Impairments in laterodorsal tegmentum to VTA projections underlie glucocorticoid-triggered reward deficits.

Ventral tegmental area (VTA) activity is critical for reward/reinforcement and is tightly modulated by the laterodorsal tegmentum (LDT). In utero exposure to glucocorticoids (iuGC) triggers prominent motivation deficits but nothing is known about the impact of this exposure in the LDT-VTA circuit. We show that iuGC-rats have long-lasting changes in cholinergic markers in the LDT, together with a decrease in LDT basal neuronal activity. Interestingly, upon LDT stimulation, iuGC animals present a decrease in the magnitude of excitation and an increase in VTA inhibition, as a result of a shift in the type of cells that respond to the stimulus. In agreement with LDT-VTA dysfunction, we show that iuGC animals present motivational deficits that are rescued by selective optogenetic activation of this pathway. Importantly, we also show that LDT-VTA optogenetic stimulation is reinforcing, and that iuGC animals are more susceptible to the reinforcing properties of LDT-VTA stimulation.

Serotonergic Projections Govern Postnatal Neuroblast Migration.

In many vertebrates, postnatally generated neurons often migrate long distances to reach their final destination, where they help shape local circuit activity. Concerted action of extrinsic stimuli is required to regulate long-distance migration. Some migratory principles are evolutionarily conserved, whereas others are species and cell type specific. Here we identified a serotonergic mechanism that governs migration of postnatally generated neurons in the mouse brain. Serotonergic axons originating from the raphe nuclei exhibit a conspicuous alignment with subventricular zone-derived neuroblasts. Optogenetic axonal activation provides functional evidence for serotonergic modulation of neuroblast migration. Furthermore, we show that the underlying mechanism involves serotonin receptor 3A (5HT3A)-mediated calcium influx. Thus, 5HT3A receptor deletion in neuroblasts impaired speed and directionality of migration and abolished calcium spikes. We speculate that serotonergic modulation of postnatally generated neuroblast migration is evolutionarily conserved as indicated by the presence of serotonergic axons in migratory paths in other vertebrates.

Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance.

Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health-promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce learned helplessness behaviours such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioural and biological responses to stress later in life. Juvenile, male F344 rats were fed diets containing either GOS and PDX alone, LAC alone, or GOS, PDX and LAC. All diets altered gut bacteria, while diets containing GOS and PDX increased Lactobacillus spp. After 4 weeks, rats were exposed to inescapable stress, and either immediately killed for blood and tissues, or assessed for learned helplessness 24 h later. Diets did not attenuate stress effects on spleen weight, corticosterone and blood glucose; however, all diets differentially attenuated stress-induced learned helplessness. Notably, in situ hybridization revealed that all diets reduced stress-evoked cfos mRNA in the dorsal raphe nucleus (DRN), a structure important for learned helplessness behaviours. In addition, GOS, PDX and LAC diet attenuated stress-evoked decreases in mRNA for the 5-HT1A autoreceptor in the DRN and increased basal BDNF mRNA within the prefrontal cortex. These data suggest early life diets containing prebiotics and/or LAC promote behavioural stress resistance and uniquely modulate gene expression in corresponding circuits.

Effects of perinatal protein malnutrition and fenfluramine action on food intake and neuronal activation in the hypothalamus and raphe nuclei of neonate rats.

In neonatal rats, hunger and satiety responses occur particularly via dehydration and gastric distention, respectively. The control of food intake in newborns is yet to be fully consolidated, particularly with respect to the participation of the hypothalamic nuclei and their relationship with the serotonergic pathway. Moreover, it is unclear how the environmental stressors in early life, like undernutrition, interfere in these events. Therefore, this study examined the serotonin-system's impact on food intake in rat neonates at postnatal day (P) 10 and P18 and the manner in which protein undernutrition during pregnancy and lactation interferes in this behavior. To accomplish this, Wistar rats were used, nutritionally manipulated by a diet having two protein levels, (8% and 17%) during pregnancy and lactation, to form the Control (n=10) and Low protein groups (n=10). At 10 and 18 postnatal days pups received an acute dose of fenfluramine (3mg/kg) or saline (0.9% NaCl) and subjected to milk consumption testing and then perfused to obtain the brains for the analysis of cell activation of the immunoreactive c-Fos in the hypothalamic and raphe nuclei. At 10days a reduction in weight gain was observed in both groups. On comparison of the neuronal activation for the paraventricular nucleus, an increased activation in response to fenfluramine was observed. At 18days, the weight gain percentage differed between the groups according to the nutritional manipulation, in which the control animals had no significant change while the undernourished presented increased weight gain with the use of fenfluramine. The marking of c-Fos in response to fenfluramine in the hypothalamic and raphe nuclei revealed, an especially lower activation of the PVN, MnR and DR compared intra-group. However when evaluating the effect of undernutrition, marking activation was observed to increase in all the nuclei analyzed, in the hypothalamus and raphe. Data from this study indicate that the action of serotonin via food intake in the neonates may have been delayed by early protein undernutrition.

Prenatal stress alters diazepam withdrawal syndrome and 5HT1A receptor expression in the raphe nuclei of adult rats.

Early-life events have long-term effects on brain structures and cause behavioral alterations that persist into adulthood. The present experiments were designed to investigate the effects of prenatal stress on diazepam-induced withdrawal syndrome and serotonin-1A (5HT1A) receptor expression in the raphe nuclei of adult offspring. The results of the present study reveal that maternal exposure to chronic footshock stress increased the anxiety-like behavior in the prenatally stressed (PS) animals withdrawn from chronic diazepam (2.5mg/kg/day i.p for 1week). Moreover, prenatal stress induced a down-regulation of 5HT1A mRNA in the raphe nuclei of adult offspring. To our knowledge, this study is the first to demonstrate that maternal exposure to chronic footshock stress enhances diazepam withdrawal symptoms and alters 5HT1A receptor gene expression in the raphe nuclei of adult offspring. Thus, more studies are needed to clarify the mechanisms underlying the decrease of 5HT1A receptors expression in the raphe nuclei of PS rats.

Ascending serotonin neuron diversity under two umbrellas.

Forebrain serotonin relevant for many psychological disorders arises in the hindbrain, primarily within the dorsal and median raphe nuclei (DR and MR). These nuclei are heterogeneous, containing several distinct groups of serotonin neurons. Here, new insight into the afferent and efferent connectivity of these areas is reviewed in correlation with their developmental origin. These data suggest that the caudal third of the DR, the area originally designated B6, may be misidentified as part of the DR as it shares many features of connectivity with the MR. By considering the rostral DR independently and affiliating the B6 to the MR, the diverse subgroups of serotonin neurons can be arranged with more coherence into two umbrella groups, each with distinctive domains of influence. Serotonin neurons within the rostral DR are uniquely interconnected with brain areas associated with emotion and motivation such as the amygdala, accumbens and ventral pallidum. In contrast serotonin neurons in the B6 and MR are characterized by their dominion over the septum and hippocampus. This distinction between the DR and B6/MR parallels their developmental origin and likely impacts their role in both behavior and psychopathology. Implications and further subdivisions within these areas are discussed.

[EXPRESSION OF SEROTONIN TRANSPORT PROTEIN IN THE DORSAL RAPHE NUCLEUS IN THE EARLY POSTNATAL PERIOD IN RATS].

In this work an expression of serotonin transport protein (5-HTT) was studied in the dorsal raphe nucleus (DRN)--in its dorsal, ventral and lateral subnuclei in Wistar rats (n = 15) during the early postnatal period. Histological methods and immunocytochemical staining demonstrating 5-HTT were used in the investigation. It was shown that at postnatal Day 5 major part of neurons of the subnuclei studied intensively expressed 5-HTT. However, by Day 10, the level of its expression decreased dramatically, but with age (by Day 20) the expression was increased once again. This was manifested by the augmentation of size of 5-HTT-positive neuronal population, the increase in the density of plexus network of their processes. The detected changes of 5-HTT expression indicate the varying degrees of functional activity of serotonin in the DRN in the early postnatal period.

Dorsal raphe serotonin neurons in mice: immature hyperexcitability transitions to adult state during first three postnatal weeks suggesting sensitive period for environmental perturbation.

Trauma during early life is a major risk factor for the development of anxiety disorders and suggests that the developing brain may be particularly sensitive to perturbation. Increased vulnerability most likely involves altering neural circuits involved in emotional regulation. The role of serotonin in emotional regulation is well established, but little is known about the postnatal development of the raphe where serotonin is made. Using whole-cell patch-clamp recording and immunohistochemistry, we tested whether serotonin circuitry in the dorsal and median raphe was functionally mature during the first 3 postnatal weeks in mice. Serotonin neurons at postnatal day 4 (P4) were hyperexcitable. The increased excitability was due to depolarized resting membrane potential, increased resistance, increased firing rate, lack of 5-HT1A autoreceptor response, and lack of GABA synaptic activity. Over the next 2 weeks, membrane resistance decreased and resting membrane potential hyperpolarized due in part to potassium current activation. The 5-HT1A autoreceptor-mediated inhibition did not develop until P21. The frequency of spontaneous inhibitory and excitatory events increased as neurons extended and refined their dendritic arbor. Serotonin colocalized with vGlut3 at P4 as in adulthood, suggesting enhanced release of glutamate alongside enhanced serotonin release. Because serotonin affects circuit development in other brain regions, altering the developmental trajectory of serotonin neuron excitability and release could have many downstream consequences. We conclude that serotonin neuron structure and function change substantially during the first 3 weeks of life during which external stressors could potentially alter circuit formation.

[Development of the habenulointerpeduncular tract in rats].

Development of the habenulointerpeduncular tract has been carried out on fixed brain preparations obtained from 21 day rat embryos and from neonatal animals on the 0 and 9 days of postnatal development by diffusion oflipophilic fluorescent carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) through neuron membranes. The marker was introduced into the nuclei of the habenula, the interpeduncular nucleus, and into the area of raphe nuclei. Neurons and fibers that contained Dil were identified on vibratome sections by fluorescent and confocal microscopy. we have found that reciprocal links between the lateral habenula nucleus and raphe nuclei are formed in the prenatal period by stage E21. Raphe nuclei innervating neurons were located in dorso- and ventrocaudal parts of the lateral habenula nucleus. Projections of the medial habenula nucleus onto interpeduncular nucleus were found only in the postnatal P2 period. Neurons that provide a source of these projections form characteristic assemblies inside the medial habenula nucleus. Therefore, the present study for the first time describes heterogenic formation of different projection systems that are involved in the habenulointerpeduncular tract of rats at perinatal ontogenesis.

Development of the serotonergic cells in murine raphe nuclei and their relations with rhombomeric domains.

The raphe nuclei represent the origin of central serotonergic projections. The literature distinguishes seven nuclei grouped into rostral and caudal clusters relative to the pons. The boundaries of these nuclei have not been defined precisely enough, particularly with regard to developmental units, notably hindbrain rhombomeres. We hold that a developmental point of view considering rhombomeres may explain observed differences in connectivity and function. There are twelve rhombomeres characterized by particular genetic profiles, and each develops between one and four distinct serotonergic populations. We have studied the distribution of the conventional seven raphe nuclei among these twelve units. To this aim, we correlated 5-HT-immunoreacted neurons with rhombomeric boundary landmarks in sagittal mouse brain sections at different developmental stages. Furthermore, we performed a partial genoarchitectonic analysis of the developing raphe nuclei, mapping all known serotonergic differentiation markers, and compared these results, jointly with others found in the literature, with our map of serotonin-containing populations, in order to examine regional variations in correspondence. Examples of regionally selective gene patterns were identified. As a result, we produced a rhombomeric classification of some 45 serotonergic populations, and suggested a corresponding modified terminology. Only a minor rostral part of the dorsal raphe nucleus lies in the midbrain. Some serotonergic neurons were found in rhombomere 4, contrary to the conventional assumption that it lacks such neurons. We expect that our reclassification of raphe nuclei may be useful for causal analysis of their differential molecular specification, as well as for studies of differential connectivity and function.

[Characteristic of serotoninergic neurons of medullary nucleus raphe obscurus in norm and in serotoninergic system deficiency during the prenatal period of development in rats].

Morphological characteristics of the serotoninergic neurons forming nucleus raphe obscurus (NRO), were studied in rats at the early stages (days 5, 10, 12 and 14) of the postnatal period in normal rats and in animals whose prenatal development took place under the conditions of serotonin deficiency. NRO was found to contain three subpopulations serotonin-producing neurons (large, medium and small), which had different sensitivity to serotonin level during development. The results have shown that serotoninergic system deficiency during the prenatal period resulted in the changes of NRO structural organization and in the decrease of the rate of this nucleus formation, serotonin-producing neurons differentiation and the reduction of their total number by approximately a factor of 1.6. At the same time, the significant changes of the dimensions of serotoninergic neurons of all types took place. In control animals, the size of large, medium and small neurons was 1.8, 1.4 and 1.5 times greater than that in experimental animals, respectively. Reduction of the neuron dimensions was associated with the changes of a nucleo-cytoplasmic ratio. The volume of the cytoplasm and of Nissl bodies was significantly decreased. Along with it, the cell destruction was noted that increased with age. Synchronously with it, the marked astrocytic reaction developed, which could further lead to gliosis.

[Synaptogenesis in the dorsal raphe nucleus of rat medulla oblongata in serotonin deficiency].

The purpose of the present study was to examine the synaptogenesis in the dorsal raphe nucleus (DRN) in Wistar rats (n = 8-10 for each time point) in the end of prenatal (days 19 and 20) and early postnatal (days 5 and 20) periods, and to determine the role of serotonin in the formation of synaptic contacts during this period of development. It is shown that at prenatal dayl9 neuropil started to develop in DRN -d, DRN -v and DRN -1 in control (intact) animals, while the synaptic contacts appeared on cell processes. At prenatal day20 synaptic contacts were detected for the first time on neuronal cell body surface. The density of synaptophysin-positive granules on both the cell processes in the neuropil, and neuronal cell bodies was sharply and considerably increased by postnatal day 5. Subsequently, until postnatal day 20, the augmentation of their density was insignificant. Serotonin deficiency in a second half of prenatal development, induced by a single injection of parachlorophenylalanine to female rats at gestational day 16 resulted in a significant delay of synaptogenesis in DRN of their offspring in both prenatal and early postnatal periods. With the increase of postnatal age the density synaptic contacts was unequally augmented in various parts of DRN: in DNR-d it approached the control level, while in DRN-v and DRN-1 it remained significantly reduced. The results received suggest serotonin participation in synaptogenesis in DRN.

Development by environment interactions controlling tryptophan hydroxylase expression.

Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin (5-hydroxytryptamine; 5-HT). Two isoforms of tryptophan hydroxylase, derived from different genes, tph1 and tph2, have been identified. The tph1 isoform is expressed in peripheral tissues, whereas tph2 is brain and neuron-specific. Recent studies suggest that tph2 expression and brain serotonin turnover are upregulated in depressed suicide patients, and drug-free depressed patients, respectively. Increased tph2 expression could result from genetic influences, early life developmental influences, adverse experience during adulthood, or interactions among these factors. Studies in rodents support the hypothesis that interactions between early life developmental influences and adverse experience during adulthood play an important role in determining tph2 expression. In this review, we highlight the evidence for the effects of adverse early life experience and stressful experience during adulthood on both tph1 and tph2 expression.

The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain.

A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei.

Heterogeneity of central serotonin (5-HT) raphe neurons is suggested by numerous lines of evidence, but its genetic basis remains elusive. The transcription factor Pet1 is required for the acquisition of serotonergic identity in a majority of neurons in the raphe nuclei. Nevertheless, a subset of 5-HT neurons differentiates in Pet1 knock-out mice. We show here that these residual 5-HT neurons outline a unique subpopulation of raphe neurons with highly selective anatomical targets and characteristic synaptic differentiations. In Pet1 knock-out mice, 5-HT innervation strikingly outlines the brain areas involved in stress responses with dense innervation to the basolateral amygdala, the paraventricular nucleus of the hypothalamus, and the intralaminar thalamic nuclei. In these regions, 5-HT terminals establish asymmetric synaptic junctions. This target selectivity could not be related to altered growth of the remaining 5-HT neurons, as indicated by axon tracing and cell culture analyses. The residual 5-HT axon terminals are functional with maintained release properties in vitro and in vivo. The functional consequence of this uneven distribution of 5-HT innervation on behavior was characterized. Pet1 knock-out mice showed decreased anxiety behavior in novelty exploration and increased fear responses to conditioned aversive cues. Overall, our findings lead us to propose the existence of Pet1-dependent and Pet1-resistant 5-HT neurons targeting different brain centers that might delineate the anatomical basis for a dual serotonergic control on stress responses.

Efficacy of post-insult minocycline administration to alter long-term hypoxia-ischemia-induced damage to the serotonergic system in the immature rat brain.

Neuroinflammation is a key mechanism contributing to long-term neuropathology observed after neonatal hypoxia-ischemia (HI). Minocycline, a second-generation tetracycline, is a potent inhibitor of neuroinflammatory mediators and is successful for at least short-term amelioration of neuronal injury after neonatal HI. However the long-term efficacy of minocycline to prevent injury to a specific neuronal network, such as the serotonergic (5-hydroxytryptamine, 5-HT) system, is not known. In a post-natal day 3 (P3) rat model of preterm HI we found significant reductions in 5-HT levels, 5-HT transporter expression and numbers of 5-HT-positive dorsal raphé neurons 6 weeks after insult compared to control animals. Numbers of activated microglia were significantly elevated in the thalamus and dorsal raphé although the greatest numbers were observed in the thalamus. Brain levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were also significantly elevated on P45 in the thalamus and frontal cortex. Post-insult administration of minocycline for 1 week (P3-P9) attenuated the P3 HI-induced increases in numbers of activated microglia and levels of TNF-α and IL-1ß on P45 with concurrent changes in serotonergic outcomes. The parallel prevention of P3 HI-induced serotonergic changes suggests that inhibition of neuroinflammation within the first week after P3 HI injury was sufficient to prevent long-term neuroinflammation as well as serotonergic system damage still evident at 6 weeks. Thus early, post-insult administration of minocycline may target secondary neuroinflammation and represent a long-term therapy to preserve the integrity of the central serotonergic network in the preterm neonate.

Postnatal fluoxetine treatment affects the development of serotonergic neurons in rats.

The goal of the present study was to investigate morphological changes in the serotonergic neurons/terminals in the dorsal (DR) and median (MnR) raphe nuclei and on the hippocampal dentate gyrus (DG) in neonatal rats treated from the 1st to the 21st postnatal day with fluoxetine (10 mg/kg sc, daily) or drug vehicle (0.9% saline 1 ml/kg). The results show that postnatal chronic treatment with fluoxetine promoted: (1) a smaller body weight increase during the pre-weaning period; (2) smaller number of 5-HT neurons in the DR; (3) smaller 5-HT neuronal cell bodies (area, perimeter and diameter) in the DR and the MnR and (4) diminished serotonergic terminals in the DG. These data suggest that the development of the serotonergic system was impaired and that early exposure to fluoxetine damaged the morphology of 5-HT neurons in young adult rats. While these findings are consistent with other work, more studies are needed to better clarify the effects of postnatal chronic treatment with fluoxetine on the serotonergic system and, consequently, on the functions modulated by serotonin.

Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior.

Genetic programs, environmental factors, and electrical activity interact to drive the maturation of the brain. Although the cascade of transcription factors that leads to specification of the serotonergic phenotype has been well characterized, its interactions with electrical activity are not known. Here we show that spontaneous calcium spike activity in the hindbrain of developing Xenopus laevis larvae modulates the specification of serotonergic neurons via regulation of expression of the Lmx1b transcription factor. Activity acts downstream of Nkx2.2 but upstream of Lmx1b, leading to regulation of the serotonergic phenotype. Using global manipulation of activity and targeted alteration of Lmx1b expression, we also demonstrate that changes in the number of serotonergic neurons change larval swimming behavior. The results link activity-dependent regulation of a transcription factor to transmitter specification and altered behavior.

Postnatal changes in serotonergic innervation to the hippocampus of methyl-CpG-binding protein 2-null mice.

Rett syndrome is a progressive neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Previous reports have revealed serotonergic function to be altered in the medullas of patients with Rett syndrome and in an animal model of the disease. However, it has remained unclear whether a genetic loss of MeCP2 disrupts serotonergic innervation to the forebrain. In this study, we measured levels of monoamines by high-performance liquid chromatography with electrochemical detection in selected regions of the forebrains of Mecp2-null mice (Mecp2-/y) and wild-type mice (Mecp2+/y) on postnatal day (P) 14, P28, P42 and P56. The levels of hippocampal serotonin (5-HT) and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were significantly lower in Mecp2-null mice than in age-matched wild-type mice on P28, P42 and P56. Immunohistochemical analysis revealed a loss of 5-HT-immunoreactive fibers in the Mecp2-null hippocampus on P56. By contrast, in the raphe region of Mecp2-null mice, there were significant decreases in 5-HT and noradrenaline levels, but these differences later disappeared and there was no change in the number of 5-HT-immunoreactive neuronal cell bodies. Furthermore, we conducted an experiment comparing HPLC measurements in presymptomatic heterozygous females (Mecp2+/-) and wild-type female littermates (Mecp2+/+) on P56. Significant decreases in hippocampal 5-HT and 5-HIAA contents in Mecp2-heterozygous mice were revealed, and these were not accompanied by changes in 5-HT or noradrenaline contents in the raphe region. Therefore, these results indicated decreases in serotonergic innervation to the hippocampus in Mecp2-null males and Mecp2 heterozygous females. We speculate that disturbances in serotonergic neurotransmission in the hippocampus may be linked to the behavioral abnormalities seen in Rett syndrome, such as increased anxiety-like behaviors and reduced exploratory locomotion. MeCP2 may be required for stable serotonergic homeostasis and serotonergic innervation to the hippocampus during postnatal development.

[Development of serotonergic neurons of dorsal raphe nuclei in mice with knockout of monoamine oxidase A and 5-HT1A and 5-HT1B autoreceptor].

The morphological changes in the development of serotonergic neurons of the dorsal raphe nuclei in the medulla oblongata was studied by immunocytochemistry in mice with knockout of 1A and 1B serotonin autoreceptors as well as monoamine oxidase A. Serotonin autoreceptors regulate electric activity of serotonergic neurons as well as the synthesis and release of the neurotransmitter, while monoamine oxidase A catalyzes its degradation. These genetic modifications proved to have no effect on the number of serotonergic neurons in the medulla oblongata but induced morphofunctional changes. Decreased cell size and increased intracellular serotonin level were observed in the case of monoamine oxidase A deficiency, while excessive cell size and decreased intracellular serotonin level were observed in the case of autoreceptor deficiency. The data obtained confirm the hypothesis of autoregulation of serotonergic neurons in development.