Serotonin Neurons Research Articles

Estrogen and Serotonin: Complexity of Interactions and Implications for Epileptic Seizures and Epileptogenesis.

A burgeoning literature documents the confluence of ovarian steroids and central serotonergic systems in the in-junction of epileptic seizures and epileptogenesis. Estrogen administration in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e. Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform activity in either direction i.e administration of 5-HT agonists or reuptake inhibitors leads to the acti-vation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal excitability hence abatement of seizure threshold in experimental animal models. Serotonergic neurotransmission is influenced by the organizational activity of ster-oid hormones in the growing brain and the actuation effects of steroids which come in adulthood. It is further established that ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a profound effect on sero-tonergic transmission. This review features 5-HT1A and 5-HT3 receptors as potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous neuronal activity. Indeed 5-HT3 receptors mediate cross-talk be-tween estrogenic and serotonergic pathways, and could be well exploited for combinatorial drug therapy against epileptogen-esis.

Abstract # 2043 Contributions of inflammatory cytokine signaling to the enduring effects of early-life stress: A serotonin connection?

Early-life stress (ELS) increases risk for neurobehavioral disorders including addiction, anxiety and depression. We showed that i.p. lipopolysaccharide or poly I:C can elicit rapid changes in the activity of CNS serotonin transporters (SERTs), as well as anxiety and despair-like behavor, effects that are lost in IL-1 receptor knockout mice. These effects were absent in mice with serotonin-neuron specific elimination of p38alpha MAP kinase, a major signaling mechanism for IL-1 receptors. To determine whether IL-1 receptor signaling supports enduring changes in serotonin neuron function and behavior, we adopted a maternal separation paradigm as a rodent model of ELS. We separated C57BL/6J mouse pups from dams for 3 h once a day for two weeks from PND 1-14, a developmental window where manipulation of serotonin signaling produces adult anxiety and despair-like behaviors. We found that MS leads to both early and persistent elevations in brain and spleen inflammatory cytokines, including IL-1beta, as well as adult increases in anxiety and despair-like behavior. Remarkably, adult IL-1R KO mice demonstrated resilience to the behavioral effects of MS. Inflammatory cytokines, SERT activity and serotonin turnover, were altered in juvenile mice sacrificed immediately after MS, effects absent in IL-1R KO mice. These findings suggest that ELS may induce IL-R mediated alterations in serotonergic signaling that can trigger enduring effects in behavior, an hypothesis currently being explored in conditional IL-1 receptor deficient mice.

Flipping behavior under threat

Neuroscience Could it be that the brain in a state of emergency or under intense threat operates in a fundamentally different way? Seo et al. found that mice paused when serotonin neurons were transiently stimulated in low- or medium-threat environments, but when this same neural population was stimulated in high-threat environments, mice tried to escape. Recordings from these neurons indicated that movement-related neural tuning flipped between environments. Neural activity decreased when movement was initiated in low-threat environments but increased in high-threat environments. Science , this issue p. [538][1] [1]: /lookup/doi/10.1126/science.aau8722

Intense threat switches dorsal raphe serotonin neurons to a paradoxical operational mode.

Survival depends on the selection of behaviors adaptive for the current environment. For example, a mouse should run from a rapidly looming hawk but should freeze if the hawk is coasting across the sky. Although serotonin has been implicated in adaptive behavior, environmental regulation of its functional role remains poorly understood. In mice, we found that stimulation of dorsal raphe serotonin neurons suppressed movement in low- and moderate-threat environments but induced escape behavior in high-threat environments, and that movement-related dorsal raphe serotonin neural dynamics inverted in high-threat environments. Stimulation of dorsal rapheγ-aminobutyric acid (GABA) neurons promoted movement in negative but not positive environments, and movement-related GABA neural dynamics inverted between positive and negative environments. Thus, dorsal raphe circuits switch between distinct operational modes to promote environment-specific adaptive behaviors.

Physiological dosages of estradiol and diarylpropionitrile decrease depressive behavior and increase tryptophan hydroxylase expression in the dorsal raphe nucleus of rats subjected to the forced swim test.

The dorsal raphe nucleus (DR) is a crucial source of serotonin (5-HT) neurons involved in the regulation of stress-induced depression. Estrogen receptors have been identified in the DR, yet the role of estrogen in modulating this adaptive response is incompletely understood. The current study investigated the effects of different dosages of estradiol (E2, 10 and 50 μg/rat/day for 11 consecutive days) and selective estrogen receptor modulators: Diarylpropionitrile (DPN, 10 μg/rat/day for 11 consecutive days) and propyl pyrazole triol (PPT, 10 μg/rat/day for 11 consecutive days) on behavior and the expression of tryptophan hydroxylase (TPH) and glucocorticoid receptor in the DR of ovariectomized rats subjected to the forced swim test (FST). 10 μg E2 and DPN, an estrogen receptor β agonist, increased swimming and decreased immobility in the FST, while 50 μg E2 and PPT, an estrogen receptor α agonist, failed to influence the behavior of the rats in the FST. Similarly, 10 μg E2 and DPN increased TPH protein expression in the DR, while 50 μg E2 and PPT did not. Both 10 μg E2 and 50 μg E2 increased glucocorticoid receptor protein expression in the DR. Interestingly, 50 μg E2 led to a greater increase in plasma corticosterone levels compared with 10 μg E2. These observations suggest that a physiological dosage of E2 reduces depressive behavior and enhances TPH expression. High dosage of E2 lacks antidepressant activity in part due to heightened effects on corticosterone levels, which may conversely decrease TPH expression in the DR.

Effects of Caffeine on the Organism—Literature Review

Caffeine is the most widely consumed stimulant. Caffeine is known to in-crease energetic metabolism throughout the brain, but it also decreases cerebral blood flow, inducing relative cerebral hypoperfusion. Caffeine ac-tivates norepinephrine neurons and appears to affect the local release of dopamine. Many of the warning effects of caffeine may be related to the action of methylxanthine on serotonin neurons. In this sense, this study aimed to identify the main effects of caffeine on the body. This is a literature review study addressing the main effects of caffeine on the body. In order to select the studies, an online survey of articles has been conducted on sites such as the Scientific Electronic Library Online (SciELO), Medical Literature Analysis and Retrieval System Online (MEDLINE) and Latin American and Caribbean Literature in Health Sciences (LILACS), using the descriptors “caffeine”, “effects of caffeine” and “methylxanthine”. We included the studies published between the years 2000 to 2018, which explicitly contemplate the evaluated aspects. In general, caffeine has effects on anxiety and sleep that vary according to individual sensitivity to methylxanthine. The central nervous system does not appear to develop a great tolerance to the effects of caffeine, although the symptoms of dependence and withdrawal are reported.

Dorsal Raphe Dual Serotonin-Glutamate Neurons Drive Reward by Establishing Excitatory Synapses on VTA Mesoaccumbens Dopamine Neurons

SUMMARYDorsal raphe (DR) serotonin neurons provide a major input to the ventral tegmental area (VTA). Here, we show that DR serotonin transporter (SERT) neurons establish both asymmetric and symmetric synapses on VTA dopamine neurons, but most of these synapses are asymmetric. Moreover, the DR-SERT terminals making asymmetric synapses on VTA dopamine neurons coexpress vesicular glutamate transporter 3 (VGluT3; transporter for accumulation of glutamate for its synaptic release), suggesting the excitatory nature of these synapses. VTA photoactivation of DR-SERT fibers promotes conditioned place preference, elicits excitatory currents on mesoaccumbens dopamine neurons, increases their firing, and evokes dopamine release in nucleus accumbens. These effects are blocked by VTA inactivation of glutamate and serotonin receptors, supporting the idea of glutamate release in VTA from dual DR SERT-VGluT3 inputs. Our findings suggest a path-specific input from DR serotonergic neurons to VTA that promotes reward by the release of glutamate and activation of mesoaccumbens dopamine neurons.

Serotonin2B receptors exert a GABA-mediated inhibitory control on dorsal raphe nucleus serotonin neuron activity: a microdialysis study in the rat

Serotonin2B receptors exert a GABA-mediated inhibitory control on dorsal raphe nucleus serotonin neuron activity: a microdialysis study in the rat

Somato-Dendritic Regulation of Raphe Serotonin Neurons; A Key to Antidepressant Action.

Several lines of evidence implicate serotonin (5-hydroxytryptamine, 5-HT)in regulating personality traits and mood control. Serotonergic neurons are classically thought to be tonic regular-firing, “clock-like” neurons. Neurotransmission by serotonin is tightly regulated by the serotonin transporter (SERT) and by autoreceptors (serotonin receptors expressed by serotonin neurons) through negative feedback inhibition at the cell bodies and dendrites (5-HT1A receptors) of the dorsal raphe nuclei or at the axon terminals (5-HT1B receptors). In dorsal raphe neurons, the release of serotonin from vesicles in the soma, dendrites, and/or axonal varicosities is independent of classical synapses and can be induced by neuron depolarization, by the stimulation of L-type calcium channels, by activation of glutamatergic receptors, and/or by activation of 5-HT2 receptors. The resulting serotonin release displays a slow kinetic and a large diffusion. This process called volume transmission may ultimately affect the rate of discharge of serotonergic neurons, and their tonic activity. The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking SERT but rely on consequences of chronic exposure, i.e., a selective desensitization of somatodendritic 5-HT1A autoreceptors. Agonist stimulation of 5-HT2B receptors mimicked behavioral and neurogenic SSRI actions, and increased extracellular serotonin in dorsal raphe. By contrast, a lack of effects of SSRIs was observed in the absence of 5-HT2B receptors (knockout-KO), even restricted to serotonergic neurons (Htr2b5-HTKO mice). The absence of 5-HT2B receptors in serotonergic neurons is associated with a higher 5-HT1A-autoreceptor reactivity and thus a lower firing activity of these neurons. In agreement, mice with overexpression of 5-HT1A autoreceptor show decreased neuronal activity and increased depression-like behavior that is resistant to SSRI treatment. We propose thus that the serotonergic tone results from the opposite control exerted by somatodendritic (Gi-coupled) 5-HT1A and (Gq-coupled) 5-HT2B receptors on dorsal raphe neurons. Therefore, 5-HT2B receptors may contribute to SSRI therapeutic effects by their positive regulation of adult raphe serotonergic neurons. Deciphering the molecular mechanism controlling extrasynaptic release of serotonin, and how autoreceptors interact in regulating the tonic activity of serotonergic neurons, is critical to fully understand the therapeutic effect of SSRIs.

5-Hydroxytryptamine and Dopamine Neurons in the Cerebellum of the New-Hatching Yangtze Alligator Alligator sinensis.

Nissl and immunohistochemical staining methods were used to morphologically characterize the cerebellum of the new-hatching Yangtze alligator, and the cerebellar histological structure and the distribution profiles of 5-hydroxytryptamine (5-HT) and dopamine (DA) neurons were investigated for the first time. The results of cerebellar histological structure showed that there was a ventriculus cerebelli in the cerebellum of the new-hatching Yangtze alligator, the surface of the cerebellar cortex was not very smooth, the cerebellar cortex could be divided into four layers, which include external granular layer, molecular layer, Purkinje cell layer and granular layer, Purkinje cell layer could be characterized specially by multilayer, two cerebellar nuclei termed as the nucleus cerebelli lateralis and the nucleus cerebelli medialis were found in the cerebellar medulla. 5-hydroxytryptamine-immunoreactive (5-HT-IR) and dopamine-immunoreactive (DA-IR) neurons and fibers distributed widely in the cerebellum. The structures and profiles of 5-HT-IR and DA-IR neurons and fibers in the cerebellum of the Yangtze alligator were similar to that reported in other reptiles, but also had some specific features. The abundance of 5-HT and DA in cerebellum suggested that these highly conserved neurotransmitters would play important roles in motor control. Anat Rec, 302:861-868, 2019. © 2018 Wiley Periodicals, Inc.

Response dynamics of midbrain dopamine neurons and serotonin neurons to heroin, nicotine, cocaine, and MDMA

Heroin, nicotine, cocaine, and MDMA are abused by billions of people. They are believed to target midbrain dopamine neurons and/or serotonin neurons, but their effects on the dynamic neuronal activity remain unclear in behaving states. By combining cell-type-specific fiber photometry of Ca2+ signals and intravenous drug infusion, here we show that these four drugs of abuse profoundly modulate the activity of mouse midbrain dopamine neurons and serotonin neurons with distinct potency and kinetics. Heroin strongly activates dopamine neurons, and only excites serotonin neurons at higher doses. Nicotine activates dopamine neurons in merely a few seconds, but produces minimal effects on serotonin neurons. Cocaine and MDMA cause long-lasting suppression of both dopamine neurons and serotonin neurons, although MDMA inhibits serotonin neurons more profoundly. Moreover, these inhibitory effects are mediated through the activity of dopamine and serotonin autoreceptors. These results suggest that the activity of dopamine neurons and that of serotonin neurons are more closely associated with the drug's reinforcing property and the drug's euphorigenic property, respectively. This study also shows that our methodology may facilitate further in-vivo interrogation of neural dynamics using animal models of drug addiction.

Serotonin Subsystems Modulate Diverse and Opposite Behavioral Functions.

Pioneering work showed that serotonin (5-HT) neurons have the unique capacity to engage in different and opposed aspects of motivated behaviors such as reward and punishment responses. These findings provided strong evidence about the functional heterogeneity of 5-HT neurons, and their possible engagement in multiple and behaviorally distinct neural subsystems. A recent study provides further compelling evidence supporting this notion, in which two ascending 5-HT circuits modulate opposed aspects of motivated behaviors.

Chronic methylphenidate treatment during adolescence has long-term effects on monoaminergic function.

Psychostimulants like methylphenidate or D-amphetamine are often prescribed for attention deficit and hyperactivity disorders in children. Whether such drugs can be administered into a developing brain without consequences in adulthood is still an open question. Here, using in vivo extracellular electrophysiology in anesthetised preparations, combined with behavioural assays, we have examined the long-term consequences in adulthood of a chronic methylphenidate oral administration (5 mg/kg/day, 15 days) in early adolescent (post-natal day 28) and late adolescent (post-natal day 42) rats, by evaluating body weight change, sucrose preference (indicator of anhedonia), locomotor sensitivity to D-amphetamine and electrical activities of ventral tegmental area dopamine and dorsal raphe nucleus serotonin neurons. Chronic methylphenidate treatment during early or late adolescence did not induce weight deficiencies and anhedonia-like behaviours at adulthood. However, it increased bursting activities of dorsal raphe nucleus serotonin neurons. Furthermore, chronic methylphenidate treatment during early but not during late adolescence enhanced D-amphetamine-induced rearing activity, as well as ventral tegmental area dopamine cell excitability (firing, burst and population activity), associated with a partial desensitisation of dopamine D2 auto-receptors. We have demonstrated here that early, but not late, adolescent exposure to oral methylphenidate may induce long-lasting effects on monoamine neurotransmission. The possible clinical implication of these data will be discussed.

SSRIs target prefrontal to\xa0raphe circuits during development modulating synaptic connectivity and emotional behavior

Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0–P10), Slc6a4/SERT is transiently expressed in a subset of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.

Monoamines in the enteric nervous system

Recent advances in neurogastroenterology have extended and refined our knowledge on the roles monoamines play in physiology and pathophysiology of the gastrointestinal tract. The catecholamine noradrenaline, as the primary transmitter of postganglionic sympathetic neurons, orchestrates motility and secretory reflexes and controls arterial perfusion as well as immune functions. The catecholamine dopamine is produced by a subpopulation of enteric neurons which possibly use it as transmitter. Serotonin, largely produced by enterochromaffin cells and to a small extent by enteric neurons profoundly affects gut motility, enteric neuron development and is also involved in immunomodulation. However, its mode of action and the relative contribution of non-neuronal versus neuronal serotonin was recently subject to debate again. Histamine, although entirely of non-neuronal origin, is pivotal for gastrointestinal neuroimmunomodulation besides its paracrine effect in gastric HCl production.

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

The central serotonin2B receptor (5-HT2BR) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT2BR antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 μM) administration of the selective 5-HT2BR antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABAA antagonist bicuculline (100 μM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 μM) administration of the selective 5-HT1AR antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 μM) was potentiated by the intra-DRN administration (0.5 μM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT2BR mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT2BRs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC.

5-HT2A Receptor Agonist-Induced Hyperthermia Is Induced via Vasoconstriction by Peripheral 5-HT2A Receptors and Brown Adipose Tissue Thermogenesis by Peripheral Serotonin Loss at a High Ambient Temperature.

Recreational drugs such as 3,4-methylenedioxymethamphetamine and cocaine induce hyperthermia, which is affected by ambient temperature. 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe), a selective agonist of 5-HT2A receptor used as a recreational drug, reportedly induces hyperthermia. This study aimed to verify whether 25B-NBOMe induces ambient temperature-dependent hyperthermia and to clarify its mechanism. Eight-week-old male Sprague-Dawley rats were administered intraperitoneal injection of 25B-NBOMe at an ambient temperature of 23°C or 29°C. 25B-NBOMe administration at 23°C did not change the core body temperature of the rats, whereas administration at 29°C induced significant hyperthermia 30-120 minutes postadministration. Tail surface temperature temporarily decreased 30 minutes postadministration, indicating heat storage by peripheral vasoconstriction despite a high ambient temperature. Because 25B-NBOMe-induced-hyperthermia was suppressed by sarpogrelate, but not by destruction of central noradrenaline or serotonin neurons, peripheral 5-HT2A receptors were considered contributors to the development of hyperthermia at a high ambient temperature, independently from central neurons. The temperature of brown adipose tissue (BAT) increased 60-120 minutes postadministration of 25B-NBOMe at 29°C, indicating thermogenesis. Previous studies have reported that peripheral serotonin contributes to the inhibition of BAT thermogenesis. Decreased plasma serotonin levels were observed at 29°C, and serotonin administration partially suppressed 25B-NBOMe-induced hyperthermia at a high ambient temperature, suggesting that decreased levels of peripheral serotonin induced BAT thermogenesis. Our findings indicate that 25B-NBOMe induces hyperthermia at a high ambient temperature via vasoconstriction regulated by 5-HT2A receptors and BAT thermogenesis mediated by decreased levels of plasma serotonin. Thus, peripheral serotonin plays a partial but important role in thermoregulation.

Cav1.2 L-type calcium channels regulate stress coping behavior via serotonin neurons

Human genetic variation in the gene CACNA1C, which codes for the alpha-1c subunit of Cav1.2 L-type calcium channels (LTCCs), has been broadly associated with enhanced risk for neuropsychiatric disorders including major depression, bipolar and schizophrenia. Little is known about the specific neural circuits through which CACNA1C and Cav1.2 LTCCs impact disease etiology. However, serotonin (5-HT) neurotransmission has been consistently implicated in these neuropsychiatric disorders and Cav1.2 LTCCs may influence 5-HT neuron activity during relevant behavioral states such as stress. We utilized a temporally controlled and 5-HT neuron specific Cacna1c knockout mouse model to assess stress-coping behavior using the forced swim test and dorsal raphe (DR) 5-HT neuron Fos activation. Furthermore, we assessed 5-HT1A receptor function and feedback inhibition of the DR following administration of the 5-HT1A antagonist WAY-100635. We find that 5-HT neuron Cacna1c knockout disrupts active-coping behavior in the forced swim test and that this behavioral effect is rescued by blocking 5-HT1A receptors. Moreover, Cacna1c knockout mice display enhanced Fos expression in caudal DR 5-HT neurons and an enhanced response to a 5-HT1A receptor antagonist in rostral DR 5-HT neurons, indicating that loss of Cacna1c disrupts both 5-HT neuron activation and 5-HT1A dependent feedback inhibition across the caudal to rostral DR. Collectively, these results reveal an important role for 5-HT neuron Cav1.2 LTCCs in stress-coping behavior and 5-HT1A receptor function. This suggests that alterations in CACNA1C function or expression could influence the development or treatment of neuropsychiatric disorder through serotonergic mechanisms.

Evidence for intact 5-HT1A receptor-mediated feedback inhibition following sustained antidepressant treatment in a rat model of depression

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress.

Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ ininput and output connectivity, physiological response properties, and behavioral functions.