticosterone levels than SHR‐RA and SD‐RA pups at P7 (11,485 vs. 8078 & 8970 pg/mL respectively, P<0.05) and P10 (11,708 vs. 9040 & 6,529 pg/mL respectively, P<0.05). At P15 SD‐CIH, SHR‐CIH and SHR‐RA pups all have significantly higher corticosterone levels than SD‐RA pups; 2) Relative to the SD‐RA pups, SD‐CIH pups have a significantly higher total number of 5HT neurons and primarily due to increased number of Ki67/5HT‐ir positive neurons in the medulla. When compared to SD rats, we noticed that SHR pups appear to have more Ki67/5HT‐ir neurons which contribute to an increase in total number of 5HT neurons in the medulla than SD‐CIH & SD‐RA (P<0.01); and 3) the offspring pups of SHRs have the highest mortality rate during repetitive exposure of anoxia at all ages tested. Our data suggest that both gestational CIH and uncontrolled hypertension may lead to an impaired 5HT system in the offspring pups. The uncontrolled high blood pressure during pregnancy may cause placental insufficiency and contribute to failed autoresuscitation in response to repetitive anoxia in early postnatal life.Support or Funding InformationDartmouth UGAR, NIH HD036379, NIH HL28066

The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning.

The CCK(1) receptor is a G-protein-coupled receptor activated by the sulfated forms of cholecystokinin (CCK), a gastrin-like peptide released in the gastrointestinal tract and mammal brain. A substantial body of research supports the hypothesis that CCK(1)r stimulates gallbladder contraction and pancreatic secretion in the gut, as well as satiety in brain. However, this receptor may also fulfill relevant roles in behavior, thanks to its widespread distribution in the brain. The strategic location of CCK(1)r in mesolimbic structures and specific hypothalamic and brainstem nuclei lead to complex interactions with neurotransmitters like dopamine, serotonin, and glutamate, as well as hypothalamic hormones and neuropeptides. The activity of CCK(1)r maintains adequate levels of dopamine and regulates the activity of serotonin neurons of raphe nuclei, which makes CCK(1)r an interesting therapeutic target for the development of adjuvant treatments for schizophrenia, drug addiction, and mood disorders. Unexplored functions of CCK(1)r, like the transmission of interoceptive sensitivity in addition to the regulation of hypothalamic hormones and neurotransmitters affecting emotional states, well-being, and attachment behaviors, may open exciting roads of research. The absence of specific ligands for the CCK(1) receptor has complicated the study of its distribution in brain so that research about its impact on behavior has been published sporadically over the last 30 years. The present review reunites all this body of evidence in a comprehensive way to summarize our knowledge about the actual role of CCK in the neurobiology of mental illness.

Activity patterns of serotonin neurons underlying cognitive flexibility.

Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine-serotonin opponency with potential clinical implications.

Oral 5-Hydroxytryptophan (5-HTP) Does not Affect Grooved Pegboard Test Performance

Abstract: There is limited knowledge of the neurocognitive effects of the serotonin precursor 5-hydroxytryptophan (5-HTP), which is sold over-the-counter as a nutritional supplement. Animal studies have demonstrated that exogenous 5-HTP promotes the production of ectopic serotonin in dopaminergic neurons—an effect that may reduce dopamine output in these cells. Behavioral studies in humans have demonstrated specific 5-HTP induced cognitive deficits on the Iowa Gambling Task and the Tower of London task that are likely the result of reduced forebrain dopamine. However, it remains unclear if 5-HTP induced performance decrements observed on the Tower of London task were the result of a motor or cognitive impairment. The objective of this double-blind, placebo-controlled study was to clarify this point by determining if oral administration of 150 mg of 5-HTP disrupts fine motor control, as measured by the Grooved Pegboard Test. Seventy five university undergraduates received either a placebo or 5-HTP and completed the Grooved Pegboard Test. The groups did not differ in the amount of time needed to complete the place (p = 0.67) and remove (p = 0.48) components of the Grooved Pegboard Test. Therefore, 5-HTP induced reductions in performance on the Tower of London task appear to be cognitive in nature, and are unlikely to be the result of fine motor impairment (as measured by the Grooved Pegboard Test). These results also provide important safety information for 5-HTP by demonstrating that a 150 mg oral dose does not generally alter fine motor function.

Identifying Candidate Genes that Underlie Cellular pH Sensitivity in Serotonin Neurons Using Transcriptomics: A Potential Role for Kir5.1 Channels.

Ventilation is continuously adjusted by a neural network to maintain blood gases and pH. Acute CO2 and/or pH regulation requires neural feedback from brainstem cells that encode CO2/pH to modulate ventilation, including but not limited to brainstem serotonin (5-HT) neurons. Brainstem 5-HT neurons modulate ventilation and are stimulated by hypercapnic acidosis, the sensitivity of which increases with increasing postnatal age. The proper function of brainstem 5-HT neurons, particularly during post-natal development is critical given that multiple abnormalities in the 5-HT system have been identified in victims of Sudden Infant Death Syndrome. Here, we tested the hypothesis that there are age-dependent increases in expression of pH-sensitive ion channels in brainstem 5-HT neurons, which may underlie their cellular CO2/pH sensitivity. Midline raphe neurons were acutely dissociated from neonatal and mature transgenic SSePet-eGFP rats [which have enhanced green fluorescent protein (eGFP) expression in all 5-HT neurons] and sorted with fluorescence-activated cell sorting (FACS) into 5-HT-enriched and non-5-HT cell pools for subsequent RNA extraction, cDNA library preparation and RNA sequencing. Overlapping differential expression analyses pointed to age-dependent shifts in multiple ion channels, including but not limited to the pH-sensitive potassium ion (K+) channel genes kcnj10 (Kir4.1), kcnj16 (Kir5.1), kcnk1 (TWIK-1), kcnk3 (TASK-1) and kcnk9 (TASK-3). Intracellular contents isolated from single adult eGFP+ 5-HT neurons confirmed gene expression of Kir4.1, Kir5.1 and other K+ channels, but also showed heterogeneity in the expression of multiple genes. 5-HT neuron-enriched cell pools from selected post-natal ages showed increases in Kir4.1, Kir5.1, and TWIK-1, fitting with age-dependent increases in Kir4.1 and Kir5.1 protein expression in raphe tissue samples. Immunofluorescence imaging confirmed Kir5.1 protein was co-localized to brainstem neurons and glia including 5-HT neurons as expected. However, Kir4.1 protein expression was restricted to glia, suggesting that it may not contribute to 5-HT neuron pH sensitivity. Although there are caveats to this approach, the data suggest that pH-sensitive Kir5.1 channels may underlie cellular CO2/pH chemosensitivity in brainstem 5-HT neurons.

A translational approach to clinical practice via stress-responsive glucocorticoid receptor signaling.

A recent article by Kwan and colleagues could elegantly demonstrate the necessary interaction between neuronal serotonin (5-HT) systems and the hypothalamic-pituitary-adrenal (HPA) axis through glucocorticoid receptors (GR), producing an adequate stress response, in this case, responding to hypoxia with an increase in hematopoietic stem and progenitor cells (HSPC). There is an intricate system connecting brain, body and mind and this exchange is only possible when all these systems-nervous, endocrine, and immune-have receptors on critical cells to receive information (via messenger molecules) from each of the other systems. There is evidence that the expression and function of GR in the hippocampus, mainly MR, is regulated by the stimulation of 5-HT receptors. Stressful stimuli increase 5-HT release and turnover in the hippocampus, and it seems reasonable to suggest that some of the changes in mineralocorticoid and GR expression may be mediated, in part at least, by the increase in 5-HT. Also serotonin and HPA axis dysfunctions have already been implicated in a variety of psychiatric disorders, especially depression. Early life stress (ELS) can have profound impact on these systems and can predispose subjects to a variety of adult metabolic and psychiatric conditions. It is important to analyze the mechanisms of this complex interaction and its subsequent programming effects on the stress systems, so that we can find new ways and targets for treatment of psychiatric disorders. Different areas of research on basic biological sciences are now being integrated and this approach will hopefully provide several new insights, new pharmacological targets and improve our global understanding of these highly debilitating chronic conditions, that we now call mental disorders.

The roles of the orbitofrontal cortex via the habenula in non-reward and depression, and in the responses of serotonin and dopamine neurons

Cortical regions such as the orbitofrontal cortex involved in reward and in non-reward and which are implicated in depression, and the amygdala, are connected to the habenula via the striatum and pallidum, and via subcortical limbic structures. The habenula in turn projects to the raphe nuclei, the source of the serotonin-containing neurons that project to the forebrain. It is proposed that this provides a route for cortical signals related to reward, and to not obtaining expected rewards, to influence the serotonin-containing neuronal system that is influenced by many antidepressant treatments. This helps to provide a more circuit-based understanding of the brain mechanisms related to depression, and how some treatments influence this system. The habenula also projects via the rostromedial tegmental nucleus to the dopamine-containing neurons, and this, it is proposed, provides a route for reward prediction error signals and other reward- and punishment-related signals of cortical and striatal origin to influence the dopamine system.

Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons.

Serotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions.

Slow motion.

Optogenetic stimulation of serotonin neurons in the dorsal raphe causes mice to move more slowly without causing any apparent motor deficits or anxiety-like effects.